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Clinical Trial Results:
A Phase III, Randomized, Open-Label, 3-Arm Study To Determine the Efficacy and Safety of Lenalidomide (Revlimid®) Plus Low-Dose Dexamethasone When Given Until Progressive Disease or for 18 Four-Week Cycles Versus the Combination of Melphalan, Prednisone, and Thalidomide Given for 12 Six-Week Cycles in Patients with Previously Untreated Multiple Myeloma Who Are Either 65 Years of Age or Older or Not Candidates for Stem Cell Transplantation (IFM 07-01)

Summary
EudraCT number	2007-004823-39
Trial protocol	FR GB IE IT AT ES SE BE PT DE GR
Global end of trial date	14 Jul 2016

Results information
Results version number	v1(current)
This version publication date	12 Aug 2017
First version publication date	12 Aug 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CC-5013-MM-020

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Celgene Corporation

Sponsor organisation address

86 Morris Avenue, Summit, United States, 07901

Public contact

Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@celgene.com

Scientific contact

Annette Ervin-Haynes, Executive Director, Clinical Research and Development, Celgene Corporation, 01 908-673-9732, aervin-haynes@celgene.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

14 Jul 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Jul 2016

Was the trial ended prematurely?

Main objective of the trial

To compare the efficacy of lenalidomide plus low-dose dexamethasone given until progressive disease to that of the combination of melphalan, prednisone, and thalidomide given for 12 six week cycles.

Protection of trial subjects

Patient Confidentiality, Personal Data Protection and Biomarker Consent

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Aug 2008

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy, Regulatory reason

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Korea, Republic of: 56

Country: Number of subjects enrolled

China: 47

Country: Number of subjects enrolled

Taiwan: 11

Country: Number of subjects enrolled

France: 459

Country: Number of subjects enrolled

Italy: 148

Country: Number of subjects enrolled

Germany: 97

Country: Number of subjects enrolled

Spain: 87

Country: Number of subjects enrolled

Greece: 86

Country: Number of subjects enrolled

United Kingdom: 71

Country: Number of subjects enrolled

Belgium: 52

Country: Number of subjects enrolled

Austria: 41

Country: Number of subjects enrolled

Portugal: 27

Country: Number of subjects enrolled

Switzerland: 26

Country: Number of subjects enrolled

Sweden: 19

Country: Number of subjects enrolled

Canada: 252

Country: Number of subjects enrolled

Australia: 72

Country: Number of subjects enrolled

United States: 60

Country: Number of subjects enrolled

New Zealand: 12

Worldwide total number of subjects

1623

EEA total number of subjects

1087

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

1475

85 years and over

Subject disposition

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Recruitment details

This study was conducted in the Europe, Asia, North America and Pacific regions. Participants were randomized at 246 sites (165 in Europe, 23 in Asia, 39 in North America, and 19 in the Pacific). The study was co-sponsored by Intergroupe Francophone du Myélome (IFM) (for sites in France, Switzerland, and Belgium) and Celgene Corporation.

Screening details

Participants were stratified at randomization by 1) age (≤ 75 versus > 75 years), 2) stage (International Staging System Stages I or II versus Stage III), and 3) country.

Period 1 title

Active Treatment Phase (Ph) (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Lenalidomide and Low-Dose Dexamethasone (Rd)

Arm description

Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day treatment (rx) cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at (@) the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.

Arm type

Experimental

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

Other name

Revlimid CC-5013

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Lenalidomide 25 mg PO QD on days 1 to 21 of each 28-day treatment cycle until disease progression. Subjects with moderate to severe renal insufficiency received 10-15 mg lenalidomide PO on days 1-21 of each 28-day treatment cycle.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Decadron, Dexasone, Diodex, Hexadrol, Maxidex

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Dexamethasone 40 mg PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression. Those with moderate to severe renal insufficiency receive 20 - 40 mg PO on days 1, 8, 15, and 22 of a 28-day cycle

Lenalidomide and Dexamethasone Rd18

Arm description

Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on the same schedule as above for up to 18 cycles until PD or intolerable toxicity.

Arm type

Experimental

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

Other name

Revlimid, CC-5013

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Lenalidomide 25 mg PO QD on days 1 to 21 of each 28-day treatment cycle for up to 18 cycles or until disease progression. Subjects with moderate to severe renal insufficiency received 10-15 mg lenalidomide PO on days 1-21 of each 28-day treatment cycle.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Decadron, Dexasone, Diodex, Hexadrol, Maxidex

Pharmaceutical forms

Tablet, Tablet

Routes of administration

Oral use, Oral use

Dosage and administration details

Dexamethasone 40 mg PO on days 1, 8, 15, and 22 of a 28-day cycle. Those with moderate to severe renal insufficiency receive 20 - 40 mg PO on days 1, 8, 15, and 22 of a 28-day cycle up to 18 cycles or until disease progression.

Melphalan + Prednisone + Thalidomide (MPT)

Arm description

Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity.

Arm type

Active comparator

Investigational medicinal product name

Melphalan

Investigational medicinal product code

Other name

Alkeran, L-PAM, L-Sarcolysin, Phenylalanine Mustard

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Melphalan 0.25 mg/kg PO QD on days 1 to 4 of each 42-day cycle up to 12 cycles or until disease progression.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Deltasone, Orasone, Adasone, Deltacortisone, Prednisonum

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 2 mg/kg PO on days 1 to 4 of each 42-day cycle up to 12 cycles or until disease progression.

Investigational medicinal product name

Thalidomide

Investigational medicinal product code

Other name

Thalomid, Immunoprin, Talidex, Talizer, Neurosedyn

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle for up to 12 cycles or disease progression.

Number of subjects in period 1	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Started	535	541	547
Safety Population	532	540	541
Untreated	3	1	6
Completed	0	0	0
Not completed	535	541	547
Adverse event, serious fatal	60	28	37
Study Close Out	64	26	21
Consent withdrawn by subject	16	16	21
Adverse event, non-fatal	68	71	76
Miscellaneous	52	34	47
Lost to follow-up	-	2	2
Disease Progression	273	362	339
Protocol deviation	2	2	4

Baseline characteristics

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Reporting group title

Lenalidomide and Low-Dose Dexamethasone (Rd)

Reporting group description

Reporting group title

Lenalidomide and Dexamethasone Rd18

Reporting group description

Reporting group title

Melphalan + Prednisone + Thalidomide (MPT)

Reporting group description

Reporting group values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)	Total
Number of subjects	535	541	547	1623
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	73.2 ( 6.57 )	72.9 ( 6.5 )	73.1 ( 6.32 )	-
Gender, Male/Female
Units: Subjects
Female	241	268	260	769
Male	294	273	287	854
Race/Ethnicity, Customized
Units: Subjects
Asian	40	43	44	127
Black or African American	9	6	5	20
Native Hawaiian or other Pacific Islanders	1	0	1	2
White or Caucasion	474	480	491	1445
Other, Miscellaneous	6	11	3	20
Missing	5	1	3	9
International Staging System (ISS)
International Staging System (ISS): ISS is used as a staging system for multiple myeloma and divides myeloma into 3 stages based only on the serum beta-2 microglobulin and serum albumin levels. Higher stages represent more advanced disease.
Units: Subjects
Stage I	106	106	103	315
Stage II	227	229	225	681
Stage III	202	206	219	627
Eastern Cooperative Oncology Group (ECOG) Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status is used to assess the progress of disease in a patient, how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis.
Units: Subjects
0 (fully active)	155	163	156	474
1 (restrictive but ambulatory)	257	263	275	795
2 (ambulatory but unable to work)	119	113	111	343
3-4 (limited self-care, completely disabled)	2	2	2	6
Missing	2	0	3	5
Creatinine clearance
Units: Subjects
>=60 ml/min	269	280	285	834
<60 ml/min	266	261	261	788
Missing	0	0	1	1
Beta2 Microglobulin
Units: Subjects
>5.5 mg/L	224	224	234	682
<=5.5 mg/L	309	316	312	937
Missing	2	1	1	4
Albumin
Units: Subjects
<=35 g/L	192	209	223	624
> 35 g/L	343	331	324	998
Missing	0	1	0	1
Lactic Dehydrogenase
Units: Subjects
<200 U/L	448	442	434	1324
>=200 U/L	86	99	112	297
Missing	1	0	1	2
Multiple Myeloma Subtype
Units: Subjects
Immunoglobulin A	138	142	123	403
Immunoglobulin A and Immunoglobulin G	7	6	8	21
Immunoglobulin A and Immunoglobulin M	0	0	1	1
Immunoglobulin D	4	7	4	15
Immunoglobulin G	334	331	350	1015
Immunoglobulin M	3	1	1	5
Not available (includes light-chain disease)	49	54	60	163
Cytogenetic Risk
Cytogenetic risk categories are mutually exclusive. Definitions: Adverse risk category: t(4:14), t(14:16), del (13q) or monosomy 13, del (17p), 1q gain; Non-adverse risk categories include favorable hyperdiploidy: t(11:14), gains of 5/9/15; normal: a normal result, gains other than 5/9/15, IgH deletion, and uncertain risk: probes used for analysis cannot place participant in any risk categories. Not evaluable: no specimen received, test failure or insufficient number of cells available for analysis.
Units: Subjects
Adverse Risk	170	185	189	544
Favorable Hyperdiploidy	112	103	102	317
Normal	148	131	141	420
Uncertain Risk	38	56	40	134
Not evaluable	34	35	44	113
Missing	33	31	31	95

End points

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Reporting group title

Lenalidomide and Low-Dose Dexamethasone (Rd)

Reporting group description

Reporting group title

Lenalidomide and Dexamethasone Rd18

Reporting group description

Reporting group title

Melphalan + Prednisone + Thalidomide (MPT)

Reporting group description

Primary: Kaplan-Meier Estimates of Progression-free survival (PFS) Based on the Response Assessment by the Independent Review Adjudication Committee (IRAC)

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End point title

Kaplan-Meier Estimates of Progression-free survival (PFS) Based on the Response Assessment by the Independent Review Adjudication Committee (IRAC)

End point description

PFS was calculated as the time from randomization to the lst documented PD or death due to any cause during the study, which ever occurred first based on the International Myeloma Working Group Uniform Response criteria (IMWG). Those who withdrew for any reason or received another anti-myeloma therapy (AMT) without documented PD were censored on the date of their last response assessment, prior to receiving other AMT. Censoring PFS rules: - No baseline assessments and no progression or death documented within the 2 scheduled assessments; Death within the lst two assessments without any response assessment; Progression documented between scheduled assessments; Death between assessments; no progression; study discontinuations for reasons other than PD or death; new AMT started prior to PD; death or PD after an extended lost to follow-up time period (2 or more missed scheduled assessment's). Intent to Treat population = subjects who were randomized even if no study drug was given.

End point type

Primary

End point timeframe

From date of randomization until the data cut-off date of 24 May 2013. Median follow-up time for all participants was 17.1 months.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	535	541	547
Units: months
median (confidence interval 95%)	25.5 (20.7 to 29.4)	20.7 (19.4 to 22)	21.2 (19.3 to 23.2)

Statistical Analysis 1

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Melphalan + Prednisone + Thalidomide (MPT) v Lenalidomide and Low-Dose Dexamethasone (Rd)

Number of subjects included in analysis

1082

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00006 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

0.85

Notes
[1] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 2

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

1076

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00001 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

0.82

Notes
[2] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 3

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1088

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.70349 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.2

Notes
[3] - The p-value is based on the unstratified log-rank test.

Primary: Kaplan-Meier Estimates of PFS Based on the Response Assessment by the Investigator Assessment at the Time of Final Analysis

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End point title

Kaplan-Meier Estimates of PFS Based on the Response Assessment by the Investigator Assessment at the Time of Final Analysis

End point description

End point type

Primary

End point timeframe

From date of randomization to date of data cut-off date of 21 January 2016; median follow-up for all subjects was 17.7 months

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	535	541	547
Units: months
median (confidence interval 95%)	26 (20.7 to 29.7)	21 (19.7 to 22.4)	21.9 (19.8 to 23.9)

Statistical Analysis 1

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1082

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.59

upper limit

0.79

Notes
[4] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 2

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

1076

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001 ^[5]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

0.81

Notes
[5] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 3

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1088

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.91161 ^[6]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.14

Notes
[6] - The p-value is based on the unstratified log-rank test.

Secondary: Kaplan Meier Estimates of Overall Survival (OS) at the Time of Final Analysis

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End point title

Kaplan Meier Estimates of Overall Survival (OS) at the Time of Final Analysis

End point description

Overall survival was defined as the time between randomization and death. Subjects who died, regardless of the cause of death, were considered to have had an event. All subjects who were lost to follow-up prior to the end of the trial or who were withdrawn from the trial were censored at the time of last contact. Subjects who were still being treated were censored at the last available date the participant was known to be alive. ITT population (ITT) = all subjects who were randomized, independent of whether they received study treatment or not.

End point type

Secondary

End point timeframe

From date of randomization to date of data cut-off of 21 January 2016; median follow-up for all subjects was 48.3 months

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	535	541	547
Units: months
median (confidence interval 95%)	59.1 (53.9 to 65.9)	62.3 (53.6 to 68.7)	49.1 (44.3 to 53.5)

Statistical Analysis 1

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1082

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00234 ^[7]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

0.92

Notes
[7] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 2

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

1076

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.82903 ^[8]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.2

Notes
[8] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 3

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1088

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00119 ^[9]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

0.9

Notes
[9] - The p-value is based on the unstratified log-rank test.

Secondary: Percentage of Participants With an Objective Response based on IRAC Review

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End point title

Percentage of Participants With an Objective Response based on IRAC Review

End point description

Objective response according to IMWG Uniform Response Criteria was defined as a best overall response including a complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IRAC Review. A CR is defined as: negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is: ≥ 50% reduction of serum M-Protein and reduction in urinary M-protein by ≥ 90% or to <200 mg/24 hours. If present at baseline a ≥ 50% reduction in size of soft tissue plasmacytomas. The ITT population includes all subjects who were randomized, independent of whether they received study treatment or not.

End point type

Secondary

End point timeframe

Disease response was assessed every 28 days until the end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	535	541	547
Units: percentage of participants
number (not applicable)	75.1	73.4	62.3

Statistical Analysis 1

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1082

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.83

Confidence interval

level

95%

sides

2-sided

lower limit

1.41

upper limit

2.37

Statistical Analysis 2

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

1076

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.53065

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.44

Statistical Analysis 3

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1088

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.67

Confidence interval

level

95%

sides

2-sided

lower limit

1.29

upper limit

2.15

Secondary: Percentage of Participants With an Objective Response based on Investigator Assessment at the Time of Final Analysis

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End point title

Percentage of Participants With an Objective Response based on Investigator Assessment at the Time of Final Analysis

End point description

End point type

Secondary

End point timeframe

Disease response was assessed every 28 days until end of treatment or the data cut-off date of 21 January 2016; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	535	541	547
Units: percentage of participants
number (not applicable)	80.7	78.6	67.5

Statistical Analysis 1

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1082

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

2.02

Confidence interval

level

95%

sides

2-sided

lower limit

1.53

upper limit

2.68

Statistical Analysis 2

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

1076

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.405

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.54

Statistical Analysis 3

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1088

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00004

Method

Fisher exact

Parameter type

Log odds ratio

Point estimate

1.77

Confidence interval

level

95%

sides

2-sided

lower limit

1.35

upper limit

2.32

Secondary: Kaplan Meier estimates of duration of myeloma response as determined by the IRAC

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End point title

Kaplan Meier estimates of duration of myeloma response as determined by the IRAC

End point description

Duration of response was defined as the duration from the time when the response criteria were first met for CR or VGPR or PR based on IMWG criteria until the first date the response criteria were met for progressive disease or until the participant died from any cause, whichever occurred first. Includes subjects with at least a partial response.

End point type

Secondary

End point timeframe

Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median follow-up for responders was 20.1 months

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	402	397	341
Units: months
median (confidence interval 95%)	35 (27.9 to 43.4)	22.1 (20.3 to 24)	22.3 (20.2 to 24.9)

Statistical Analysis 1

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001 ^[10]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

0.76

Notes
[10] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 2

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

799

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001 ^[11]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

0.72

Notes
[11] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 3

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

738

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7674 ^[12]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.23

Notes
[12] - The p-value is based on the unstratified log-rank test.

Secondary: Kaplan Meier estimates of duration of myeloma response as determined by an investigator assessment at the Time of Final Analysis

Top of page

End point title

Kaplan Meier estimates of duration of myeloma response as determined by an investigator assessment at the Time of Final Analysis

End point description

End point type

Secondary

End point timeframe

Disease response was assessed every 28 days until end of treatment; data cut-off date of 21 January 2016; median follow-up for responders was 19.9 months.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	432	425	369
Units: months
median (confidence interval 95%)	31.5 (26.2 to 37.3)	21.5 (19.2 to 23)	22.1 (20.3 to 24.5)

Statistical Analysis 1

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001 ^[13]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.61

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

0.72

Notes
[13] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 2

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

857

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001 ^[14]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.61

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

0.72

Notes
[14] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 3

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

794

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.99537 ^[15]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.17

Notes
[15] - The p-value is based on the unstratified log-rank test.

Secondary: Time to first response based on the review by the IRAC

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End point title

Time to first response based on the review by the IRAC

End point description

The time to first myeloma response was defined as the time from randomization to the time when the response criteria for at least a PR was first met based on the IMWG criteria. Includes subjects with at least a partial response.

End point type

Secondary

End point timeframe

Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	402	397	341
Units: months
median (full range (min-max))	1.8 (0.7 to 22.2)	1.8 (0.8 to 17.1)	2.8 (1.3 to 49.7)

Statistical Analysis 1

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Statistical Analysis 2

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

799

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.46672

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Statistical Analysis 3

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

738

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Time to first response based on the investigator asssessment at the Time of Final Analysis

Top of page

End point title

Time to first response based on the investigator asssessment at the Time of Final Analysis

End point description

The time to first myeloma response was defined as the time from randomization to the time when the response criteria for at least a PR was first met based on the IMWG criteria assessed by the investigator. Includes subjects with at least a partial response.

End point type

Secondary

End point timeframe

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	430	425	368
Units: months
median (full range (min-max))	1.8 (0.5 to 22.2)	1.8 (0.8 to 34.8)	2.8 (1.2 to 56.3)

Statistical Analysis 1

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

798

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Statistical Analysis 2

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

855

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.46987

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Statistical Analysis 3

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

793

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Kaplan Meier Estimates of Time to Treatment Failure (TTF)

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End point title

Kaplan Meier Estimates of Time to Treatment Failure (TTF)

End point description

TTF is defined as the time between the randomization and discontinuation of study treatment for any reason, including disease progression (determined by IRAC based on the IMWG response criteria), treatment toxicity, start of another anti-myeloma therapy (AMT) and death. Includes the ITT population = subjects who were randomized, independent of whether they received study treatment or not.

End point type

Secondary

End point timeframe

From date of randomization until the data cut-off of 24 May 2013; median follow up for all participants was 16.1 months.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	535	541	547
Units: months
median (confidence interval 95%)	16.9 (14.1 to 18.4)	17.2 (14.6 to 18.2)	14.1 (12 to 16.1)

Statistical Analysis 1

Statistical analysis description

Based on a stratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1082

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00012 ^[16]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.68

upper limit

0.88

Notes
[16] - The p-value is based on unstratified log-rank test.

Statistical Analysis 2

Statistical analysis description

Based on a stratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

1076

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00187 ^[17]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

0.93

Notes
[17] - The p-value is based on unstratified log-rank test.

Statistical Analysis 3

Statistical analysis description

Based on a stratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1088

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.45973 ^[18]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.08

Notes
[18] - The p-value is based on unstratified log-rank test.

Secondary: Kaplan Meier Estimates of Time to Treatment Failure (TTF) at the Time of Final Analysis

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End point title

Kaplan Meier Estimates of Time to Treatment Failure (TTF) at the Time of Final Analysis

End point description

Time to treatment failure (TTF) is defined as the time between the randomization and discontinuation of study treatment for any reason, including disease progression (determined by the investigators assessment based on the IMWG response criteria), treatment toxicity, start of another anti-myeloma therapy (AMT), and death. ITT population = subjects who were randomized, independent of whether they received study treatment or not.

End point type

Secondary

End point timeframe

From date of randomization until the date of the data cut-off of 21 January 2016; median follow up for all participants was 16.1 months.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	535	541	547
Units: months
median (confidence interval 95%)	16.9 (14.1 to 18.4)	17.2 (14.6 to 18.2)	14.1 (12 to 16.1)

Statistical Analysis 1

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1082

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00002 ^[19]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

0.86

Notes
[19] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 2

Statistical analysis description

Based on unstratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

1076

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00126 ^[20]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

0.92

Notes
[20] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 3

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1088

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.27704 ^[21]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.06

Notes
[21] - The p-value is based on the unstratified log-rank test.

Secondary: Kaplan Meier Estimates for time to second-line anti-myeloma treatment (AMT)

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End point title

Kaplan Meier Estimates for time to second-line anti-myeloma treatment (AMT)

End point description

Time to second-line anti-myeloma therapy was defined as time from randomization to the start of another non-protocol anti-myeloma therapy. Includes ITT population.

End point type

Secondary

End point timeframe

From date of randomization until the data cut-off of 24 May 2013; median follow-up for all participants was 23.0 months

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	535 ^[22]	541	547
Units: months
median (confidence interval 95%)	39.1 (32.8 to 99999)	28.5 (26.9 to 30.4)	26.7 (24 to 29.9)

Notes
[22] - 99999 = Could not be estimated due to the low number of events at the time of analysis.

Statistical Analysis 1

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1082

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001 ^[23]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

0.78

Notes
[23] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 2

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

1076

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

= 0.00067 ^[25]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.74

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

0.88

Notes
[24] - Based on unstratified Cox proportional hazards model.
[25] - The p-value is based on the unstratified log-rank test.

Statistical Analysis 3

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1088

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.12333 ^[26]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.03

Notes
[26] - The p-value is based on unstratified log-rank test.

Secondary: Kaplan Meier Estimates for time to second-line AMT at the Time of Final Analysis

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End point title

Kaplan Meier Estimates for time to second-line AMT at the Time of Final Analysis

End point description

Time to second-line anti-myeloma therapy was defined as time from randomization to the start of another non-protocol anti-myeloma therapy. Includes ITT population.

End point type

Secondary

End point timeframe

From date of randomization until the date of the data cut-off of 21 January 2016; median follow-up for all participants was 23.0 months.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	535	541	547
Units: months
median (full range (min-max))	36.7 (31.9 to 45.2)	28.5 (26.9 to 30.4)	26.7 (24 to 29.1)

Statistical analysis 1

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1082

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.00001 ^[27]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

0.73

Notes
[27] - The p-value is based on unstratified log-rank test.

Statistical analysis 2

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

1076

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00001 ^[28]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

0.83

Notes
[28] - The p-value is based on unstratified log-rank test.

Statistical Analysis 3

Statistical analysis description

Hazard Ratio is based on stratified Cox proportional hazards model.

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

1088

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.05821 ^[29]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

Notes
[29] - The p-value is based on unstratified log-rank test.

Secondary: Percentage of Participants with a myeloma response by adverse risk cytogenetic risk category based on IRAC review

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End point title

Percentage of Participants with a myeloma response by adverse risk cytogenetic risk category based on IRAC review

End point description

Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place those in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas. ITT with cytogenetic adverse risk.

End point type

Secondary

End point timeframe

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	170	185	189
Units: percentage of participants
number (not applicable)	70	69.7	58.2

Statistical Analysis 1

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

359

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02134

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.68

Confidence interval

level

95%

sides

2-sided

lower limit

1.08

upper limit

2.59

Statistical Analysis 2

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

355

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

1.59

Statistical Analysis 3

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02374

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.65

Confidence interval

level

95%

sides

2-sided

lower limit

1.08

upper limit

2.53

Secondary: Percentage of participants with a myeloma response by favorable hyperdiploidy risk cytogenetic risk category based on IRAC Review

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End point title

Percentage of participants with a myeloma response by favorable hyperdiploidy risk cytogenetic risk category based on IRAC Review

End point description

Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas. ITT with favorable hyperdiploidy risk

End point type

Secondary

End point timeframe

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	112	103	102
Units: percentage of participants
number (not applicable)	80.4	81.6	70.6

Statistical Analysis 1

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.11152

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

3.21

Statistical Analysis 2

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

215

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.86336

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

1.83

Statistical Analysis 3

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.07321

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.96

upper limit

3.55

Secondary: Percentage of participants with a myeloma response by normal risk cytogenetic risk category based on IRAC Review

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End point title

Percentage of participants with a myeloma response by normal risk cytogenetic risk category based on IRAC Review

End point description

Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas. ITT population with normal risk.

End point type

Secondary

End point timeframe

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	148	131	141
Units: percentage of participants
number (not applicable)	80.4	74.8	61

Statistical Analysis 1

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

289

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00043

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

2.62

Confidence interval

level

95%

sides

2-sided

lower limit

1.55

upper limit

4.45

Statistical Analysis 2

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

279

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.31274

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.38

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

2.43

Statistical Analysis 3

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

272

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01936

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

1.13

upper limit

3.19

Secondary: Percentage of participants with a myeloma response by uncertain risk cytogenetic risk category based on IRAC Review

Top of page

End point title

Percentage of participants with a myeloma response by uncertain risk cytogenetic risk category based on IRAC Review

End point description

Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas. ITT population with uncertain risk.

End point type

Secondary

End point timeframe

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	38	56	40
Units: percentage of participants
number (not applicable)	60.5	76.8	57.5

Statistical Analysis 1

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.82128

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

2.8

Statistical Analysis 2

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.11041

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

0.46

Confidence interval

level

95%

sides

2-sided

lower limit

0.19

upper limit

1.14

Statistical Analysis 3

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.07302

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

2.44

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

5.91

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Domain

Top of page

End point title

Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in QOL or functioning and positive values indicate improvement.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	508 ^[30]	507 ^[31]	508 ^[32]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	0.4 ( 23.98 )	-1.3 ( 23.93 )	1 ( 23.68 )
Month 3	4.8 ( 24.15 )	4.7 ( 25.15 )	4.3 ( 26.04 )
Month 6	5.9 ( 25.93 )	5.4 ( 23.88 )	6.1 ( 25.98 )
Month 12	4.8 ( 26.42 )	3.2 ( 25.38 )	6.5 ( 25.9 )
Month 18	6.4 ( 28.02 )	5.7 ( 24.86 )	4.8 ( 27.05 )
Study discontinuation	-0.1 ( 27.07 )	5 ( 27.33 )	0.3 ( 28.07 )

Notes
[30] - Month 1 = 438 Month 3 = 421 Month 6 = 369 Month 12 = 302 Month 18 = 246 Discontinuation = 203
[31] - Month 1 = 441 Month 3 = 413 Month 6 = 376 Month 12 = 299 Month 18 = 238 Discontinuation = 261
[32] - Month 1 = 415 Month 3 = 396 Month 6 = 351 Month 12 = 252 Month 18 = 178 Discontinuation = 257

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Top of page

End point title

Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	511 ^[33]	514 ^[34]	509 ^[35]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	-1.7 ( 21.11 )	-1.4 ( 19.56 )	-0.9 ( 21.28 )
Month 3	3.4 ( 23.33 )	4.7 ( 22.94 )	2.2 ( 23.68 )
Month 6	4.7 ( 25.09 )	7.6 ( 22.85 )	5.3 ( 24.52 )
Month 12	5 ( 25.65 )	7.4 ( 23.4 )	6.9 ( 27.22 )
Month 18	6.9 ( 26.71 )	6.8 ( 23.58 )	8.3 ( 27.1 )
Discontinuation Visit	-0.1 ( 29.7 )	3 ( 27.32 )	-0.1 ( 27.58 )

Notes
[33] - Month 1 = 445 Month 3 = 426 Month 6 = 376 Month 12 = 307 Month 18 = 247 Discontinuation = 207
[34] - Month 1 = 449 Month 3 = 421 Month 6 = 382 Month 12 = 302 Month 18 = 243 Discontinuation = 267
[35] - Month 1 = 419 Month 3 = 396 Month 6 = 352 Month 12 = 253 Month 18 = 183 Discontinuation = 256

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Role Functioning Domain

Top of page

End point title

Change From Baseline in the EORTC QLQ-C30 Role Functioning Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Role Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	509 ^[36]	508 ^[37]	508 ^[38]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	-2.7 ( 29.94 )	-4.6 ( 28.2 )	-2.4 ( 30.48 )
Month 3	2.4 ( 33.32 )	6.3 ( 32.43 )	4.1 ( 34.23 )
Month 6	6.3 ( 35.44 )	8.6 ( 32.42 )	8.2 ( 36.09 )
Month 12	7.8 ( 36.6 )	9.4 ( 34.15 )	11.8 ( 38.94 )
Month 18	8 ( 35.34 )	9.1 ( 34.35 )	14.5 ( 39.03 )
Discontinuation Visit	-0.3 ( 39.58 )	3.8 ( 36.34 )	-1 ( 38.41 )

Notes
[36] - Month 1 = 442 Month 3 = 422 Month 6 = 373 Month 12 = 305 Month 18 = 245 Discontinuation = 206
[37] - Month 1 = 445 Month 3 = 419 Month 6 = 378 Month 12 = 300 Month 18 = 240 Discontinuation = 264
[38] - Month 1 = 415 Month 3 = 395 Month 6 = 352 Month 12 = 252 Month 18 = 182 Discontinuation = 256

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain

Top of page

End point title

Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1(Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	509 ^[39]	510 ^[40]	510 ^[41]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	0.6 ( 22.13 )	0.1 ( 20.73 )	1 ( 21.52 )
Month 3	3.8 ( 22.29 )	3.9 ( 22.11 )	2.1 ( 22.27 )
Month 6	4.6 ( 24.36 )	5.8 ( 22.39 )	5.5 ( 22.55 )
Month 12	4.6 ( 24.08 )	4.9 ( 22.23 )	5.1 ( 22.37 )
Month 18	5.8 ( 25.61 )	3.1 ( 23.31 )	5.1 ( 22.99 )
Discontinuation Visit	2.6 ( 24.3 )	3.7 ( 23.77 )	0 ( 24.72 )

Notes
[39] - Month 1 = 443 Month 3 = 423 Month 6 = 375 Month 12 = 305 Month 18 = 246 Discontinuation = 205
[40] - Month 1 = 446 Month 3 = 415 Month 6 = 379 Month 12 = 301 Month 18 = 242 Discontinuation = 263
[41] - Month 1 = 419 Month 3 = 397 Month 6 = 351 Month 12 = 254 Month 18 = 179 Discontinuation = 256

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Cognitive Functioning Domain

Top of page

End point title

Change From Baseline in the EORTC QLQ-C30 Cognitive Functioning Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Cognitive Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	509 ^[42]	510 ^[43]	510 ^[44]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	-1.2 ( 21.73 )	-1.7 ( 19.08 )	-1.8 ( 24.07 )
Month 3	-0.7 ( 22.89 )	1.8 ( 20.94 )	-1.5 ( 24.02 )
Month 6	-0.9 ( 22.57 )	0.9 ( 19.77 )	-0.3 ( 23.55 )
Month 12	-1.6 ( 25.05 )	-1.2 ( 20.19 )	-0.6 ( 22.97 )
Month 18	-2.2 ( 25.61 )	-2.8 ( 20.97 )	-0.7 ( 23.99 )
Discontinuation Visit	-4.9 ( 27.57 )	-2.6 ( 22.34 )	-7.1 ( 25.15 )

Notes
[42] - Month 1 = 443 Month 3 = 424 Month 6 = 375 Month 12 = 306 Month 18 = 246 Discontinuation = 206
[43] - Month 1 = 447 Month 3 = 415 Month 6 = 379 Month 12 = 301 Month 18 = 242 Discontinuation = 263
[44] - Month 1 = 419 Month 3 = 397 Month 6 = 353 Month 12 = 254 Month 18 = 179 Discontinuation = 256

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Social Functioning Domain

Top of page

End point title

Change From Baseline in the EORTC QLQ-C30 Social Functioning Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Social Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1(Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	505 ^[45]	503 ^[46]	503 ^[47]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	-4.3 ( 29.1 )	-2.2 ( 27.44 )	-1.4 ( 30.52 )
Month 3	0.7 ( 29.36 )	2 ( 30.93 )	2.4 ( 30.7 )
Month 6	4 ( 32.48 )	5.2 ( 28.5 )	3.4 ( 35.24 )
Month 12	2.9 ( 34.96 )	3.8 ( 32.29 )	5.8 ( 33.68 )
Month 18	4.2 ( 34.99 )	3.2 ( 31.67 )	6 ( 35.2 )
Discontinuation Visit	-1.2 ( 33.5 )	2.7 ( 33.37 )	-3.5 ( 33.2 )

Notes
[45] - Month 1 = 439 Month 3 = 419 Month 6 = 374 Month 12 = 305 Month 18 = 247 Discontinuation = 204
[46] - Month 1 = 441 Month 3 = 410 Month 6 = 374 Month 12 = 298 Month 18 = 239 Discontinuation = 257
[47] - Month 1 = 414 Month 3 = 389 Month 6 = 348 Month 12 = 252 Month 18 = 177 Discontinuation = 254

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Fatigue Domain

Top of page

End point title

Change From Baseline in the EORTC QLQ-C30 Fatigue Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1(Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	511 ^[48]	514 ^[49]	512 ^[50]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	2.6 ( 25.32 )	4.4 ( 24.03 )	2.8 ( 25.44 )
Month 3	-2.5 ( 28.15 )	-3.4 ( 25.16 )	-1.8 ( 28.53 )
Month 6	-3.7 ( 28.54 )	-5.9 ( 26.37 )	-4.5 ( 29.09 )
Month 12	-4.3 ( 29.47 )	-2.3 ( 26.63 )	-3.9 ( 29.56 )
Month 18	-3.1 ( 29.82 )	0.1 ( 29.12 )	-4.3 ( 30.05 )
Discontinuation Visit	0.3 ( 29.75 )	-1.6 ( 29.11 )	2.7 ( 30.15 )

Notes
[48] - Month 1 = 445 Month 3 = 425 Month 6 = 376 Month 12 = 306 Month 18 = 244 Discontinuation = 207
[49] - Month 1 = 448 Month 3 = 423 Month 6 = 383 Month 12 = 303 Month 18 = 242 Discontinuation = 267
[50] - Month 1 = 421 Month 3 = 400 Month 6 = 355 Month 12 = 255 Month 18 = 184 Discontinuation = 258

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Pain Domain

Top of page

End point title

Change From Baseline in the EORTC QLQ-C30 Pain Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Pain Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	511 ^[51]	514 ^[52]	512 ^[53]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	-5.4 ( 31.89 )	-4.4 ( 30.7 )	-7.8 ( 30.93 )
Month 3	-13.4 ( 34.28 )	-13.1 ( 32.32 )	-12.1 ( 31.98 )
Month 6	-14.4 ( 35.64 )	-16.1 ( 33.44 )	-13.4 ( 34.45 )
Month 12	-14 ( 36.05 )	-14.7 ( 32.34 )	-14.3 ( 32.85 )
Month 18	-14.4 ( 35.03 )	-12.4 ( 35.28 )	-14.7 ( 32.81 )
Discontinuation Visit	-8 ( 39.37 )	-7.9 ( 37.65 )	-6 ( 37.09 )

Notes
[51] - Month 1 = 446 Month 3 = 426 Month 6 = 379 Month 12 = 306 Month 18 = 248 Discontinuation = 207
[52] - Month 1 = 453 Month 3 = 423 Month 6 = 384 Month 12 = 304 Month 18 = 242 Discontinuation = 266
[53] - Month 1 = 423 Month 3 = 399 Month 6 = 355 Month 12 = 255 Month 18 = 183 Discontinuation = 259

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Nausea/Vomiting Domain

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End point title

Change From Baseline in the EORTC QLQ-C30 Nausea/Vomiting Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Nausea/Vomiting Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	511 ^[54]	513 ^[55]	512 ^[56]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	1.8 ( 20.05 )	-0.5 ( 23.19 )	4 ( 22.91 )
Month 3	-1.1 ( 19.42 )	-2.5 ( 21.92 )	-1.2 ( 19.89 )
Month 6	-1.3 ( 18.53 )	-4 ( 21.52 )	-3.9 ( 19.57 )
Month 12	-2.2 ( 17.16 )	-3.6 ( 18.86 )	-3.9 ( 19.09 )
Month 18	-2.3 ( 19.2 )	-2.7 ( 18.92 )	-3.9 ( 19.44 )
Discontinuation Visit	0.4 ( 21.43 )	-4.2 ( 24.37 )	1 ( 21.46 )

Notes
[54] - Month 1 = 446 Month 3 = 426 Month 6 = 377 Month 12 = 306 Month 18 = 246 Discontinuation = 206
[55] - Month 1 = 449 Month 3 = 422 Month 6 = 381 Month 12 = 302 Month 18 = 242 Discontinuation = 267
[56] - Month 1 = 424 Month 3 = 399 Month 6 = 355 Month 12 = 255 Month 18 = 184 Discontinuation = 258

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain

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End point title

Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnoea Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1(Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	509 ^[57]	508 ^[58]	506 ^[59]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	0.9 ( 30.87 )	3.6 ( 29.85 )	4.2 ( 32.04 )
Month 3	-0.8 ( 31.87 )	-1.9 ( 29.45 )	2 ( 32.49 )
Month 6	-2.3 ( 33.12 )	-2.9 ( 29.66 )	0.1 ( 30.29 )
Month 12	-3.5 ( 30.97 )	-1.6 ( 29.23 )	-1.6 ( 32.76 )
Month 18	-1.8 ( 32.73 )	2.9 ( 28.33 )	0.4 ( 32.68 )
Discontinuation Visit	-1 ( 37.42 )	0.8 ( 31.01 )	7.8 ( 33.72 )

Notes
[57] - Month 1 = 439 Month 3 = 423 Month 6 = 372 Month 12 = 303 Month 18 = 244 Discontinuation = 204
[58] - Month 1 = 440 Month 3 = 417 Month 6 = 375 Month 12 = 294 Month 18 = 238 Discontinuation = 262
[59] - Month 1 = 417 Month 3 = 390 Month 6 = 351 Month 12 = 253 Month 18 = 182 Discontinuation = 255

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Insomnia Domain

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End point title

Change From Baseline in the EORTC QLQ-C30 Insomnia Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Insomnia Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	510 ^[60]	513 ^[61]	511 ^[62]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	2.1 ( 33.34 )	3.2 ( 34.32 )	-10.5 ( 30.47 )
Month 3	0.2 ( 35.11 )	-1.3 ( 33.54 )	-8.9 ( 35.28 )
Month 6	-1.2 ( 34.84 )	-1.9 ( 31.43 )	-11.6 ( 32.96 )
Month 12	-1 ( 34.78 )	1.1 ( 32.47 )	-9.6 ( 31 )
Month 18	-0.5 ( 37.11 )	1.4 ( 35.72 )	-6 ( 34.42 )
Discontinuation Visit	-5.2 ( 36.47 )	-1.6 ( 31.27 )	-4.5 ( 36.98 )

Notes
[60] - Month 1 = 443 Month 3 = 422 Month 6 = 374 Month 12 = 303 Month 18 = 243 Discontinuation = 204
[61] - Month 1 = 447 Month 3 = 420 Month 6 = 382 Month 12 = 300 Month 18 = 241 Discontinuation = 265
[62] - Month 1 = 421 Month 3 = 399 Month 6 = 353 Month 12 = 253 Month 18 = 182 Discontinuation = 254

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Appetite Loss Domain

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End point title

Change From Baseline in the EORTC QLQ-C30 Appetite Loss Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Appetite Loss Scale is scored between 0 and 100, with a high score indicating a higher level of appetite loss. Negative change from Baseline values indicate improvement in appetite and positive values indicate worsening of appetite.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	509 ^[63]	512 ^[64]	510 ^[65]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	1.3 ( 33.46 )	2.9 ( 31.87 )	1 ( 32.35 )
Month 3	-5.9 ( 38.34 )	-3.3 ( 35.25 )	-6.2 ( 35.03 )
Month 6	-9.8 ( 40.02 )	-8.6 ( 33.98 )	-13.5 ( 35.98 )
Month 12	-7.3 ( 37.07 )	-6.4 ( 35.3 )	-10.5 ( 34.16 )
Month 18	-8.1 ( 35.97 )	-5.1 ( 33.29 )	-12.2 ( 31.88 )
Discontinuation Visit	-1 ( 36.77 )	-7.5 ( 37.49 )	-2.6 ( 37.18 )

Notes
[63] - Month 1 = 442 Month 3 = 424 Month 6 = 374 Month 12 = 307 Month 18 = 246 Discontinuation = 203
[64] - Month 1 = 447 Month 3 = 421 Month 6 = 381 Month 12 = 299 Month 18 = 241 Discontinuation = 267
[65] - Month 1 = 422 Month 3 = 396 Month 6 = 354 Month 12 = 253 Month 18 = 183 Discontinuation = 257

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Constipation Domain

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End point title

Change From Baseline in the EORTC QLQ-C30 Constipation Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Constipation Scale is scored between 0 and 100, with a high score indicating a higher level of constipation. Negative change from Baseline values indicate improvement in constipation and positive values indicate worsening of constipation.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	508 ^[66]	511 ^[67]	510 ^[68]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	8.3 ( 36.74 )	6.3 ( 36.18 )	18.4 ( 41.23 )
Month 3	1.8 ( 37.53 )	0 ( 37.02 )	13.9 ( 39.3 )
Month 6	-2.4 ( 37.51 )	-5.1 ( 37.39 )	6.8 ( 40.41 )
Month 12	-2.4 ( 38.79 )	-5.2 ( 38.09 )	3.7 ( 38.28 )
Month 18	-4.5 ( 35.42 )	-5.9 ( 36.65 )	0 ( 37.06 )
Discontinuation Visit	-7.9 ( 39.98 )	-7.5 ( 39.2 )	-2.2 ( 38.86 )

Notes
[66] - Month 1 = 441 Month 3 = 422 Month 6 = 373 Month 12 = 304 Month 18 = 246 Discontinuation = 203
[67] - Month 1 = 446 Month 3 = 416 Month 6 = 377 Month 12 = 301 Month 18 = 242 Discontinuation = 261
[68] - Month 1 = 419 Month 3 = 397 Month 6 = 353 Month 12 = 255 Month 18 = 179 Discontinuation = 257

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Diarrhea Domain

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End point title

Change From Baseline in the EORTC QLQ-C30 Diarrhea Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Diarrhea Scale is scored between 0 and 100, with a high score indicating a higher level of diarrhea. Negative change from Baseline values indicate improvement in diarrhea and positive values indicate worsening of diarrhea. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	508 ^[69]	509 ^[70]	510 ^[71]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	3.8 ( 25.53 )	2.3 ( 24.94 )	-0.6 ( 18.79 )
Month 3	3.7 ( 24.99 )	3.4 ( 27.27 )	-2.4 ( 18.61 )
Month 6	8.2 ( 28.36 )	6 ( 27.95 )	-2.2 ( 21.19 )
Month 12	11.8 ( 31.35 )	9.1 ( 28.74 )	-2.5 ( 17.26 )
Month 18	14.8 ( 31.2 )	10.9 ( 30.96 )	-1.7 ( 17.46 )
Discontinuation Visit	10.8 ( 29.56 )	6.4 ( 31.38 )	-0.5 ( 19.39 )

Notes
[69] - Month 1 = 438 Month 3 = 419 Month 6 = 373 Month 12 = 303 Month 18 = 246 Discontinuation = 206
[70] - Month 1 = 444 Month 3 = 413 Month 6 = 376 Month 12 = 299 Month 18 = 241 Discontinuation = 261
[71] - Month 1 = 416 Month 3 = 395 Month 6 = 351 Month 12 = 253 Month 18 = 178 Discontinuation = 255

No statistical analyses for this end point

Secondary: Change From Baseline in the EORTC QLQ-C30 Financial Difficulties Domain

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End point title

Change From Baseline in the EORTC QLQ-C30 Financial Difficulties Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Financial Difficulties Scale is scored between 0 and 100, with a high score indicating a higher level of financial difficulties. Negative change from Baseline values indicate improvement in financial difficulties and positive values indicate worsening of financial difficulties. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	501 ^[72]	504 ^[73]	502 ^[74]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	2.1 ( 21.43 )	-0.3 ( 20.59 )	0.5 ( 22.98 )
Month 3	1.9 ( 23.09 )	-0.4 ( 21.88 )	1.9 ( 21.48 )
Month 6	1.4 ( 22.92 )	-0.3 ( 21.24 )	0.7 ( 24.57 )
Month 12	0.4 ( 23.99 )	1.6 ( 23.28 )	1.1 ( 23.16 )
Month 18	2 ( 22.23 )	1.8 ( 23.3 )	0.4 ( 21.2 )
Discontinuation Visit	1.9 ( 27.19 )	0.5 ( 23.84 )	5 ( 24.82 )

Notes
[72] - Month 1 = 435 Month 3 = 413 Month 6 = 370 Month 12 = 302 Month 18 = 244 Discontinuation = 197
[73] - Month 1 = 441 Month 3 = 407 Month 6 = 373 Month 12 = 299 Month 18 = 239 Discontinuation = 255
[74] - Month 1 = 409 Month 3 = 388 Month 6 = 345 Month 12 = 249 Month 18 = 174 Discontinuation = 254

No statistical analyses for this end point

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Disease Symptoms Scale

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End point title

Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Disease Symptoms Scale

End point description

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; a higher score indicates more severe disease symptom(s). Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	510 ^[75]	512 ^[76]	511 ^[77]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	-4 ( 18.75 )	-4.1 ( 19.37 )	-4.4 ( 19.04 )
Month 3	-9.1 ( 21.66 )	-10 ( 19.97 )	-7 ( 20.43 )
Month 6	-8.8 ( 20.89 )	-9.9 ( 20.94 )	-7.9 ( 21.94 )
Month 12	-7.8 ( 21.74 )	-8.7 ( 20.29 )	-6.5 ( 21.58 )
Month 18	-8.7 ( 23.5 )	-6.2 ( 23.3 )	-7.9 ( 21.26 )
Discontinuation Visit	-3.5 ( 24.82 )	-4.5 ( 24.9 )	-3.7 ( 23.54 )

Notes
[75] - Month 1 = 442 Month 3 = 422 Month 6 = 375 Month 12 = 306 Month 18 = 249 Discontinuation = 205
[76] - Month 1 = 448 Month 3 = 418 Month 6 = 381 Month 12 = 303 Month 18 = 243 Discontinuation = 266
[77] - Month 1 = 421 Month 3 = 396 Month 6 = 353 Month 12 = 254 Month 18 = 183 Discontinuation = 259

No statistical analyses for this end point

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Side Effects Treatment Scale

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End point title

Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Side Effects Treatment Scale

End point description

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; a higher score represents a more severe overall side effect of treatment. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	509 ^[78]	511 ^[79]	510 ^[80]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	2.5 ( 13.72 )	4 ( 14.89 )	5.6 ( 15 )
Month 3	1 ( 15.23 )	1.2 ( 14.67 )	3.5 ( 15.4 )
Month 6	1.7 ( 15.58 )	-0.4 ( 14.39 )	2.9 ( 17.28 )
Month 12	1.9 ( 14.49 )	1.2 ( 16.2 )	4.7 ( 17.17 )
Month 18	2.2 ( 15.63 )	2.3 ( 17.36 )	4.3 ( 16.37 )
Discontinuation Visit	0.6 ( 15.85 )	-1 ( 15.81 )	3.8 ( 16.52 )

Notes
[78] - Month 1 = 438 Month 3 = 421 Month 6 = 374 Month 12 = 305 Month 18 = 247 Discontinuation = 205
[79] - Month 1 = 446 Month 3 = 417 Month 6 = 378 Month 12 = 301 Month 18 = 243 Discontinuation = 262
[80] - Month 1 = 418 Month 3 = 393 Month 6 = 351 Month 12 = 254 Month 18 = 182 Discontinuation = 258

No statistical analyses for this end point

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Future Perspective Scale

Top of page

End point title

Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Future Perspective Scale

End point description

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; for the future perspective scale, a higher score indicates a better perspective of the future. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	504 ^[81]	508 ^[82]	509 ^[83]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	4.7 ( 22.17 )	3.9 ( 20.94 )	3.3 ( 23.2 )
Month 3	8.5 ( 23.28 )	9.2 ( 22.95 )	6.3 ( 25.06 )
Month 6	9.8 ( 23.67 )	12.3 ( 24.84 )	8 ( 25.26 )
Month 12	10.8 ( 21.9 )	12.1 ( 24.41 )	10 ( 26.3 )
Month 18	12.7 ( 23.96 )	11.7 ( 24.76 )	9.5 ( 21.75 )
Discontinuation Visit	5.8 ( 25.91 )	8.8 ( 26.71 )	3.2 ( 27.13 )

Notes
[81] - Month 1 = 433 Month 3 = 416 Month 6 = 367 Month 12 = 303 Month 18 = 245 Discontinuation = 203
[82] - Month 1 = 443 Month 3 = 414 Month 6 = 377 Month 12 = 299 Month 18 = 239 Discontinuation = 264
[83] - Month 1 = 415 Month 3 = 394 Month 6 = 350 Month 12 = 249 Month 18 = 179 Discontinuation = 254

No statistical analyses for this end point

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Body Image Scale

Top of page

End point title

Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Body Image Scale

End point description

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; for the body image scale, a higher score indicates a better body image. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	492 ^[84]	498 ^[85]	504 ^[86]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	-4.5 ( 29.44 )	-1.5 ( 27.19 )	-1.6 ( 29.97 )
Month 3	-1.7 ( 27.54 )	0.8 ( 26.23 )	-3 ( 29.38 )
Month 6	-1.4 ( 27.84 )	1.5 ( 29.72 )	-2.8 ( 33.07 )
Month 12	-1.4 ( 29.6 )	-0.4 ( 31.64 )	-2.6 ( 31.96 )
Month 18	-2.3 ( 28.09 )	-0.3 ( 31.04 )	-1.1 ( 33.6 )
Discontinuation Visit	-5.6 ( 34.29 )	1.8 ( 30.66 )	-5.6 ( 33.73 )

Notes
[84] - Month 1 = 417 Month 3 = 404 Month 6 = 357 Month 12 = 292 Month 18 = 236 Discontinuation = 197
[85] - Month 1 = 422 Month 3 = 398 Month 6 = 366 Month 12 = 284 Month 18 = 227 Discontinuation = 253
[86] - Month 1 = 408 Month 3 = 387 Month 6 = 347 Month 12 = 242 Month 18 = 174 Discontinuation = 250

No statistical analyses for this end point

Secondary: Change From Baseline in the European Quality of Life-5 Dimensions (EQ-5D) Health Utility Index Score

Top of page

End point title

Change From Baseline in the European Quality of Life-5 Dimensions (EQ-5D) Health Utility Index Score

End point description

EQ-5D is a self-administered questionnaire that assesses health-related quality of life. The EQ-5D descriptive health profile comprises five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 3 levels of response: No problem (1), some problems (2), and extreme problems (3). A unique EQ-5D health state is defined by combining one level from each of the five dimensions into a single utility index score. EQ-5D index values range from -0.59 to 1.00 where higher EQ-5D scores represent better health status. A positive change from baseline score indicates improvement in health status and better health state. Includes the ITT population with available data.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	490 ^[87]	492 ^[88]	490 ^[89]
Units: units on a scale
arithmetic mean (standard deviation)
Month 1	0 ( 0.29 )	0 ( 0.31 )	0 ( 0.28 )
Month 3	0.1 ( 0.33 )	0.1 ( 0.32 )	0.1 ( 0.32 )
Month 6	0.1 ( 0.32 )	0.1 ( 0.31 )	0.1 ( 0.34 )
Month 12	0.1 ( 0.33 )	0.1 ( 0.31 )	0.1 ( 0.35 )
Month 18	0.1 ( 0.36 )	0.1 ( 0.32 )	0.1 ( 0.35 )
Discontinuation Visit	0 ( 0.4 )	0 ( 0.35 )	0 ( 0.39 )

Notes
[87] - Month 1 = 400 Month 3 = 389 Month 6 = 341 Month 12 = 283 Month 18 = 219 Discontinuation = 186
[88] - Month 1 = 420 Month 3 = 383 Month 6 = 351 Month 12 = 278 Month 18 = 230 Discontinuation = 231
[89] - Month 1 = 381 Month 3 = 366 Month 6 = 323 Month 12 = 231 Month 18 = 170 Discontinuation = 240

No statistical analyses for this end point

Secondary: Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Per Year

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End point title

Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Per Year

End point description

HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU Analysis may help in evaluating potential costs and budget impact of new treatments from a payer perspective. The rate of inpatient hospitalizations per patient year was calculated as the total number of hospitalizations divided by the total number of patient-years followed in the study period. Patient-years (PY) were calculated as the duration from baseline to last available HRQL assessment for each patient. HRU data not analyzed.

End point type

Secondary

End point timeframe

Day 1 (randomization) up to last visit completed 25 July 2016

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	0 ^[90]	0 ^[91]	0 ^[92]
Units: hospitalizations per patient year
number (not applicable)

Notes
[90] - 0 = HRU data not analyzed.
[91] - 0 = HRU data not analyzed.
[92] - 0 = HRU data not analyzed.

No statistical analyses for this end point

Secondary: Number of Participants With Adverse Events (AEs) During the Active Treatment Phase

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End point title

Number of Participants With Adverse Events (AEs) During the Active Treatment Phase

End point description

A treatment emergent adverse event (TEAE) is any AE occurring or worsening on or after the first treatment of any study drug, and within 30 days after the last dose of the last study drug. Severity grades according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) on a 1-5 scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5=Death related to AE. A serious AE is any AE occurring at any dose that: • Results in death; • Is life-threatening; • Requires or prolongs existing inpatient hospitalization; • Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect; • Constitutes an important medical event. Safety population included all subjects who received at least one dose of treatment in any arm.

End point type

Secondary

End point timeframe

From first dose of study drug through 28 days following the discontinuation visit from active treatment phase; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	532	540	541
Units: Participants
≥ 1 adverse event (AE)	529	536	539
≥ 1 grade (Gr) 3 or 4 AE	453	433	480
≥ 1 grade (Gr) 5 AE	50	36	38
≥ 1 serious adverse event (SAE)	359	308	270
≥ 1 AE related to Len/Dex/MPT	506	501	527
≥ 1 AE related to Lenalidomide	482	481	0
≥ 1 AE related to dexamethasone	429	410	0
≥ 1 AE related to melphalan	0	0	441
≥ 1 AE related to prednisone	0	0	326
≥ 1 AE related to thalidomide	0	0	493
≥1 AE related to Len/Dex or MPT	269	269	145
≥ 1 Gr 3 or 4 AE related to Len/Dex/MPT	373	326	423
≥ 1 grade 3 or 4 AE related to Lenalidomide	342	290	0
≥ 1 grade 3 or 4 AE related to dexamethasone	229	177	0
≥ 1 grade 3 or 4 AE related to melphalan	0	0	307
≥ 1 grade 3 or 4 AE related to prednisone	0	0	118
≥ 1 grade 3 or 4 AE related to Thalidomide	0	0	316
≥1 Gr 3 or 4 AE related to Len/Dex or MPT	131	104	49
≥ 1 Grade 5 AE related to Len/Dex/MPT	17	11	10
≥ 1 Grade 5 AE related to Lenalidomide	12	9	0
≥ 1 Grade 5 AE related to Dexamethasone	16	7	0
≥ 1 Grade 5 AE related to melphalan	0	0	6
≥ 1 Grade 5 AE related to prednisone	0	0	5
≥ 1 Grade 5 AE related to Thalidomide	0	0	5
≥ 1 Grade 5 AE related to Len/Dex or MPT	11	5	2
≥1 SAE related to Len/Dex/MPT	195	158	142
≥1 SAE related to Lenalidomide	165	130	0
≥1 SAE related to dexamethasone	130	97	0
≥1 SAE related to melphalan	0	0	75
≥1 SAE related to prednisone	0	0	62
≥1 SAE related to thalidomide	0	0	94
≥1 SAE related to Len/Dex or MPT	95	64	27
≥1 AE leading to Len/Dex/MPT Withdrawal	157	109	153
≥1 AE leading to Lenalidomide withdrawal	109	93	0
≥1 AE leading to dexamethasone withdrawal	152	104	0
≥1 AE leading to melphalan withdrawal	0	0	83
≥1 AE leading to prednisone withdrawal	0	0	78
≥1 AE leading to Thalidomide withdrawal	0	0	146
≥1AE leading to Len/Dex OR MPT Withdrawal	96	84	71
≥1 AE leading to Len/Dex/MPT reduction	279	214	348
≥1 AE leading to Lenalidomide reduction	203	155	0
≥1 AE leading to dexamethasone reduction	170	118	0
≥1 AE leading to melphalan reduction	0	0	199
≥1 AE leading to prednisone reduction	0	0	47
≥1 AE leading to thalidomide reduction	0	0	254
≥1AE leading to Len/Dex OR MPT reduction	30	20	2
≥1 AE leading to Len/Dex/ MPT interruption	368	321	419
≥1 AE leading to Lenalidomide interruption	353	301	0
≥1 AE leading to dexamethasone interruption	319	280	0
≥1 AE leading to melphalan interruption	0	0	328
≥1 AE leading to prednisone interruption	0	0	324
≥1 AE leading to Thalidomide interruption	0	0	388
≥1 AE leading to Len/Dex or MPT interruption	290	241	249

No statistical analyses for this end point

Secondary: Shift from baseline to most extreme postbaseline value in creatinine clearance (CrCl) during the active treatment phase

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End point title

Shift from baseline to most extreme postbaseline value in creatinine clearance (CrCl) during the active treatment phase

End point description

Renal function was assessed for participants from baseline to the most extreme value in creatinine clearance calculated using the Cockcroft-Gault estimation. Safety Population with baseline and postbaseline CrCl data.

End point type

Secondary

End point timeframe

Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	494	506	484
Units: participants
CrCl< 30 mL/min to CrCl< 30 mL/min	15	17	19
CrCl < 30 mL/min to CrCl ≥ 30 but < 50 mL/min	18	14	19
CrCl < 30 mL/min to CrCl ≥ 50 but < 80 mL/min	7	8	5
CrCl< 30 mL/min to ≥ 80 mL/min	2	2	0
CrCl≥ 30 but < 50 mL/min to < 30 mL/min	1	2	0
CrCl ≥ 30 but < 50 mL/min to CrCl ≥ 30 but < 50 mL	37	41	41
CrCl ≥ 30 but < 50 mL/min to CrCl ≥ 50 but < 80 mL	67	55	65
CrCl ≥ 30 but < 50 mL/min to ≥ 80 mL/min	9	12	2
CrCl ≥ 50 but < 80 mL to CrCl< 30 mL/min	0	0	0
CrCl ≥ 50 but < 80 mL to CrCl ≥ 30 but < 50 mL/min	4	1	4
CrCl ≥ 50 but < 80 mL to CrCl ≥ 50 but < 80 mL/min	112	130	102
CrCl ≥ 50 but < 80 mL to ≥ 80 mL/min	107	99	97
CrCl ≥ 80 mL/min to CrCl< 30 mL/min	0	1	0
CrCl ≥ 80 mL/min to CrCl ≥ 30 but < 50 mL/min	0	0	0
CrCl ≥ 80 mL/min to CrCl ≥ 50 but < 80 mL/min	6	10	9
CrCl ≥ 80 mL/min to CrCl ≥ 80 mL/min	109	114	121

No statistical analyses for this end point

Secondary: Shift from baseline to most extreme postbaseline value in absolute neutrophil count during the active treatment phase

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End point title

Shift from baseline to most extreme postbaseline value in absolute neutrophil count during the active treatment phase

End point description

Neutrophil counts was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale. Safety Population; includes participants with baseline and postbaseline absolute neutrophil laboratory test grade information.

End point type

Secondary

End point timeframe

Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	525	534	526
Units: participants
Normal Baseline Grade to Normal Postbaseline Grade	103	133	37
Normal Baseline Grade to Grade 1 postbaseline	96	85	79
Normal Baseline Grade to Grade 2 postbaseline	121	109	128
Normal Baseline Grade to Grade 3 postbaseline	70	71	141
Normal Baseline Grade to Grade 4 postbaseline	21	30	45
Grade 1 Baseline to Normal postbaseline Grade	7	6	2
Grade 1 Baseline to Grade 1 postbaseline	8	11	2
Grade 1 Baseline to Grade 2 postbaseline	17	15	11
Grade1 Baseline Grade to Grade3 postbaseline Grade	25	30	20
Grade 1 Baseline to Grade 4 postbaseline	9	4	21
Grade 2 Baseline to normal postbaseline Grade	1	0	0
Grade 2 Baseline to Grade 1 postbaseline	1	1	1
Grade 2 Baseline to Grade 2 postbaseline	14	11	7
Grade 2 Baseline to Grade 3 postbaseline	18	18	21
Grade 2 Baseline to Grade 4 postbaseline	9	5	10
Grade 3 Baseline to Normal postbaseline Grade	0	0	0
Grade 3 Baseline to Grade 1 postbaseline	0	0	0
Grade 3 Baseline to Grade 2 postbaseline	2	1	0
Grade 3 Baseline to Grade 3 postbaseline	2	2	0
Grade 3 Baseline to Grade 4 postbaseline	0	2	1
Grade 4 Baseline to Normal postbaseline Grade	0	0	0
Grade 4 Baseline to Grade1 postbaseline Grade 1	1	0	0
Grade 4 Baseline to Grade 2 postbaseline	0	0	0
Grade 4 Baseline to Grade 3 postbaseline	0	0	0
Grade 4 Baseline Grade to Grade 4 postbaseline	0	0	0

No statistical analyses for this end point

Secondary: Shift from baseline to most extreme in hemoglobin during the active treatment phase

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End point title

Shift from baseline to most extreme in hemoglobin during the active treatment phase

End point description

Hemoglobin was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale. Safety Population; Includes participants with baseline and postbaseline hemoglobin laboratory test grade information.

End point type

Secondary

End point timeframe

Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	527	535	526
Units: participants
Normal Baseline Grade to Normal Postbaseline Grade	6	10	9
Normal Baseline Grade to Grade 1 postbaseline	39	30	25
Normal Baseline Grade to Grade 2 postbaseline	8	8	4
Normal Baseline Grade to Grade 3 postbaseline	0	1	1
Normal Baseline Grade to Grade 4 postbaseline	0	0	0
Grade 1 Baseline to Normal postbaseline	0	0	0
Grade 1 Baseline to Grade 1 postbaseline	106	126	110
Grade 1 Baseline to Grade 2 postbaseline	128	123	123
Grade 1 Baseline to Grade 3 postbaseline	25	17	20
Grade 1 Baseline to Grade 4 postbaseline	2	5	4
Grade 2 Baseline to normal postbaseline Grade	0	0	0
Grade 2 Baseline to Grade 1 postbaseline	8	12	14
Grade 2 Baseline to Grade 2 postbaseline	125	135	133
Grade 2 Baseline to Grade 3 postbaseline	48	41	47
Grade 2 Baseline to Grade 4 postbaseline	4	9	11
Grade 3 Baseline to Normal postbaseline Grade	0	0	0
Grade 3 Baseline to Grade 1 postbaseline	0	1	0
Grade 3 Baseline to Grade 2 postbaseline	12	4	10
Grade 3 Baseline to Grade 3 postbaseline	10	8	10
Grade 3 Baseline to Grade 4 postbaseline	5	3	2
Grade 4 Baseline to Normal postbaseline Grade	0	0	0
Grade 4 Baseline to Grade 1 postbaseline	0	0	0
Grade 4 Baseline to Grade 2 postbaseline	0	0	1
Grade 4 Baseline to Grade 3 postbaseline	0	1	0
Grade 4 Baseline to Grade 4 postbaseline	1	1	2

No statistical analyses for this end point

Secondary: Shift from baseline to most extreme postbaseline extreme value in platelet count during the active treatment phase

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End point title

Shift from baseline to most extreme postbaseline extreme value in platelet count during the active treatment phase

End point description

Improvement in platelets was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale. Safety population; includes participants with baseline and postbaseline platelet laboratory test grade information.

End point type

Secondary

End point timeframe

Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	527	535	526
Units: participants
Normal Baseline Grade to Normal Postbaseline Grade	197	197	165
Normal Baseline Grade to Grade 1 postbaseline	216	211	208
Normal Baseline Grade to Grade 2 postbaseline	24	30	27
Normal Baseline Grade to Grade 3 postbaseline	15	12	31
Normal Baseline Grade to Grade 4 postbaseline	4	5	11
Grade 1 Baseline to Normal postbaseline Grade	1	3	6
Grade 1 Baseline to Grade 1 postbaseline	34	38	51
Grade 1 Baseline to Grade 2 postbaseline	15	19	7
Grade 1 Baseline to Grade 3 postbaseline	10	12	10
Grade 1 Baseline to Grade 4 postbaseline	2	1	1
Grade 2 Baseline to normal postbaseline Grade	0	0	0
Grade 2 Baseline to Grade 1 postbaseline	0	1	2
Grade 2 Baseline to Grade 2 postbaseline	3	3	1
Grade 2 Baseline to Grade 3 postbaseline	3	2	2
Grade 2 Baseline to Grade 4 postbaseline	1	0	2
Grade 3 Baseline to Normal postbaseline Grade	0	0	0
Grade 3 Baseline to Grade 1 postbaseline	0	0	0
Grade 3 Baseline to Grade 2 postbaseline	0	0	1
Grade 3 Baseline to Grade 3 postbaseline	0	0	1
Grade 3 Baseline to Grade 4 postbaseline	2	1	0
Grade 4 Baseline to Normal postbaseline Grade	0	0	0
Grade 4 Baseline to Grade 1 postbaseline	0	0	0
Grade 4 Baseline to Grade 2 postbaseline	0	0	0
Grade 4 Baseline to Grade 3 postbaseline	0	0	0
Grade 4 Baseline to Grade 4 postbaseline	0	0	0

No statistical analyses for this end point

Secondary: Improvement of infection rate by observing the historical data compared to the clinical data base

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End point title

Improvement of infection rate by observing the historical data compared to the clinical data base

End point description

Improvement of infection rate by observing historical data compared to the data within the clinical database was not analyzed.

End point type

Secondary

End point timeframe

Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	0 ^[93]	0 ^[94]	0 ^[95]
Units: participants
number (not applicable)

Notes
[93] - Data for infection rate was not analyzed.
[94] - Data for infection rate was not analyzed.
[95] - Data for infection rate was not analyzed.

No statistical analyses for this end point

Secondary: Percentage of participants with an objective response after second-line anti-myeloma treatment at the Time of Final Analysis

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End point title

Percentage of participants with an objective response after second-line anti-myeloma treatment at the Time of Final Analysis

End point description

Objective response according to IMWG Uniform Response Criteria was defined as a best overall response including a complete response (CR), very good partial response (VGPR) or partial response (PR) based on the Investigators Review. A CR is defined as: negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas. Includes ITT population that received second-line AMT.

End point type

Secondary

End point timeframe

End point values	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone Rd18	Melphalan + Prednisone + Thalidomide (MPT)
Number of subjects analysed	299	377	381
Units: percentage of participants
number (not applicable)	46.2	53.1	45.7

Statistical analysis 1

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

680

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.93824

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.38

Statistical analysis 2

Comparison groups

Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18

Number of subjects included in analysis

676

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.08836

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.03

Statistical Analysis 3

Comparison groups

Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)

Number of subjects included in analysis

758

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.04974

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.34

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

1.79

Adverse events

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Timeframe for reporting adverse events

From the first dose of study drug treatment to at least 28 days after discontinuation of active treatment for those not continuing in the PFS phase; Up to the last study visit of 14 July 2016.

Adverse event reporting additional description

Median duration of treatment was 80.2 weeks in the Rd arm, 72.0 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.1

Reporting group title

Lenalidomide and Low-Dose Dexamethasone (Rd)

Reporting group description

Subjects received 25 mg lenalidomide (R) PO QD on days 1 to 21 of each 28-day treatment cycle plus 40 mg dexamethasone (d) PO QD on days 1, 8, 15, and 22 of a 28-day cycle until disease progression; (subjects > 75 years of age received 20 mg dexamethasone).

Reporting group title

Lenalidomide and Dexamethasone (Rd18)

Reporting group description

Subjects received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle plus 40 mg dexamethasone (d) PO daily on days 1, 8, 15, and 22 of a 28-day cycle for 18 four-week cycle or until disease progression; (participants > 75 years of age received 20 mg dexamethasone).

Reporting group title

Melphalan + Prednisone + Thalidomide (MPT)

Reporting group description

Subjects received melphalan (M) 0.25 mg/kg PO QD on days 1 to 4 of each 42-day cycle up to 12 cycles plus prednisone (P) at 2 mg/kg PO QD on days 1 to 4 of each 42-day cycle up to 12 cycles and thalidomide (T) 200 mg PO QD on days 1 to 41 of each 42-day cycle for up to 12 cycles until progressive PD.

Serious adverse events	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone (Rd18)	Melphalan + Prednisone + Thalidomide (MPT)
Total subjects affected by serious adverse events
subjects affected / exposed	378 / 532 (71.05%)	308 / 540 (57.04%)	270 / 541 (49.91%)
number of deaths (all causes)	55	36	38
number of deaths resulting from adverse events	17	11	10
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACUTE LYMPHOCYTIC LEUKAEMIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ACUTE MYELOID LEUKAEMIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BASAL CELL CARCINOMA
subjects affected / exposed	11 / 532 (2.07%)	4 / 540 (0.74%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	8 / 24	2 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BLADDER CANCER
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BLADDER TRANSITIONAL CELL CARCINOMA
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BOWEN'S DISEASE
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 6	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BREAST CANCER
subjects affected / exposed	1 / 532 (0.19%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BREAST CANCER IN SITU
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CANCER PAIN
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARCINOID TUMOUR OF THE APPENDIX
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIAC MYXOMA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COLON ADENOMA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COLON CANCER METASTATIC
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COLON CANCER STAGE IV
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENDOMETRIAL CANCER METASTATIC
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENDOMETRIAL CANCER STAGE III
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTRIC CANCER
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL NEOPLASM
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEPATIC NEOPLASM MALIGNANT
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LENTIGO MALIGNA
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LEUKAEMIA PLASMACYTIC
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG ADENOCARCINOMA METASTATIC
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG ADENOCARCINOMA STAGE IV
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG CANCER METASTATIC
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG NEOPLASM
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG NEOPLASM MALIGNANT
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG SQUAMOUS CELL CARCINOMA STAGE I
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG SQUAMOUS CELL CARCINOMA STAGE UNSPECIFIED
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MALIGNANT MELANOMA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MENINGIOMA
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
METASTASES TO CENTRAL NERVOUS SYSTEM
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
METASTATIC MALIGNANT MELANOMA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MULTIPLE MYELOMA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
MYELODYSPLASTIC SYNDROME
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEOPLASM SWELLING
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OESOPHAGEAL ADENOCARCINOMA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ORAL NEOPLASM BENIGN
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PLASMACYTOMA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
PROSTATE CANCER
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PROSTATE CANCER RECURRENT
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PROSTATIC ADENOMA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RECTAL CANCER
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SALIVARY GLAND CANCER
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SMALL INTESTINE CARCINOMA METASTATIC
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA OF SKIN
subjects affected / exposed	16 / 532 (3.01%)	5 / 540 (0.93%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	20 / 37	2 / 9	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TRANSITIONAL CELL CANCER OF THE RENAL PELVIS AND URETER
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TUMOUR FLARE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
AORTIC ANEURYSM
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
AORTIC ANEURYSM RUPTURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
AORTIC DISSECTION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARTERIAL HAEMORRHAGE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEEP VEIN THROMBOSIS
subjects affected / exposed	19 / 532 (3.57%)	11 / 540 (2.04%)	8 / 541 (1.48%)
occurrences causally related to treatment / all	18 / 19	10 / 11	8 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMATOMA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERTENSION
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERTENSIVE CRISIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	8 / 532 (1.50%)	7 / 540 (1.30%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 9	1 / 9	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOVOLAEMIC SHOCK
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ORTHOSTATIC HYPOTENSION
subjects affected / exposed	3 / 532 (0.56%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIPHERAL ARTERY ANEURYSM
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIPHERAL ARTERY THROMBOSIS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PHLEBITIS
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	5 / 541 (0.92%)
occurrences causally related to treatment / all	0 / 2	0 / 0	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SHOCK
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
THROMBOPHLEBITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
THROMBOPHLEBITIS SUPERFICIAL
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
THROMBOSIS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VENOUS THROMBOSIS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	12 / 532 (2.26%)	2 / 540 (0.37%)	5 / 541 (0.92%)
occurrences causally related to treatment / all	2 / 16	2 / 3	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHEST DISCOMFORT
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHEST PAIN
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
CHILLS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEATH
subjects affected / exposed	3 / 532 (0.56%)	3 / 540 (0.56%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 3	1 / 3	1 / 1
deaths causally related to treatment / all	1 / 3	1 / 3	1 / 1
FATIGUE
subjects affected / exposed	3 / 532 (0.56%)	3 / 540 (0.56%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	2 / 3	2 / 4	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	16 / 532 (3.01%)	13 / 540 (2.41%)	12 / 541 (2.22%)
occurrences causally related to treatment / all	7 / 17	4 / 17	5 / 16
deaths causally related to treatment / all	1 / 2	0 / 4	1 / 6
GENERALISED OEDEMA
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERPYREXIA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERTHERMIA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOTHERMIA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFLAMMATION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFLUENZA LIKE ILLNESS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INJECTION SITE HAEMORRHAGE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MALAISE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUCOSAL INFLAMMATION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MULTI-ORGAN FAILURE
subjects affected / exposed	0 / 532 (0.00%)	3 / 540 (0.56%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 4	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 3	1 / 3
NON-CARDIAC CHEST PAIN
subjects affected / exposed	4 / 532 (0.75%)	4 / 540 (0.74%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OEDEMA PERIPHERAL
subjects affected / exposed	5 / 532 (0.94%)	2 / 540 (0.37%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	1 / 5	3 / 3	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PAIN
subjects affected / exposed	5 / 532 (0.94%)	0 / 540 (0.00%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERFORMANCE STATUS DECREASED
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	22 / 532 (4.14%)	11 / 540 (2.04%)	8 / 541 (1.48%)
occurrences causally related to treatment / all	3 / 29	5 / 15	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPINAL PAIN
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUDDEN DEATH
subjects affected / exposed	5 / 532 (0.94%)	2 / 540 (0.37%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	1 / 5	0 / 2	0 / 2
deaths causally related to treatment / all	1 / 5	0 / 2	0 / 2
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ULCER HAEMORRHAGE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
AMYLOIDOSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANAPHYLACTIC SHOCK
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DRUG HYPERSENSITIVITY
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERSENSITIVITY
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
BENIGN PROSTATIC HYPERPLASIA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EPIDIDYMITIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GENITAL PROLAPSE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PROSTATITIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ACUTE PULMONARY OEDEMA
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
ACUTE RESPIRATORY DISTRESS SYNDROME
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ACUTE RESPIRATORY FAILURE
subjects affected / exposed	3 / 532 (0.56%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	1 / 3	2 / 2	1 / 2
deaths causally related to treatment / all	0 / 1	1 / 1	1 / 1
ASTHMA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHIECTASIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHOPNEUMOPATHY
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHOSPASM
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
subjects affected / exposed	12 / 532 (2.26%)	5 / 540 (0.93%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	2 / 16	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COUGH
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	14 / 532 (2.63%)	7 / 540 (1.30%)	8 / 541 (1.48%)
occurrences causally related to treatment / all	2 / 15	5 / 8	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DYSPNOEA EXERTIONAL
subjects affected / exposed	3 / 532 (0.56%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EPISTAXIS
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	4 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMOPTYSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMOTHORAX
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOXIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTERSTITIAL LUNG DISEASE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG DISORDER
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	1 / 532 (0.19%)	3 / 540 (0.56%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
PNEUMONIA ASPIRATION
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY ALVEOLAR HAEMORRHAGE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY ARTERIAL HYPERTENSION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	20 / 532 (3.76%)	15 / 540 (2.78%)	20 / 541 (3.70%)
occurrences causally related to treatment / all	21 / 21	15 / 15	18 / 21
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 1
PULMONARY HAEMORRHAGE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
PULMONARY HYPERTENSION
subjects affected / exposed	3 / 532 (0.56%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY INFARCTION
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY OEDEMA
subjects affected / exposed	6 / 532 (1.13%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 7	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY THROMBOSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY ALKALOSIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY DISTRESS
subjects affected / exposed	3 / 532 (0.56%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 4	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY FAILURE
subjects affected / exposed	8 / 532 (1.50%)	5 / 540 (0.93%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	1 / 8	4 / 6	1 / 4
deaths causally related to treatment / all	0 / 1	3 / 3	0 / 0
SLEEP APNOEA SYNDROME
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
AGITATED DEPRESSION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANXIETY
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COMPLETED SUICIDE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
CONFUSIONAL STATE
subjects affected / exposed	7 / 532 (1.32%)	6 / 540 (1.11%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	4 / 8	3 / 7	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
DELIRIUM
subjects affected / exposed	4 / 532 (0.75%)	2 / 540 (0.37%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 4	1 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEPRESSED MOOD
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEPRESSION
subjects affected / exposed	4 / 532 (0.75%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 4	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DISORIENTATION
subjects affected / exposed	0 / 532 (0.00%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EUPHORIC MOOD
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HALLUCINATION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IMPAIRED SELF-CARE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MAJOR DEPRESSION
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MENTAL STATUS CHANGES
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUICIDE ATTEMPT
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BIOPSY BONE MARROW ABNORMAL
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BLOOD BILIRUBIN INCREASED
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BLOOD CREATININE INCREASED
subjects affected / exposed	2 / 532 (0.38%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS WORSENED
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EJECTION FRACTION DECREASED
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMOGLOBIN ABNORMAL
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEART RATE INCREASED
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEPATIC ENZYME INCREASED
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTERNATIONAL NORMALISED RATIO INCREASED
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LIVER FUNCTION TEST ABNORMAL
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PROTEIN URINE PRESENT
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PROTHROMBIN TIME RATIO INCREASED
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TROPONIN INCREASED
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TROPONIN T INCREASED
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
WEIGHT DECREASED
subjects affected / exposed	3 / 532 (0.56%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 3	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
ACCIDENTAL OVERDOSE
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	1 / 1	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ACETABULUM FRACTURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ALCOHOL POISONING
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANKLE FRACTURE
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BLADDER INJURY
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CERVICAL VERTEBRAL FRACTURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CLAVICLE FRACTURE
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CONTUSION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CRANIOCEREBRAL INJURY
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FACE INJURY
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FALL
subjects affected / exposed	5 / 532 (0.94%)	3 / 540 (0.56%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	1 / 5	1 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEMORAL NECK FRACTURE
subjects affected / exposed	3 / 532 (0.56%)	2 / 540 (0.37%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 3	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEMUR FRACTURE
subjects affected / exposed	6 / 532 (1.13%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FOOT FRACTURE
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FRACTURED SACRUM
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEAD INJURY
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEART INJURY
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HIP FRACTURE
subjects affected / exposed	4 / 532 (0.75%)	2 / 540 (0.37%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 4	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HUMERUS FRACTURE
subjects affected / exposed	6 / 532 (1.13%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 6	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INCISIONAL HERNIA
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFUSION RELATED REACTION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
JAW FRACTURE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
JOINT DISLOCATION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LACERATION
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUMBAR VERTEBRAL FRACTURE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MEDICATION ERROR
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MENISCUS LESION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OVERDOSE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PELVIC FRACTURE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POST PROCEDURAL HAEMATOMA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PUBIS FRACTURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RADIUS FRACTURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY FUME INHALATION DISORDER
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RIB FRACTURE
subjects affected / exposed	2 / 532 (0.38%)	3 / 540 (0.56%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPINAL COMPRESSION FRACTURE
subjects affected / exposed	6 / 532 (1.13%)	3 / 540 (0.56%)	5 / 541 (0.92%)
occurrences causally related to treatment / all	3 / 7	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPINAL FRACTURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STERNAL FRACTURE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
SUBDURAL HAEMATOMA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUBDURAL HAEMORRHAGE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
TENDON RUPTURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
THORACIC VERTEBRAL FRACTURE
subjects affected / exposed	0 / 532 (0.00%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TRANSFUSION-RELATED ACUTE LUNG INJURY
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TRAUMATIC FRACTURE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ULNA FRACTURE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UPPER LIMB FRACTURE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
WRIST FRACTURE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
LEFT VENTRICLE OUTFLOW TRACT OBSTRUCTION
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
THALASSAEMIA BETA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
ACUTE CORONARY SYNDROME
subjects affected / exposed	5 / 532 (0.94%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 5	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	6 / 532 (1.13%)	1 / 540 (0.19%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	2 / 6	2 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
ANGINA PECTORIS
subjects affected / exposed	7 / 532 (1.32%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 7	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANGINA UNSTABLE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARRHYTHMIA
subjects affected / exposed	0 / 532 (0.00%)	2 / 540 (0.37%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARRHYTHMIA SUPRAVENTRICULAR
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARTERIOSCLEROSIS CORONARY ARTERY
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATRIAL FIBRILLATION
subjects affected / exposed	18 / 532 (3.38%)	12 / 540 (2.22%)	9 / 541 (1.66%)
occurrences causally related to treatment / all	8 / 22	3 / 13	2 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATRIAL FLUTTER
subjects affected / exposed	3 / 532 (0.56%)	2 / 540 (0.37%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	1 / 3	0 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATRIAL THROMBOSIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATRIOVENTRICULAR BLOCK
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATRIOVENTRICULAR BLOCK COMPLETE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRADYARRHYTHMIA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRADYCARDIA
subjects affected / exposed	2 / 532 (0.38%)	2 / 540 (0.37%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 2	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIAC AMYLOIDOSIS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIAC ARREST
subjects affected / exposed	5 / 532 (0.94%)	3 / 540 (0.56%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 6	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 2	0 / 0
CARDIAC FAILURE
subjects affected / exposed	13 / 532 (2.44%)	11 / 540 (2.04%)	8 / 541 (1.48%)
occurrences causally related to treatment / all	3 / 22	5 / 17	5 / 9
deaths causally related to treatment / all	0 / 3	0 / 2	0 / 1
CARDIAC FAILURE CONGESTIVE
subjects affected / exposed	7 / 532 (1.32%)	5 / 540 (0.93%)	5 / 541 (0.92%)
occurrences causally related to treatment / all	0 / 11	3 / 8	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIAC FLUTTER
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIO-RESPIRATORY ARREST
subjects affected / exposed	0 / 532 (0.00%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
CARDIOGENIC SHOCK
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
CARDIOMYOPATHY
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIOPULMONARY FAILURE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 2
CONGESTIVE CARDIOMYOPATHY
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COR PULMONALE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CORONARY ARTERY DISEASE
subjects affected / exposed	5 / 532 (0.94%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CORONARY ARTERY INSUFFICIENCY
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CORONARY ARTERY STENOSIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIASTOLIC DYSFUNCTION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERTENSIVE HEART DISEASE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LEFT VENTRICULAR DYSFUNCTION
subjects affected / exposed	1 / 532 (0.19%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LEFT VENTRICULAR FAILURE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
MITRAL VALVE INCOMPETENCE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MYOCARDIAL INFARCTION
subjects affected / exposed	7 / 532 (1.32%)	2 / 540 (0.37%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	1 / 8	2 / 4	1 / 2
deaths causally related to treatment / all	0 / 2	1 / 1	1 / 1
MYOCARDIAL ISCHAEMIA
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NODAL ARRHYTHMIA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PALPITATIONS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERICARDIAL EFFUSION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERICARDITIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RIGHT VENTRICULAR FAILURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SICK SINUS SYNDROME
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SINOATRIAL BLOCK
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SINUS ARREST
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SINUS BRADYCARDIA
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	1 / 532 (0.19%)	2 / 540 (0.37%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 1	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TACHYARRHYTHMIA
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TACHYCARDIA
subjects affected / exposed	1 / 532 (0.19%)	4 / 540 (0.74%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VENTRICULAR FLUTTER
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VENTRICULAR TACHYCARDIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
ALTERED STATE OF CONSCIOUSNESS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
APHASIA
subjects affected / exposed	0 / 532 (0.00%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRAIN STEM INFARCTION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
CAROTID ARTERY STENOSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CAUDA EQUINA SYNDROME
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CEREBRAL HAEMORRHAGE
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
CEREBRAL INFARCTION
subjects affected / exposed	4 / 532 (0.75%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 4	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CEREBRAL ISCHAEMIA
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	2 / 2	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	8 / 532 (1.50%)	3 / 540 (0.56%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	3 / 9	3 / 3	1 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 2
COMA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CONVULSION
subjects affected / exposed	3 / 532 (0.56%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COORDINATION ABNORMAL
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEMENTIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIZZINESS
subjects affected / exposed	5 / 532 (0.94%)	0 / 540 (0.00%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	0 / 6	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DYSTONIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EPIDURITIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EPILEPSY
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GRAND MAL CONVULSION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GUILLAIN-BARRE SYNDROME
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMORRHAGIC STROKE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEADACHE
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEMIPARESIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOAESTHESIA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ISCHAEMIC CEREBRAL INFARCTION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ISCHAEMIC STROKE
subjects affected / exposed	4 / 532 (0.75%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LACUNAR INFARCTION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LETHARGY
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LOSS OF CONSCIOUSNESS
subjects affected / exposed	1 / 532 (0.19%)	2 / 540 (0.37%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 1	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MOTOR NEURONE DISEASE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PARAESTHESIA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PARALYSIS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PARAPARESIS
subjects affected / exposed	0 / 532 (0.00%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PARAPLEGIA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PARKINSON'S DISEASE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PARKINSONISM
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIPHERAL MOTOR NEUROPATHY
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIPHERAL SENSORIMOTOR NEUROPATHY
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POLYNEUROPATHY
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POST HERPETIC NEURALGIA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PRESYNCOPE
subjects affected / exposed	6 / 532 (1.13%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 6	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PYRAMIDAL TRACT SYNDROME
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RADICULITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
REPETITIVE SPEECH
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SCIATICA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SOMNOLENCE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPEECH DISORDER
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPINAL CORD COMPRESSION
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUBARACHNOID HAEMORRHAGE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	9 / 532 (1.69%)	3 / 540 (0.56%)	8 / 541 (1.48%)
occurrences causally related to treatment / all	2 / 10	1 / 3	5 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TRANSIENT GLOBAL AMNESIA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TRANSIENT ISCHAEMIC ATTACK
subjects affected / exposed	2 / 532 (0.38%)	2 / 540 (0.37%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 2	1 / 2	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TRIGEMINAL NEURALGIA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VASCULAR ENCEPHALOPATHY
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	24 / 532 (4.51%)	15 / 540 (2.78%)	23 / 541 (4.25%)
occurrences causally related to treatment / all	9 / 31	12 / 19	17 / 29
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANAEMIA HAEMOLYTIC AUTOIMMUNE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DISSEMINATED INTRAVASCULAR COAGULATION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEBRILE BONE MARROW APLASIA
subjects affected / exposed	0 / 532 (0.00%)	2 / 540 (0.37%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	5 / 532 (0.94%)	8 / 540 (1.48%)	13 / 541 (2.40%)
occurrences causally related to treatment / all	4 / 5	8 / 8	12 / 14
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMOLYSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERVISCOSITY SYNDROME
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOCOAGULABLE STATE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IDIOPATHIC THROMBOCYTOPENIC PURPURA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LEUKOPENIA
subjects affected / exposed	0 / 532 (0.00%)	3 / 540 (0.56%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	0 / 0	4 / 5	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LYMPHADENITIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LYMPHOPENIA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	9 / 532 (1.69%)	5 / 540 (0.93%)	7 / 541 (1.29%)
occurrences causally related to treatment / all	9 / 10	4 / 5	7 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PANCYTOPENIA
subjects affected / exposed	1 / 532 (0.19%)	2 / 540 (0.37%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	0 / 1	2 / 2	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	5 / 532 (0.94%)	6 / 540 (1.11%)	10 / 541 (1.85%)
occurrences causally related to treatment / all	2 / 5	10 / 12	8 / 13
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
BLINDNESS UNILATERAL
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CATARACT
subjects affected / exposed	5 / 532 (0.94%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 8	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHOROIDAL DETACHMENT
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CONJUNCTIVAL OEDEMA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIABETIC RETINOPATHY
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIPLOPIA
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GLAUCOMA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OCULAR HYPERTENSION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UVEITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VISION BLURRED
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL DISTENSION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN
subjects affected / exposed	5 / 532 (0.94%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	1 / 5	0 / 1	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN UPPER
subjects affected / exposed	0 / 532 (0.00%)	3 / 540 (0.56%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL WALL HAEMATOMA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COLITIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COLITIS ISCHAEMIC
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COLONIC POLYP
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	5 / 532 (0.94%)	3 / 540 (0.56%)	5 / 541 (0.92%)
occurrences causally related to treatment / all	4 / 5	1 / 3	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	9 / 532 (1.69%)	8 / 540 (1.48%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	5 / 9	4 / 8	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIVERTICULAR PERFORATION
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
DIVERTICULUM
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DYSPHAGIA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENTERITIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENTEROCOLITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENTEROCUTANEOUS FISTULA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENTEROVESICAL FISTULA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FAECALOMA
subjects affected / exposed	0 / 532 (0.00%)	3 / 540 (0.56%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTRIC DISORDER
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTRIC ULCER
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTRIC ULCER HAEMORRHAGE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTRITIS
subjects affected / exposed	3 / 532 (0.56%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	3 / 532 (0.56%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL MOTILITY DISORDER
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL NECROSIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL STENOSIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GINGIVAL BLEEDING
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMATEMESIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMORRHAGIC EROSIVE GASTRITIS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HIATUS HERNIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ILEUS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ILEUS PARALYTIC
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INGUINAL HERNIA
subjects affected / exposed	3 / 532 (0.56%)	2 / 540 (0.37%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INGUINAL HERNIA STRANGULATED
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INGUINAL HERNIA, OBSTRUCTIVE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTESTINAL ISCHAEMIA
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	2 / 2	0 / 1	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
INTESTINAL OBSTRUCTION
subjects affected / exposed	4 / 532 (0.75%)	3 / 540 (0.56%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 4	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTESTINAL PERFORATION
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LARGE INTESTINE PERFORATION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	6 / 532 (1.13%)	2 / 540 (0.37%)	7 / 541 (1.29%)
occurrences causally related to treatment / all	2 / 6	0 / 2	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NECROTISING COLITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OBSTRUCTION GASTRIC
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OESOPHAGEAL STENOSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OESOPHAGITIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ORAL DISORDER
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PANCREATITIS
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PEPTIC ULCER HAEMORRHAGE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
RECTAL HAEMORRHAGE
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RECTAL PERFORATION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
REFLUX GASTRITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SIGMOIDITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SMALL INTESTINAL OBSTRUCTION
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 1	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUBILEUS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TONGUE HAEMATOMA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UMBILICAL HERNIA, OBSTRUCTIVE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UPPER GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VOMITING
subjects affected / exposed	8 / 532 (1.50%)	4 / 540 (0.74%)	8 / 541 (1.48%)
occurrences causally related to treatment / all	2 / 8	0 / 6	10 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
BILE DUCT OBSTRUCTION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BILE DUCT STONE
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHOLANGITIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS ACUTE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHOLELITHIASIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DRUG-INDUCED LIVER INJURY
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEPATIC FAILURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
HEPATITIS ACUTE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERBILIRUBINAEMIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERTRANSAMINASAEMIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LIVER DISORDER
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
ACTINIC KERATOSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ACUTE FEBRILE NEUTROPHILIC DERMATOSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CUTANEOUS VASCULITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DECUBITUS ULCER
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DERMATITIS ALLERGIC
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DERMATITIS EXFOLIATIVE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DRUG ERUPTION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EXFOLIATIVE RASH
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERHIDROSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PRURITUS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RASH
subjects affected / exposed	5 / 532 (0.94%)	5 / 540 (0.93%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	5 / 6	3 / 5	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RASH ERYTHEMATOUS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RASH MACULAR
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RASH MACULO-PAPULAR
subjects affected / exposed	0 / 532 (0.00%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RASH PRURITIC
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SKIN ULCER
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TOXIC EPIDERMAL NECROLYSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
ACUTE PRERENAL FAILURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
AZOTAEMIA
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BLADDER PROLAPSE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DYSURIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMATURIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OLIGURIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PROTEINURIA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RENAL ARTERY STENOSIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RENAL COLIC
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	8 / 532 (1.50%)	18 / 540 (3.33%)	14 / 541 (2.59%)
occurrences causally related to treatment / all	1 / 8	4 / 25	3 / 23
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 3
RENAL FAILURE ACUTE
subjects affected / exposed	21 / 532 (3.95%)	16 / 540 (2.96%)	10 / 541 (1.85%)
occurrences causally related to treatment / all	6 / 22	5 / 16	2 / 12
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 1
RENAL FAILURE CHRONIC
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
RENAL IMPAIRMENT
subjects affected / exposed	5 / 532 (0.94%)	2 / 540 (0.37%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	1 / 5	1 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
URINARY BLADDER HAEMORRHAGE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
URINARY RETENTION
subjects affected / exposed	2 / 532 (0.38%)	4 / 540 (0.74%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 2	1 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
HYPERTHYROIDISM
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
THYROID CYST
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	1 / 532 (0.19%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARTHRITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BACK PAIN
subjects affected / exposed	22 / 532 (4.14%)	19 / 540 (3.52%)	10 / 541 (1.85%)
occurrences causally related to treatment / all	2 / 28	1 / 23	1 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BONE LESION
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BONE PAIN
subjects affected / exposed	10 / 532 (1.88%)	6 / 540 (1.11%)	6 / 541 (1.11%)
occurrences causally related to treatment / all	0 / 11	0 / 6	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
CHONDROCALCINOSIS PYROPHOSPHATE
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DUPUYTREN'S CONTRACTURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FIBROMYALGIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FLANK PAIN
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GOUTY ARTHRITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GOUTY TOPHUS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTERVERTEBRAL DISC DEGENERATION
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTERVERTEBRAL DISC DISORDER
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTERVERTEBRAL DISC PROTRUSION
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUMBAR SPINAL STENOSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MONARTHRITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUSCLE HAEMORRHAGE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUSCULAR WEAKNESS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUSCULOSKELETAL PAIN
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MYALGIA
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MYOPATHY
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NECK PAIN
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OSTEOARTHRITIS
subjects affected / exposed	2 / 532 (0.38%)	2 / 540 (0.37%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OSTEOCHONDROSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OSTEOLYSIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OSTEONECROSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OSTEONECROSIS OF JAW
subjects affected / exposed	3 / 532 (0.56%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OSTEOPOROSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OSTEOPOROTIC FRACTURE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PAIN IN EXTREMITY
subjects affected / exposed	0 / 532 (0.00%)	2 / 540 (0.37%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PATHOLOGICAL FRACTURE
subjects affected / exposed	0 / 532 (0.00%)	4 / 540 (0.74%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POLYARTHRITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SOFT TISSUE MASS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPINAL COLUMN STENOSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPINAL DISORDER
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SYNOVIAL CYST
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VERTEBRAL WEDGING
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
ABDOMINAL ABSCESS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL WALL ABSCESS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABSCESS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABSCESS LIMB
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANORECTAL INFECTION BACTERIAL
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
APPENDICITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARTHRITIS BACTERIAL
subjects affected / exposed	5 / 532 (0.94%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARTHRITIS INFECTIVE
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATYPICAL PNEUMONIA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BACTERAEMIA
subjects affected / exposed	3 / 532 (0.56%)	2 / 540 (0.37%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 3	2 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BACTERIAL SEPSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	13 / 532 (2.44%)	6 / 540 (1.11%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	4 / 15	2 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHOPNEUMONIA
subjects affected / exposed	2 / 532 (0.38%)	5 / 540 (0.93%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	1 / 2	5 / 6	1 / 2
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
BRONCHOPULMONARY ASPERGILLOSIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BURSITIS INFECTIVE STAPHYLOCOCCAL
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CAMPYLOBACTER INFECTION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	8 / 532 (1.50%)	3 / 540 (0.56%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	5 / 13	2 / 4	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS INFECTIVE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CLOSTRIDIAL INFECTION
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE COLITIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CYSTITIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEVICE RELATED INFECTION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIARRHOEA INFECTIOUS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIVERTICULITIS
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DOUGLAS' ABSCESS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EMBOLIC PNEUMONIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENDOCARDITIS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENDOCARDITIS BACTERIAL
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENDOCARDITIS STAPHYLOCOCCAL
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENDOPHTHALMITIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENTEROCOCCAL SEPSIS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENTEROCOLITIS INFECTIOUS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EPIGLOTTITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ERYSIPELAS
subjects affected / exposed	3 / 532 (0.56%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ESCHERICHIA SEPSIS
subjects affected / exposed	0 / 532 (0.00%)	3 / 540 (0.56%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ESCHERICHIA URINARY TRACT INFECTION
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FUNGAL INFECTION
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FURUNCLE
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROENTERITIS
subjects affected / exposed	0 / 532 (0.00%)	3 / 540 (0.56%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROENTERITIS SALMONELLA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROENTERITIS VIRAL
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL INFECTION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEPATITIS B
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
HERPES ZOSTER
subjects affected / exposed	3 / 532 (0.56%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 3	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFECTION
subjects affected / exposed	4 / 532 (0.75%)	1 / 540 (0.19%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	1 / 4	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
subjects affected / exposed	4 / 532 (0.75%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 8	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFECTIVE TENOSYNOVITIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFLUENZA
subjects affected / exposed	7 / 532 (1.32%)	3 / 540 (0.56%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	2 / 8	0 / 3	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
INTERVERTEBRAL DISCITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
KLEBSIELLA BACTERAEMIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
KLEBSIELLA INFECTION
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
KLEBSIELLA SEPSIS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LOBAR PNEUMONIA
subjects affected / exposed	8 / 532 (1.50%)	7 / 540 (1.30%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	4 / 9	2 / 7	1 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
LOCALISED INFECTION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	8 / 532 (1.50%)	3 / 540 (0.56%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	3 / 15	1 / 3	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG INFECTION
subjects affected / exposed	3 / 532 (0.56%)	8 / 540 (1.48%)	5 / 541 (0.92%)
occurrences causally related to treatment / all	1 / 3	5 / 9	2 / 6
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 1
LUNG INFECTION PSEUDOMONAL
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
MENINGITIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MENINGITIS CRYPTOCOCCAL
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MENINGOCOCCAL SEPSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
NEUTROPENIC SEPSIS
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	3 / 3	1 / 1	3 / 3
deaths causally related to treatment / all	1 / 1	1 / 1	1 / 1
OESOPHAGEAL CANDIDIASIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ORCHITIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OROPHARYNGEAL CANDIDIASIS
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OSTEOMYELITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIODONTITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIORBITAL ABSCESS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIORBITAL CELLULITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERITONITIS
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMOCOCCAL BACTERAEMIA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMOCOCCAL SEPSIS
subjects affected / exposed	3 / 532 (0.56%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMOCYSTIS JIROVECI PNEUMONIA
subjects affected / exposed	3 / 532 (0.56%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	3 / 3	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
PNEUMONIA
subjects affected / exposed	60 / 532 (11.28%)	48 / 540 (8.89%)	35 / 541 (6.47%)
occurrences causally related to treatment / all	37 / 71	28 / 59	17 / 42
deaths causally related to treatment / all	3 / 6	1 / 2	0 / 0
PNEUMONIA BACTERIAL
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA ESCHERICHIA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA KLEBSIELLA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA LEGIONELLA
subjects affected / exposed	2 / 532 (0.38%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 2	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA PNEUMOCOCCAL
subjects affected / exposed	4 / 532 (0.75%)	2 / 540 (0.37%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	2 / 4	2 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
PNEUMONIA STAPHYLOCOCCAL
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA STREPTOCOCCAL
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA VIRAL
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POST PROCEDURAL SEPSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POSTOPERATIVE ABSCESS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PROSTATIC ABSCESS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PSEUDOMEMBRANOUS COLITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PSEUDOMONAL SEPSIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
PULMONARY TUBERCULOSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PYELONEPHRITIS
subjects affected / exposed	4 / 532 (0.75%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PYELONEPHRITIS ACUTE
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY SYNCYTIAL VIRUS INFECTION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	9 / 532 (1.69%)	5 / 540 (0.93%)	4 / 541 (0.74%)
occurrences causally related to treatment / all	3 / 11	3 / 5	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	17 / 532 (3.20%)	10 / 540 (1.85%)	8 / 541 (1.48%)
occurrences causally related to treatment / all	7 / 25	6 / 12	4 / 10
deaths causally related to treatment / all	3 / 7	1 / 3	2 / 4
SEPTIC SHOCK
subjects affected / exposed	5 / 532 (0.94%)	7 / 540 (1.30%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	4 / 8	1 / 10	0 / 3
deaths causally related to treatment / all	2 / 4	0 / 5	0 / 3
SINUSITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SOFT TISSUE INFECTION
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL BACTERAEMIA
subjects affected / exposed	4 / 532 (0.75%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL IMPETIGO
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	1 / 532 (0.19%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL SEPSIS
subjects affected / exposed	2 / 532 (0.38%)	3 / 540 (0.56%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 4	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
STRONGYLOIDIASIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUBCUTANEOUS ABSCESS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TOOTH ABSCESS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TRACHEOBRONCHITIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TUBERCULOSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TUBERCULOUS PLEURISY
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	8 / 532 (1.50%)	9 / 540 (1.67%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	4 / 8	3 / 10	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	9 / 532 (1.69%)	5 / 540 (0.93%)	3 / 541 (0.55%)
occurrences causally related to treatment / all	2 / 12	1 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION BACTERIAL
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UROSEPSIS
subjects affected / exposed	3 / 532 (0.56%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
WHIPPLE'S DISEASE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
CACHEXIA
subjects affected / exposed	2 / 532 (0.38%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DECREASED APPETITE
subjects affected / exposed	6 / 532 (1.13%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	2 / 7	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEHYDRATION
subjects affected / exposed	7 / 532 (1.32%)	9 / 540 (1.67%)	7 / 541 (1.29%)
occurrences causally related to treatment / all	1 / 8	4 / 13	3 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIABETES MELLITUS
subjects affected / exposed	3 / 532 (0.56%)	2 / 540 (0.37%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	3 / 3	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIABETES MELLITUS INADEQUATE CONTROL
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FAILURE TO THRIVE
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FOOD INTOLERANCE
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GOUT
subjects affected / exposed	3 / 532 (0.56%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	2 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERCALCAEMIA
subjects affected / exposed	5 / 532 (0.94%)	10 / 540 (1.85%)	7 / 541 (1.29%)
occurrences causally related to treatment / all	0 / 6	0 / 10	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERGLYCAEMIA
subjects affected / exposed	4 / 532 (0.75%)	3 / 540 (0.56%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	2 / 5	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERGLYCAEMIC HYPEROSMOLAR NONKETOTIC SYNDROME
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERKALAEMIA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	2 / 541 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERURICAEMIA
subjects affected / exposed	0 / 532 (0.00%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOALBUMINAEMIA
subjects affected / exposed	1 / 532 (0.19%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOCALCAEMIA
subjects affected / exposed	5 / 532 (0.94%)	4 / 540 (0.74%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	1 / 5	0 / 8	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOGLYCAEMIA
subjects affected / exposed	4 / 532 (0.75%)	2 / 540 (0.37%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOKALAEMIA
subjects affected / exposed	6 / 532 (1.13%)	1 / 540 (0.19%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	2 / 7	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOMAGNESAEMIA
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPONATRAEMIA
subjects affected / exposed	6 / 532 (1.13%)	6 / 540 (1.11%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	2 / 7	0 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOPROTEINAEMIA
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IRON DEFICIENCY
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MALNUTRITION
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MARASMUS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
METABOLIC ACIDOSIS
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	1 / 541 (0.18%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
METABOLIC ALKALOSIS
subjects affected / exposed	0 / 532 (0.00%)	1 / 540 (0.19%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SHOCK HYPOGLYCAEMIC
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TETANY
subjects affected / exposed	1 / 532 (0.19%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TYPE 2 DIABETES MELLITUS
subjects affected / exposed	0 / 532 (0.00%)	2 / 540 (0.37%)	0 / 541 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Lenalidomide and Low-Dose Dexamethasone (Rd)	Lenalidomide and Dexamethasone (Rd18)	Melphalan + Prednisone + Thalidomide (MPT)
Total subjects affected by non serious adverse events
subjects affected / exposed	523 / 532 (98.31%)	532 / 540 (98.52%)	532 / 541 (98.34%)
Vascular disorders
DEEP VEIN THROMBOSIS
subjects affected / exposed	40 / 532 (7.52%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	44	0	0
HYPERTENSION
subjects affected / exposed	43 / 532 (8.08%)	27 / 540 (5.00%)	35 / 541 (6.47%)
occurrences all number	45	30	39
HYPOTENSION
subjects affected / exposed	52 / 532 (9.77%)	28 / 540 (5.19%)	35 / 541 (6.47%)
occurrences all number	59	30	38
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	148 / 532 (27.82%)	122 / 540 (22.59%)	123 / 541 (22.74%)
occurrences all number	360	217	211
FATIGUE
subjects affected / exposed	178 / 532 (33.46%)	176 / 540 (32.59%)	153 / 541 (28.28%)
occurrences all number	411	358	287
NON-CARDIAC CHEST PAIN
subjects affected / exposed	31 / 532 (5.83%)	27 / 540 (5.00%)	0 / 541 (0.00%)
occurrences all number	44	33	0
OEDEMA
subjects affected / exposed	38 / 532 (7.14%)	28 / 540 (5.19%)	32 / 541 (5.91%)
occurrences all number	64	33	40
OEDEMA PERIPHERAL
subjects affected / exposed	220 / 532 (41.35%)	168 / 540 (31.11%)	213 / 541 (39.37%)
occurrences all number	417	295	343
PYREXIA
subjects affected / exposed	111 / 532 (20.86%)	94 / 540 (17.41%)	69 / 541 (12.75%)
occurrences all number	165	159	96
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	129 / 532 (24.25%)	94 / 540 (17.41%)	67 / 541 (12.38%)
occurrences all number	199	118	84
DYSPHONIA
subjects affected / exposed	31 / 532 (5.83%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	35	0	0
DYSPNOEA
subjects affected / exposed	112 / 532 (21.05%)	85 / 540 (15.74%)	110 / 541 (20.33%)
occurrences all number	176	124	153
DYSPNOEA EXERTIONAL
subjects affected / exposed	30 / 532 (5.64%)	28 / 540 (5.19%)	0 / 541 (0.00%)
occurrences all number	42	32	0
EPISTAXIS
subjects affected / exposed	32 / 532 (6.02%)	31 / 540 (5.74%)	0 / 541 (0.00%)
occurrences all number	44	39	0
OROPHARYNGEAL PAIN
subjects affected / exposed	32 / 532 (6.02%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	36	0	0
PRODUCTIVE COUGH
subjects affected / exposed	35 / 532 (6.58%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	52	0	0
Psychiatric disorders
ANXIETY
subjects affected / exposed	45 / 532 (8.46%)	36 / 540 (6.67%)	41 / 541 (7.58%)
occurrences all number	54	44	45
CONFUSIONAL STATE
subjects affected / exposed	35 / 532 (6.58%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	40	0	0
DEPRESSION
subjects affected / exposed	66 / 532 (12.41%)	45 / 540 (8.33%)	30 / 541 (5.55%)
occurrences all number	81	54	36
INSOMNIA
subjects affected / exposed	150 / 532 (28.20%)	127 / 540 (23.52%)	53 / 541 (9.80%)
occurrences all number	219	196	58
Investigations
BLOOD CREATININE INCREASED
subjects affected / exposed	39 / 532 (7.33%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	74	0	0
WEIGHT DECREASED
subjects affected / exposed	73 / 532 (13.72%)	78 / 540 (14.44%)	47 / 541 (8.69%)
occurrences all number	105	102	63
Injury, poisoning and procedural complications
CONTUSION
subjects affected / exposed	39 / 532 (7.33%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	56	0	0
FALL
subjects affected / exposed	46 / 532 (8.65%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	63	0	0
Cardiac disorders
ATRIAL FIBRILLATION
subjects affected / exposed	30 / 532 (5.64%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	37	0	0
Nervous system disorders
DIZZINESS
subjects affected / exposed	87 / 532 (16.35%)	70 / 540 (12.96%)	114 / 541 (21.07%)
occurrences all number	107	91	194
DYSGEUSIA
subjects affected / exposed	41 / 532 (7.71%)	45 / 540 (8.33%)	0 / 541 (0.00%)
occurrences all number	56	54	0
HEADACHE
subjects affected / exposed	80 / 532 (15.04%)	52 / 540 (9.63%)	55 / 541 (10.17%)
occurrences all number	120	61	75
HYPOAESTHESIA
subjects affected / exposed	46 / 532 (8.65%)	0 / 540 (0.00%)	40 / 541 (7.39%)
occurrences all number	70	0	56
NEUROPATHY PERIPHERAL
subjects affected / exposed	35 / 532 (6.58%)	0 / 540 (0.00%)	62 / 541 (11.46%)
occurrences all number	93	0	123
PARAESTHESIA
subjects affected / exposed	88 / 532 (16.54%)	74 / 540 (13.70%)	102 / 541 (18.85%)
occurrences all number	143	106	241
PERIPHERAL MOTOR NEUROPATHY
subjects affected / exposed	28 / 532 (5.26%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	53	0	0
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	113 / 532 (21.24%)	93 / 540 (17.22%)	191 / 541 (35.30%)
occurrences all number	219	134	447
SOMNOLENCE
subjects affected / exposed	31 / 532 (5.83%)	0 / 540 (0.00%)	51 / 541 (9.43%)
occurrences all number	35	0	77
TREMOR
subjects affected / exposed	77 / 532 (14.47%)	73 / 540 (13.52%)	100 / 541 (18.48%)
occurrences all number	110	102	169
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	237 / 532 (44.55%)	191 / 540 (35.37%)	219 / 541 (40.48%)
occurrences all number	839	586	602
LEUKOPENIA
subjects affected / exposed	66 / 532 (12.41%)	59 / 540 (10.93%)	92 / 541 (17.01%)
occurrences all number	345	196	438
LYMPHOPENIA
subjects affected / exposed	60 / 532 (11.28%)	43 / 540 (7.96%)	71 / 541 (13.12%)
occurrences all number	219	157	364
NEUTROPENIA
subjects affected / exposed	194 / 532 (36.47%)	177 / 540 (32.78%)	325 / 541 (60.07%)
occurrences all number	955	647	1854
THROMBOCYTOPENIA
subjects affected / exposed	111 / 532 (20.86%)	99 / 540 (18.33%)	132 / 541 (24.40%)
occurrences all number	531	318	428
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	27 / 532 (5.08%)	0 / 540 (0.00%)	35 / 541 (6.47%)
occurrences all number	34	0	42
Eye disorders
CATARACT
subjects affected / exposed	84 / 532 (15.79%)	31 / 540 (5.74%)	0 / 541 (0.00%)
occurrences all number	121	40	0
VISION BLURRED
subjects affected / exposed	30 / 532 (5.64%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	39	0	0
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	68 / 532 (12.78%)	40 / 540 (7.41%)	28 / 541 (5.18%)
occurrences all number	95	59	34
ABDOMINAL PAIN UPPER
subjects affected / exposed	50 / 532 (9.40%)	34 / 540 (6.30%)	29 / 541 (5.36%)
occurrences all number	65	36	32
CONSTIPATION
subjects affected / exposed	233 / 532 (43.80%)	210 / 540 (38.89%)	282 / 541 (52.13%)
occurrences all number	354	296	452
DIARRHOEA
subjects affected / exposed	248 / 532 (46.62%)	205 / 540 (37.96%)	86 / 541 (15.90%)
occurrences all number	656	367	107
DRY MOUTH
subjects affected / exposed	38 / 532 (7.14%)	38 / 540 (7.04%)	62 / 541 (11.46%)
occurrences all number	41	44	70
DYSPEPSIA
subjects affected / exposed	59 / 532 (11.09%)	28 / 540 (5.19%)	36 / 541 (6.65%)
occurrences all number	101	35	43
NAUSEA
subjects affected / exposed	156 / 532 (29.32%)	127 / 540 (23.52%)	163 / 541 (30.13%)
occurrences all number	261	187	233
TOOTHACHE
subjects affected / exposed	28 / 532 (5.26%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	32	0	0
VOMITING
subjects affected / exposed	97 / 532 (18.23%)	66 / 540 (12.22%)	104 / 541 (19.22%)
occurrences all number	151	95	143
Skin and subcutaneous tissue disorders
DRY SKIN
subjects affected / exposed	32 / 532 (6.02%)	30 / 540 (5.56%)	36 / 541 (6.65%)
occurrences all number	36	39	41
ERYTHEMA
subjects affected / exposed	35 / 532 (6.58%)	27 / 540 (5.00%)	0 / 541 (0.00%)
occurrences all number	46	33	0
PRURITUS
subjects affected / exposed	49 / 532 (9.21%)	49 / 540 (9.07%)	0 / 541 (0.00%)
occurrences all number	62	72	0
RASH
subjects affected / exposed	117 / 532 (21.99%)	129 / 540 (23.89%)	91 / 541 (16.82%)
occurrences all number	230	238	161
Renal and urinary disorders
RENAL FAILURE
subjects affected / exposed	27 / 532 (5.08%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	30	0	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	110 / 532 (20.68%)	71 / 540 (13.15%)	67 / 541 (12.38%)
occurrences all number	183	97	88
BACK PAIN
subjects affected / exposed	175 / 532 (32.89%)	137 / 540 (25.37%)	115 / 541 (21.26%)
occurrences all number	282	213	155
BONE PAIN
subjects affected / exposed	83 / 532 (15.60%)	72 / 540 (13.33%)	58 / 541 (10.72%)
occurrences all number	136	104	93
JOINT SWELLING
subjects affected / exposed	29 / 532 (5.45%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	39	0	0
MUSCLE SPASMS
subjects affected / exposed	115 / 532 (21.62%)	102 / 540 (18.89%)	61 / 541 (11.28%)
occurrences all number	181	167	95
MUSCULAR WEAKNESS
subjects affected / exposed	46 / 532 (8.65%)	34 / 540 (6.30%)	28 / 541 (5.18%)
occurrences all number	61	51	43
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	63 / 532 (11.84%)	51 / 540 (9.44%)	39 / 541 (7.21%)
occurrences all number	84	69	45
MUSCULOSKELETAL PAIN
subjects affected / exposed	72 / 532 (13.53%)	58 / 540 (10.74%)	36 / 541 (6.65%)
occurrences all number	106	75	42
MYALGIA
subjects affected / exposed	31 / 532 (5.83%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	43	0	0
NECK PAIN
subjects affected / exposed	43 / 532 (8.08%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	58	0	0
PAIN IN EXTREMITY
subjects affected / exposed	91 / 532 (17.11%)	65 / 540 (12.04%)	60 / 541 (11.09%)
occurrences all number	140	85	78
Infections and infestations
BRONCHITIS
subjects affected / exposed	90 / 532 (16.92%)	57 / 540 (10.56%)	42 / 541 (7.76%)
occurrences all number	157	80	50
GASTROENTERITIS
subjects affected / exposed	35 / 532 (6.58%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	41	0	0
INFLUENZA
subjects affected / exposed	33 / 532 (6.20%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	38	0	0
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	29 / 532 (5.45%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	51	0	0
NASOPHARYNGITIS
subjects affected / exposed	90 / 532 (16.92%)	54 / 540 (10.00%)	33 / 541 (6.10%)
occurrences all number	165	72	44
PNEUMONIA
subjects affected / exposed	29 / 532 (5.45%)	34 / 540 (6.30%)	0 / 541 (0.00%)
occurrences all number	37	38	0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	35 / 532 (6.58%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	54	0	0
RHINITIS
subjects affected / exposed	31 / 532 (5.83%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	38	0	0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	71 / 532 (13.35%)	48 / 540 (8.89%)	31 / 541 (5.73%)
occurrences all number	123	69	42
URINARY TRACT INFECTION
subjects affected / exposed	77 / 532 (14.47%)	59 / 540 (10.93%)	38 / 541 (7.02%)
occurrences all number	133	72	52
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	128 / 532 (24.06%)	115 / 540 (21.30%)	72 / 541 (13.31%)
occurrences all number	219	156	94
HYPERGLYCAEMIA
subjects affected / exposed	61 / 532 (11.47%)	50 / 540 (9.26%)	0 / 541 (0.00%)
occurrences all number	142	158	0
HYPOCALCAEMIA
subjects affected / exposed	60 / 532 (11.28%)	54 / 540 (10.00%)	30 / 541 (5.55%)
occurrences all number	132	104	69
HYPOKALAEMIA
subjects affected / exposed	104 / 532 (19.55%)	62 / 540 (11.48%)	38 / 541 (7.02%)
occurrences all number	200	88	61
HYPOMAGNESAEMIA
subjects affected / exposed	27 / 532 (5.08%)	0 / 540 (0.00%)	0 / 541 (0.00%)
occurrences all number	54	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

08 Feb 2008

1. Added pharmacoeconomic endpoint information 2. Advancements in fluorescence in situ hybridization (FISH) testing for cytogenetics testing caused a change in cytogenetic laboratories for North American and France to compare the latest cell sorting methodology with the current standard FISH performed by a central laboratory 3. Corrected errors in wording and units 4. Added testing of creatinine clearance at Day 1 of each cycle for dose escalation of lenalidomide and melphalan 5. Added emergency procedures 6. Clarified wording for antithrombotic treatment

07 Nov 2008

1. Clarification of efficacy assessments to be performed for Arms Rd, Rd18, and MPT during different phases of the study and when they were performed if there were interruptions in the cycle; 2. Clarification of study drug cycles and procedures for study drug during interruptions of any or all study drugs; 3. Clarification of the mandatory use of central laboratory results for subject eligibility and response assessments 4. Reduction of the washout period for a course of steroid treatment from 28 days to 14 days to allow subjects who were progressing rapidly access to the clinical trial; Addition of routine neurological examinations globally throughout the active treatment phase to provide additional neurological safety information on lenalidomide and thalidomide and as well as additional information when used in combination therapies; 5. Provided investigators with additional guidance on dose modification if a Grade 3 or greater lenalidomide-related hematologic toxicity occurred; 6. Addition of a dosing cap for melphalan to minimize toxicity in subjects weighing greater than 100 kg. Establishment of melphalan dosing criteria for subjects with renal impairment. 7. Allowance of a prednisone tapering per investigator discretion to prevent/minimize toxicity in subjects; 8. Updated and clarified AE and SAE reporting procedures; 9. Updated the risk management appendices for lenalidomide to reflect new animal data and the addition of this information to the subject guidance document as well as subject information sheets for FCBP, females not of childbearing potential, and males; 10. Clarification that only the descriptive system of the EQ-5D was to be used for QOL collection. The descriptive system of the EQ-5D, the 5-question piece of the EQ-5D, was used for converting the information into utilities for economic analysis; 11. Updated the IMWG response criteria for CR and PD.

01 Apr 2011

1. Added information on collection of data during PFS follow-up, specifically data on time to first progression following discontinuation of study medication, on subjects who discontinued early or for reasons other than progression of disease. Added sensitivity analysis based on additional PFS data as described above. 2. Further defined the data collection and analysis for the pharmacoeconomic endpoint 3. Added a secondary endpoint assessing improvement in CRAB criteria for subjects during active treatment phase 4. Added a dexamethasone taper for subjects with withdrawal toxicity 5. Required that Secondary Primary Malignancies (SPMs) be treated as SAEs and reported throughout the study duration from the time of signing the Informed Consent Document (ICD) to the time all subjects were followed for at least 5 years from randomization or had died

25 Mar 2012

1. In addition to the SPM reporting requirements outlined in Amendment No. 3, Amendment No. 4 included mandatory submission of samples and corresponding reports from screening and the SPM diagnosis for subjects who developed hematologic SPMs (including AML, ALL, CLL, MDS, or myeloproliferative disorders). For these hematologic SPMs, samples and reports were to be sent to an independent central reviewer for confirmation. Added mandatory submission of diagnostic reports (eg, pathology, cytogenetics, flow cytometry) from bone marrow aspirate smears collected at screening and from the SPM diagnosis to Celgene or a designee for central review and secondary confirmation for subjects with any SPM (solid tumors and hematologic malignancies). 2. Included collection of blood, bone marrow aspirate smears, saliva, and diagnostic tumor samples from SPM diagnoses for subjects who consented to optional collection of additional samples for exploratory biomarker studies. The purpose of the optional sample collection was to assess the mechanism of action of lenalidomide, to perform exploratory analyses to identify possible markers that correlate with response to lenalidomide, and additional studies to identify genetic aberrations possibly related to the development of SPMs in subjects treated with lenalidomide.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/25184863
http://www.ncbi.nlm.nih.gov/pubmed/27124703
http://www.ncbi.nlm.nih.gov/pubmed/26659916
http://www.ncbi.nlm.nih.gov/pubmed/27325857
http://www.ncbi.nlm.nih.gov/pubmed/25769541
http://www.ncbi.nlm.nih.gov/pubmed/28373701

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Kaplan-Meier Estimates of Progression-free survival (PFS) Based on the Response Assessment by the Independent Review Adjudication Committee (IRAC)

Primary: Kaplan-Meier Estimates of Progression-free survival (PFS) Based on the Response Assessment by the Independent Review Adjudication Committee (IRAC)

Primary: Kaplan-Meier Estimates of PFS Based on the Response Assessment by the Investigator Assessment at the Time of Final Analysis

Primary: Kaplan-Meier Estimates of PFS Based on the Response Assessment by the Investigator Assessment at the Time of Final Analysis

Secondary: Kaplan Meier Estimates of Overall Survival (OS) at the Time of Final Analysis

Secondary: Kaplan Meier Estimates of Overall Survival (OS) at the Time of Final Analysis

Secondary: Percentage of Participants With an Objective Response based on IRAC Review

Secondary: Percentage of Participants With an Objective Response based on IRAC Review

Secondary: Percentage of Participants With an Objective Response based on Investigator Assessment at the Time of Final Analysis

Secondary: Percentage of Participants With an Objective Response based on Investigator Assessment at the Time of Final Analysis

Secondary: Kaplan Meier estimates of duration of myeloma response as determined by the IRAC

Secondary: Kaplan Meier estimates of duration of myeloma response as determined by the IRAC

Secondary: Kaplan Meier estimates of duration of myeloma response as determined by an investigator assessment at the Time of Final Analysis

Secondary: Kaplan Meier estimates of duration of myeloma response as determined by an investigator assessment at the Time of Final Analysis

Secondary: Time to first response based on the review by the IRAC

Secondary: Time to first response based on the review by the IRAC

Secondary: Time to first response based on the investigator asssessment at the Time of Final Analysis

Secondary: Time to first response based on the investigator asssessment at the Time of Final Analysis

Secondary: Kaplan Meier Estimates of Time to Treatment Failure (TTF)

Secondary: Kaplan Meier Estimates of Time to Treatment Failure (TTF)

Secondary: Kaplan Meier Estimates of Time to Treatment Failure (TTF) at the Time of Final Analysis

Secondary: Kaplan Meier Estimates of Time to Treatment Failure (TTF) at the Time of Final Analysis

Secondary: Kaplan Meier Estimates for time to second-line anti-myeloma treatment (AMT)

Secondary: Kaplan Meier Estimates for time to second-line anti-myeloma treatment (AMT)

Secondary: Kaplan Meier Estimates for time to second-line AMT at the Time of Final Analysis

Secondary: Kaplan Meier Estimates for time to second-line AMT at the Time of Final Analysis

Secondary: Percentage of Participants with a myeloma response by adverse risk cytogenetic risk category based on IRAC review

Secondary: Percentage of Participants with a myeloma response by adverse risk cytogenetic risk category based on IRAC review

Secondary: Percentage of participants with a myeloma response by favorable hyperdiploidy risk cytogenetic risk category based on IRAC Review

Secondary: Percentage of participants with a myeloma response by favorable hyperdiploidy risk cytogenetic risk category based on IRAC Review

Secondary: Percentage of participants with a myeloma response by normal risk cytogenetic risk category based on IRAC Review

Secondary: Percentage of participants with a myeloma response by normal risk cytogenetic risk category based on IRAC Review

Secondary: Percentage of participants with a myeloma response by uncertain risk cytogenetic risk category based on IRAC Review

Secondary: Percentage of participants with a myeloma response by uncertain risk cytogenetic risk category based on IRAC Review

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Domain

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Role Functioning Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Role Functioning Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Cognitive Functioning Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Cognitive Functioning Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Social Functioning Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Social Functioning Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Fatigue Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Fatigue Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Pain Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Pain Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Nausea/Vomiting Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Nausea/Vomiting Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Insomnia Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Insomnia Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Appetite Loss Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Appetite Loss Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Constipation Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Constipation Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Diarrhea Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Diarrhea Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Financial Difficulties Domain

Secondary: Change From Baseline in the EORTC QLQ-C30 Financial Difficulties Domain

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Disease Symptoms Scale

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Disease Symptoms Scale

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Side Effects Treatment Scale

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Side Effects Treatment Scale

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Future Perspective Scale

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Future Perspective Scale

Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Body Image Scale