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Clinical Trial Results:
A Phase III, Multicentre, Randomised, Double-Blind, Placebo-Controlled, 3-Arm Parallel Group Study to Determine the Efficacy and Safety of Lenalidomide (Revlimid) in Combination with Melphalan and Prednisone Versus Placebo Plus Melphalan and Prednisone in Subjects with Newly Diagnosed Multiple Myeloma Who Are 65 Years of Age or Older

Summary
EudraCT number	2006-001865-41
Trial protocol	NL BE FR DE IE CZ AT GB DK SE IT GR ES
Global end of trial date	13 Apr 2016

Results information
Results version number	v1(current)
This version publication date	29 Apr 2017
First version publication date	29 Apr 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-015

ISRCTN number

US NCT number

NCT00405756

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, 01 888-290-1599, ClinicalTrialDisclosure@Celgene.com

Scientific contact

Annette Ervin-Haynes, 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

17 May 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Apr 2016

Was the trial ended prematurely?

Main objective of the trial

To determine the efficacy of melphalan, prednisone and Revlimid (MPR) compared to placebo plus MP in subjects with newly diagnosed multiple myeloma (MM) who are 65 years of age or older.

Protection of trial subjects

Patient Confidentiality, Personal Data Protection and Biomarker Consent

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Feb 2007

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

Australia: 34

Country: Number of subjects enrolled

Austria: 23

Country: Number of subjects enrolled

Belgium: 26

Country: Number of subjects enrolled

Czech Republic: 36

Country: Number of subjects enrolled

Denmark: 13

Country: Number of subjects enrolled

France: 10

Country: Number of subjects enrolled

Georgia: 20

Country: Number of subjects enrolled

Germany: 60

Country: Number of subjects enrolled

Greece: 32

Country: Number of subjects enrolled

Ireland: 1

Country: Number of subjects enrolled

Italy: 70

Country: Number of subjects enrolled

Poland: 33

Country: Number of subjects enrolled

Spain: 17

Country: Number of subjects enrolled

Sweden: 3

Country: Number of subjects enrolled

Turkey: 15

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

Ukraine: 15

Country: Number of subjects enrolled

Israel: 18

Country: Number of subjects enrolled

Russian Federation: 20

Country: Number of subjects enrolled

Belarus: 5

Country: Number of subjects enrolled

Switzerland: 1

Country: Number of subjects enrolled

Netherlands: 2

Worldwide total number of subjects

459

EEA total number of subjects

331

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

453

85 years and over

Subject disposition

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Recruitment details

This study was conducted in Europe, Australia, and Israel. Subjects were randomized at 82 sites (70 in Europe, 8 in Australia, and 4 in Israel). Subjects were ≥ 65 years old with newly diagnosed multiple myeloma who were ineligible for high-dose chemotherapy supported stem cell therapy.

Screening details

Subjects were stratified at randomization by age (≤ 75 years versus > 75 years) and stage according to the International Staging System (ISS; Stages I or II versus Stage III)

Period 1 title

Induction plus Maintenance Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Blinding implementation details

The investigator, subject, and sponsor personnel responsible for the conduct of the study were blinded to each subject’s treatment assignments during the subject’s participation in the treatment period to minimize bias in the assessment of the data. The treatment assignment for each subject who discontinued the treatment period was unblinded by the investigator to guide future therapy. The blind was broken for those in the treatment period who were assessed by the investigator with PD.

Are arms mutually exclusive

Yes

Induction + Maintenance Phase: MPR+R

Arm description

During the double-blind induction phase, subjects received melphalan (M) 0.18 mg/kg by mouth (PO) daily (QD) on days 1 to 4 plus prednisone (P) 2 mg/kg PO QD on Days 1 to 4 of each 28-day cycle and lenalidomide (R) 10 mg PO QD on Days 1 to 21 of each 28-day cycle for up to 9 cycles (MPR), followed by maintenance therapy with single-agent lenalidomide (R) 10 mg PO QD on Days 1 to 21 of each 28-day cycle from cycle 10 until progressive disease (PD). If participants experienced PD during the induction or maintenance treatment periods, they were given the option to be treated with lenalidomide 25 mg PO QD on Days 1 to 21 of each 28-day cycle with or without dexamethasone 40 mg PO QD on days 1 to 4, 9 to 12 and 17 to 20 of each 28-day cycle at the discretion of the investigator.

Arm type

Experimental

Investigational medicinal product name

Melphalan

Investigational medicinal product code

Other name

Alkeran

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.18 mg/kg tablet PO QD on days 1 to 4 of each 28-day cycle up to 9 cycles

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

Other name

Revlimid

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

10 mg capsule PO QD on Days 1 to 21 of each 28-day cycle up to 9 cycles during induction period and 10 mg capsule PO QD on Days 1 to 21 of each 28-day cycle from cycle 10 until disease progression

Investigational medicinal product name

Predisone

Investigational medicinal product code

Other name

Prednisone

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 mg/kg tablet PO QD on days 1 to 4 of each 28-day cycle up to 9 cycles

Induction + Maintenance Phase: MPR+p

Arm description

During the double-blind induction phase, participants received melphalan (M) 0.18 mg/kg PO QD on days 1 to 4 plus prednisone (P) 2 mg/kg PO QD on days 1 to 4 of each 28-day cycle and lenalidomide (R) 10 mg PO QD on days 1 to 21 of each 28-day cycle for up to 9 cycles, followed by maintenance therapy with identically matching placebo (p) PO QD on days 1 to 21 of each 28-day cycle from cycle 10 until PD. If participants experienced PD during the induction or maintenance treatment periods, they were given the option to be treated with lenalidomide 25 mg PO QD on days 1 to 21 of each 28-day cycle with or without dexamethasone 40 mg PO QD on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle at the discretion of the investigator.

Arm type

Experimental

Investigational medicinal product name

Melphalan

Investigational medicinal product code

Other name

Alkeran

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.18 mg/kg tablet PO QD on days 1 to 4 of each 28-day cycle up to 9 cycles

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

Other name

Revlimid

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

10 mg capsule PO QD on Days 1 through 21 of each 28 day cycle for up to 9 cycles during induction period

Investigational medicinal product name

Predisone

Investigational medicinal product code

Other name

Prednisone

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 mg/kg tablet PO QD on days 1 to 4 of each 28-day cycle

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects in treatment arm MPR+p received placebo capsules PO QD on Days 1 through 21 of each 28-day cycle from cycle 10 until disease progression.

Induction + Maintenance Phase: MPp+p

Arm description

During the double-blind induction phase, subjects received melphalan (M) 0.18 mg/kg PO QD on days 1 to 4 plus prednisone (P) 2 mg/kg PO QD on days 1 to 4 of each 28-day cycle and identically matching placebo (p) PO QD on days 1 to 21 of each 28-day cycle for up to 9 cycles (MPp), followed by maintenance therapy with identically matching placebo (p) PO QD on days 1 to 21 of each 28-day cycle from cycle 10 until PD. If participants experienced PD during the induction or maintenance treatment periods, they were given the option to be treated with lenalidomide 25 mg PO QD on days 1 to 21 of each 28-day cycle with or without dexamethasone 40 mg PO QD on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle at the discretion of the investigator.

Arm type

Active comparator

Investigational medicinal product name

Melphalan

Investigational medicinal product code

Other name

Alkeran

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.18 mg/kg tablet PO QD on days 1 to 4 of each 28-day cycle

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Placebo

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects in treatment arm MPp+p received placebo capsules PO QD on days 1 to 21 of each 28-day cycle for up to 9 cycles, followed by maintenance therapy with identically matching placebo capsules PO QD on days 1 to 21 of each 28-day cycle from cycle 10 until PD.

Investigational medicinal product name

Predisone

Investigational medicinal product code

Other name

Prednisone

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 mg/kg tablet PO on days 1 to 4 of each 28-day cycle

Number of subjects in period 1	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Started	152	153	154
Safety population	150 ^[1]	152 ^[2]	153 ^[3]
Completed Active Treatment Per Protocol	66 ^[4]	99 ^[5]	116 ^[6]
Completed	152	153	154

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: There was no defined completion for the induction-maintenance phase. Subjects continued in the induction-maintenance phase until disease progression, then were given the option to continue to the open-label extension phase.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: There was no defined completion for the induction-maintenance phase. Subjects continued in the induction-maintenance phase until disease progression, then were given the option to continue to the open-label extension phase.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: There was no defined completion for the induction-maintenance phase. Subjects continued in the induction-maintenance phase until disease progression, then were given the option to continue to the open-label extension phase, however, this was optional.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: There was no defined completion for the induction-maintenance phase. Subjects continued in the induction-maintenance phase until disease progression, then were given the option to continue to the open-label extension phase.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: There was no defined completion for the induction-maintenance phase. Subjects continued in the induction-maintenance phase until disease progression, then were given the option to continue to the open-label extension phase.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: There was no defined completion for the induction-maintenance phase. Subjects continued in the induction-maintenance phase until disease progression, then were given the option to continue to the open-label extension phase.

Period 2 title

Open-label Extension Phase (OLEP)

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

MPR+R

Arm description

Subjects who were treated with MPR+R and experienced PD during the induction or maintenance treatment periods were given the option to be treated with lenalidomide 25 mg PO QD on Days 1 to 21 of each 28-day cycle with or without dexamethasone 40 mg PO QD on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle at the discretion of the investigator.

Arm type

Experimental

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

Other name

Revlimid

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

25 mg PO QD on Days 1 to 21 of each 28-day cycle

MPR+p

Arm description

Subjects who were treated with MPR+p and experienced PD during the induction or maintenance treatment periods were given the option to be treated with lenalidomide 25 mg PO QD on Days 1 to 21 of each 28-day cycle with or without dexamethasone 40 mg PO QD on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle at the discretion of the investigator.

Arm type

Experimental

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

Other name

Revlimid

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

25 mg PO QD on Days 1 to 21 of each 28-day cycle

MPp+p

Arm description

Subjects who were treated with MPp+p and experienced PD during the induction or maintenance treatment periods were given the option to be treated with lenalidomide 25 mg PO QD on Days 1 to 21 of each 28-day cycle with or without dexamethasone 40 mg PO QD on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle at the discretion of the investigator.

Arm type

Active comparator

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

Other name

Revlimid

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

25 mg PO QD on Days 1 to 21 of each 28-day cycle

Number of subjects in period 2 ^[7]	MPR+R	MPR+p	MPp+p
Started	24	53	81
Completed	24	53	81

Notes
[7] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: The open label extension phase was optional.

Period 3 title

Follow-up Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

MPR+R

Arm description

Subjects in the follow-up phase were followed for overall survival and subsequent anti-myeloma treatment regimens until all subjects were followed for at least 5 years from randomization or had died.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

MPR+p

Arm description

Subjects in the follow-up phase were followed for overall survival and subsequent anti-myeloma treatment regimens until all subjects were followed for at least 5 years from randomization or had died.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

MPp+p

Arm description

Subjects in the follow-up phase were followed for overall survival and subsequent anti-myeloma treatment regimens until all subjects were followed for at least 5 years from randomization or had died.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 3 ^[8]	MPR+R	MPR+p	MPp+p
Started	19	41	61
Completed	23	30	33
Not completed	88	91	87
Adverse event, serious fatal	77	85	82
Lost to follow-up	11	6	5
Joined	92	80	59
Induction-Maintance Period	92	80	59

Notes
[8] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Subjects from both the induction-maintenance phase and the OLEP were observed and monitored during the follow-up periods; therefore the number of subjects in each arm of the trial from both periods were reported in the follow-up phase and were greater than that in the OLEP.

Baseline characteristics

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Reporting group title

Induction + Maintenance Phase: MPR+R

Reporting group description

Reporting group title

Induction + Maintenance Phase: MPR+p

Reporting group description

Reporting group title

Induction + Maintenance Phase: MPp+p

Reporting group description

Reporting group values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p	Total
Number of subjects	152	153	154	459
Age Categorical
Units: Subjects
<=75 years	116	116	116	348
>75 years	36	37	38	111
Age Continuous
Units: years
arithmetic mean (standard deviation)	72 ( 5.33 )	72.1 ( 5.2 )	72 ( 5.26 )	-
Gender, Male/Female
Units: Subjects
Female	81	71	79	231
Male	71	82	75	228
Race/Ethnicity, Customized
Units: Subjects
White	151	151	151	453
Black	1	0	0	1
Hispanic	0	0	1	1
Asian / Pacific Islander	0	0	0	0
American Indian or Alaska Native	0	0	0	0
Other	0	2	2	4
International Staging System (ISS)
The ISS divides myeloma into 3 stages based only on the serum beta-2 microglobulin and serum albumin levels. Stage I: Serum beta-2 microglobulin is less than 3.5 (mg/L) and the albumin level is above 3.5 (g/L); Stage II: Neither stage I or III, meaning that either the beta-2 microglobulin level is between 3.5 and 5.5 (with any albumin level), or the albumin level is below 3.5 while the beta-2 microglobulin is less than 3.5 Stage III: Serum beta-2 microglobulin is greater than 5.5.
Units: Subjects
Stage I	28	32	28	88
Stage II	50	47	48	145
Stage III	74	74	78	226
Creatinine Clearance
Units: Subjects
>=60 ml/min	72	83	77	232
<60 ml/min	78	69	76	223
Missing	2	1	1	4
Beta2 Microglobulin
Units: Subjects
>5.5 mg/L	74	78	67	219
<=5.5 mg/L	77	75	87	239
Missing	1	0	0	1
Albumin
Units: Subjects
>35 g/L	87	82	81	250
<= 35 g/L	63	70	72	205
Missing	2	1	1	4
C-reactive Protein
Units: Subjects
>4 mg/L	64	56	64	184
<=4 mg/L	84	93	89	266
Missing	4	4	1	9
Multiple Myeloma Subtype
Units: Subjects
Immunoglobulin A (IgA)	39	38	33	110
Other	108	112	116	336
Missing	5	3	5	13
Karnofsky Performance Scale
Karnofsky Performance Scale classifies patients according to their functional impairment. Scores range from 0-100, the lower the score, the greater the impairment and worse prospect of survival for most serious illnesses.
Units: Subjects
60 = needs occasional assistance;can care for self	13	16	11	40
70 = Cares for self;unable to do active work	40	20	22	82
80 = Normal activity with efforts; some symptoms	37	54	43	134
90 = able to carry on activities, minor complaints	40	40	51	131
100 = normal; no complaints	21	23	27	71
Missing	1	0	0	1
Study Specific Characteristic \| Weight
Units: kilograms
arithmetic mean (standard deviation)	73.5 ( 14.77 )	72 ( 12.79 )	72.1 ( 15.2 )	-
Study Specific Characteristic \| Height
Units: centimeter
arithmetic mean (standard deviation)	164.8 ( 9.81 )	165.3 ( 9.33 )	165.7 ( 9.79 )	-
Study Specific Characteristic \| Systolic Blood Pressure
Units: mmHg
arithmetic mean (standard deviation)	133.9 ( 17.71 )	135.3 ( 18.49 )	136.4 ( 20.13 )	-
Study Specific Characteristic \| Diastolic Blood Pressure
Units: mmHg
arithmetic mean (standard deviation)	78.5 ( 9.53 )	77.2 ( 10.08 )	78.8 ( 10.4 )	-
Study Specific Characteristic \| Temperature
Units: degrees centigrade
arithmetic mean (standard deviation)	36.5 ( 0.41 )	36.5 ( 0.38 )	36.5 ( 0.4 )	-
Study Specific Characteristic \| Pulse
Units: beats per minute
arithmetic mean (standard deviation)	76 ( 9.77 )	77.3 ( 10.5 )	76.3 ( 10.8 )	-
Study Specific Characteristic \| Plasma Cells in the Bone Marrow
Units: percentage of plasma cells
arithmetic mean (standard deviation)	39.7 ( 24.83 )	39.3 ( 25.01 )	37.9 ( 23.65 )	-

End points

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Reporting group title

Induction + Maintenance Phase: MPR+R

Reporting group description

Reporting group title

Induction + Maintenance Phase: MPR+p

Reporting group description

Reporting group title

Induction + Maintenance Phase: MPp+p

Reporting group description

Reporting group title

MPR+R

Reporting group description

Reporting group title

MPR+p

Reporting group description

Reporting group title

MPp+p

Reporting group description

Reporting group title

MPR+R

Reporting group description

Subjects in the follow-up phase were followed for overall survival and subsequent anti-myeloma treatment regimens until all subjects were followed for at least 5 years from randomization or had died.

Reporting group title

MPR+p

Reporting group description

Subjects in the follow-up phase were followed for overall survival and subsequent anti-myeloma treatment regimens until all subjects were followed for at least 5 years from randomization or had died.

Reporting group title

MPp+p

Reporting group description

Subjects in the follow-up phase were followed for overall survival and subsequent anti-myeloma treatment regimens until all subjects were followed for at least 5 years from randomization or had died.

Primary: Kaplan Meier Estimates of Progression-free Survival (PFS) Based on the Response Assessment by the Central Adjudication Committee (CAC) and Food and Drug Administration (FDA) Censoring Rules

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End point title

Kaplan Meier Estimates of Progression-free Survival (PFS) Based on the Response Assessment by the Central Adjudication Committee (CAC) and Food and Drug Administration (FDA) Censoring Rules

End point description

PFS was calculated as the time from randomization to the earlier of the first documentation of progressive disease (PD) as determined by the CAC, or death on study due to any cause. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry [EBMT/IBMTR/ABMTR] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia. Unblinding date. Intent to Treat (ITT) population was defined as all subjects who were randomized, independent of whether they received study treatment or not.

End point type

Primary

End point timeframe

From date of randomization to data cut-off of 11 May 2010; up to 39 months

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: months
median (confidence interval 95%)	31.3 (19.84 to 99999)	14.1 (12.93 to 16.61)	12.9 (11.97 to 15.2)

Statistical Analysis 1

Statistical analysis description

PFS was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.388

Confidence interval

level

95%

sides

2-sided

lower limit

0.274

upper limit

0.55

Notes
[1] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Statistical Analysis 2

Statistical analysis description

PFS was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

< 0.001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.494

Confidence interval

level

95%

sides

2-sided

lower limit

0.344

upper limit

0.695

Notes
[2] - Based on proportional hazard models comparing the functions associated with the treatment arms.

Statistical Analysis 3

Statistical analysis description

PFS was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.118 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.586

upper limit

1.064

Notes
[3] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Primary: Kaplan Meier Estimates of Progression-free Survival Time (PFS) Based on European Medicines Agency (EMA) Guidelines Based on the Response Assessment by the CAC

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End point title

Kaplan Meier Estimates of Progression-free Survival Time (PFS) Based on European Medicines Agency (EMA) Guidelines Based on the Response Assessment by the CAC ^[4]

End point description

PFS was calculated as the time from randomization to the earlier of the first documentation of progressive disease (PD) as determined by the CAC, or death on study due to any cause. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry [EBMT/IBMTR/ABMTR] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia. Unblinding date. ITT population was defined as all subjects who were randomized, independent of whether they received study treatment or not.

End point type

Primary

End point timeframe

Date of randomization to data cut-off of 11 May 2010; up to 39 months

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The primary endpoint compares MPR+R with MP+p and the reasons only two arms are reported. The study was not designed to compare MPR+P with MP+p.

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	154
Units: months
median (confidence interval 95%)	34.1 (25.69 to 99999)	15 (12.3 to 17.24)

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[5]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.455

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

0.627

Notes
[5] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Primary: Kaplan Meier Estimates of Progression-free Survival (PFS) from Start of Maintenance Therapy Period Based on the Response Assessment by the Central Adjudication Committee (CAC)

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End point title

Kaplan Meier Estimates of Progression-free Survival (PFS) from Start of Maintenance Therapy Period Based on the Response Assessment by the Central Adjudication Committee (CAC) ^[6]

End point description

PFS calculated from the start of the Maintenance period to the earlier of the first documentation of progressive disease (PD) as determined by the CAC, or death on study due to any cause. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry [EBMT/IBMTR/ABMTR] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia. ITT population of subjects in Arms MPR+R and MPR+p who entered maintenance within the double-blind treatment period

End point type

Primary

End point timeframe

Approximately week 37 (start of cycle 10) to week 165; up to up to data cut-off of 11 May 2010

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The primary endpoint compares MPR+R with MP+p and the reasons only two arms are reported. The study was not designed to compare MPR+P with MP+p.

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p
Number of subjects analysed	88	94
Units: weeks
median (confidence interval 95%)	112 (83.29 to 99999)	32.3 (23.57 to 52.14)

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[7]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.214

upper limit

0.541

Notes
[7] - P-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Primary: Kaplan Meier Estimates of Progression-free Survival (PFS) from Start of Maintenance Therapy Period Based Investigator Assessment at a Later Cut-off date of 30 April 2013

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End point title

Kaplan Meier Estimates of Progression-free Survival (PFS) from Start of Maintenance Therapy Period Based Investigator Assessment at a Later Cut-off date of 30 April 2013 ^[8]

End point description

End point type

Primary

End point timeframe

From date of randomization to data cut-off of 30 April 2013; up to 75 months

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The primary endpoint and primary analysis of PFS compared MPR+R with MP+p and the statistical analysis was reported. The additional PFS data from start of maintenance therapy was analyzed by the investigators, but was not considered part of the primary analysis and rationale to the statistical analysis being reported between the MPR+R group and the MPR+p group.

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p
Number of subjects analysed	88	94
Units: months
median (confidence interval 95%)	21.4 (16.58 to 35.72)	6.4 (4.64 to 9.08)

Statistical Analysis 1

Statistical analysis description

PFS was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[9]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.394

Confidence interval

level

95%

sides

2-sided

lower limit

0.275

upper limit

0.564

Notes
[9] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups

Primary: Kaplan Meier Estimates of PFS Time Based on the Investigator Response Assessment at a later cut off date

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End point title

Kaplan Meier Estimates of PFS Time Based on the Investigator Response Assessment at a later cut off date

End point description

PFS was calculated as the time from randomization to the earlier of the first documentation of progressive disease (PD) as determined by the investigator, or death on study due to any cause. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry [EBMT/IBMTR/ABMTR] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia. ITT was defined as all subjects who were randomized, independent of whether they received study treatment or not.

End point type

Primary

End point timeframe

From February 2007 to May 2016; study duration of 111 months; date maximum treatment duration for MPR + R = 428 weeks, MPR + p = 162.7 weeks and MPp + P = 160.3 weeks

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: months
median (confidence interval 95%)	27.4 (21.25 to 34.34)	14.3 (13.19 to 15.69)	13.7 (12.01 to 14.77)

Statistical Analysis 1

Statistical analysis description

PFS was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[10]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.373

Confidence interval

level

95%

sides

2-sided

lower limit

0.276

upper limit

0.505

Notes
[10] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Statistical Analysis 2

Statistical analysis description

PFS was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[11]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.482

Confidence interval

level

95%

sides

2-sided

lower limit

0.354

upper limit

0.654

Notes
[11] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Secondary: Kaplan Meier Estimates of Overall Survival (OS) Based on the Investigator Response Assessment

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End point title

Kaplan Meier Estimates of Overall Survival (OS) Based on the Investigator Response Assessment

End point description

OS 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. 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 available, or clinical cut-off date, if it was earlier. ITT population was defined as all subjects who were randomized, independent of whether they received study treatment or not.

End point type

Secondary

End point timeframe

From Feb 2007 to May 2016; study duration of 111 months

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: months
median (confidence interval 95%)	55.9 (49.11 to 64.34)	53.1 (43.06 to 60.63)	53.9 (47.11 to 64.11)

Statistical Analysis 1

Statistical analysis description

OS was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.704 ^[12]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.056

Confidence interval

level

95%

sides

2-sided

lower limit

0.798

upper limit

1.396

Notes
[12] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Statistical Analysis 2

Statistical analysis description

OS was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.67 ^[13]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.942

Confidence interval

level

95%

sides

2-sided

lower limit

0.714

upper limit

1.241

Notes
[13] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Secondary: Kaplan Meier Estimates of Time to Progression (TTP) Based on Response Assessment by the Central Adjudication Committee (CAC)

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End point title

Kaplan Meier Estimates of Time to Progression (TTP) Based on Response Assessment by the Central Adjudication Committee (CAC)

End point description

TTP was the time between randomization and disease progression as determined by the CAC. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry [EBMT/IBMTR/ABMTR] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia. ITT population was defined as all participants who were randomized, independent of whether they received study treatment or not.

End point type

Secondary

End point timeframe

up to 165 weeks; up to 11 May 2010 cutoff

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: weeks
median (confidence interval 95%)	148.1 (100 to 99999)	62.7 (57.14 to 74.14)	61.3 (52.29 to 70.14)

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[14]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.337

Confidence interval

level

95%

sides

2-sided

lower limit

0.231

upper limit

0.493

Notes
[14] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[15]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.414

Confidence interval

level

95%

sides

2-sided

lower limit

0.284

upper limit

0.603

Notes
[15] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.223 ^[16]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.826

Confidence interval

level

95%

sides

2-sided

lower limit

0.606

upper limit

1.125

Notes
[16] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Secondary: Kaplan Meier Estimates of Time to Progression (TTP) Based on the Investigator Assessment with a later cut-off date

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End point title

Kaplan Meier Estimates of Time to Progression (TTP) Based on the Investigator Assessment with a later cut-off date

End point description

TTP was the time between randomization and disease progression as determined by the investigator. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry [EBMT/IBMTR/ABMTR] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia. ITT population was defined as all participants who were randomized, independent of whether they received study treatment or not.

End point type

Secondary

End point timeframe

Date of randomization to data cut-off of 30 April 2013; up to 75 months

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: months
median (confidence interval 95%)	29.1 (22.53 to 39.51)	14.6 (13.39 to 16.18)	13.9 (12.73 to 14.9)

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[17]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.325

Confidence interval

level

95%

sides

2-sided

lower limit

0.235

upper limit

0.451

Notes
[17] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[18]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.404

Confidence interval

level

95%

sides

2-sided

lower limit

0.29

upper limit

0.563

Notes
[18] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.112 ^[19]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.802

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

1.054

Notes
[19] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Secondary: Percentage of subjects in Disease Response Categories Representing Their Best Response During the Double-blind Treatment Period

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End point title

Percentage of subjects in Disease Response Categories Representing Their Best Response During the Double-blind Treatment Period

End point description

Best response was determined by the Central Assessment Committee (CAC) based on the European Group for Blood and Marrow Transplantation (EBMT) criteria: Complete Response (CR)-absence of serum and urine monoclonal paraprotein for 6 weeks, plus no increase in size or number of bone lesions, plus other factors); Partial Response (PR)-not all CR criteria, plus >=50% reduction in serum monoclonal paraprotein plus others; Stable Disease (SD)- not PR or PD; Progressive Disease (PD)- reappearance of monoclonal paraprotein, bone lesions, other; Not Evaluable (NE). ITT population was defined as all participants who were randomized, independent of whether they received study treatment or not.

End point type

Secondary

End point timeframe

Up to 165 weeks; up to data cut off of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: percentage of participants
number (not applicable)
Complete response (CR)	9.9	3.3	3.2
Partial response (PR)	67.1	64.7	46.8
Stable disease (SD)	18.4	26.1	45.5
Progressive disease (PD)	0	1.3	0
Response not evaluable (NE)	4.6	4.6	4.5

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[20]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[20] - P-value calculation excludes the category - Response not evaluable (NE)

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009 ^[21]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[21] - P-value calculation excludes the category - Response not evaluable (NE)

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[22]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[22] - P-value calculation excludes the category - Response not evaluable (NE)

Statistical Analysis 4

Statistical analysis description

Based on dichotomized response: 1) CR or PR 2) SD or PD or NE

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

3.34

Confidence interval

level

95%

sides

2-sided

lower limit

2.04

upper limit

5.47

Statistical Analysis 5

Statistical analysis description

Based on dichotomized response: 1) CR or PR 2) SD or PD or NE

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.096

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.58

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

2.62

Statistical Analysis 6

Statistical analysis description

Based on dichotomized response: 1) CR or PR 2) SD or PD or NE

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

2.12

Confidence interval

level

95%

sides

2-sided

lower limit

1.33

upper limit

3.37

Secondary: Percentage of Participants in Disease Response Categories Representing Their Best Response During the Treatment Period (Induction plus maintenance) based on the investigators assessment

Top of page

End point title

Percentage of Participants in Disease Response Categories Representing Their Best Response During the Treatment Period (Induction plus maintenance) based on the investigators assessment

End point description

Best response was determined by the Investigators based on the European Group for Blood and Marrow Transplantation (EBMT) criteria: Complete Response (CR)-absence of serum and urine monoclonal paraprotein for 6 weeks, plus no increase in size or number of bone lesions, plus other factors); Partial Response (PR)-not all CR criteria, plus >=50% reduction in serum monoclonal paraprotein plus others; Stable Disease (SD)- not PR or PD; Progressive Disease (PD)- reappearance of monoclonal paraprotein, bone lesions, other; Not Evaluable (NE). ITT was defined as all participants who were randomized, independent of whether they received study treatment or not.

End point type

Secondary

End point timeframe

Response assessed every 28 days up to 3 years, then every 56 days; From date of first dose of study drug to 30 April 2013; up to 75 months

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: percentage of subjects
number (not applicable)
CR or PR	78.9	75.8	54.5
CR	19.7	11.1	5.8
PR	59.2	64.7	48.7
SD	15.8	20.3	40.9
PD	0	1.3	0
Response not evaluable (NE)	5.3	2.6	4.5

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.031

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Statistical Analysis 4

Statistical analysis description

Dichotomized Response 1) CR or PR 2) SD or PD or NE

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

3.13

Confidence interval

level

95%

sides

2-sided

lower limit

1.89

upper limit

5.17

Statistical Analysis 5

Statistical analysis description

Dichotomized Response 1) CR or PR 2) SD or PD or NE

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.584

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

2.05

Statistical Analysis 6

Statistical analysis description

Dichotomized Response 1) CR or PR 2) SD or PD or NE

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

2.61

Confidence interval

level

95%

sides

2-sided

lower limit

1.6

upper limit

4.25

Secondary: Time to First Response

Top of page

End point title

Time to First Response

End point description

Time to first response was defined as the time from the start of treatment until first response as assessed by the Central Assessment Committee (CAC) based on European Group for Blood and Marrow Transplantation (EBMT) criteria. Participants who had achieved at least a PR or CR at the time of the analysis.

End point type

Secondary

End point timeframe

Response assessed every 28 days up to 3 years, then every 56 days; Up to 66 weeks; up to data cut-off of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	117	104	77
Units: weeks
median (full range (min-max))	8.1 (3.9 to 38)	8.1 (3.7 to 28.1)	12.3 (4.1 to 66.1)

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

194

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[23]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[23] - Rank Sum Test

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.607 ^[24]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[24] - Rank Sum Test

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[25]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[25] - Rank Sum Test

Secondary: Time to First Response based On a later cut-off date

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End point title

Time to First Response based On a later cut-off date

End point description

Time to first 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 investigators review. Participants who had achieved at least a PR or CR at the time of the analysis.

End point type

Secondary

End point timeframe

Response assessed every 28 days up to 3 years, then every 56 days; From date of first dose of study drug to 30 April 2013; up to 75 months

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	120	116	84
Units: months
median (full range (min-max))	2.8 (1.1 to 34.6)	2.7 (1 to 10.4)	3.7 (1.8 to 19.6)

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.014 ^[26]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[26] - Rank Sum Test

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

236

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.156 ^[27]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[27] - Rank Sum Test

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[28]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[28] - Rank Sum Test

Secondary: Kaplan Meier Estimates for Duration of Response as Determined by the Central Adjudication Committee (CAC)

Top of page

End point title

Kaplan Meier Estimates for Duration of Response as Determined by the Central Adjudication Committee (CAC)

End point description

Duration of myeloma response was defined as the time from the initial response date to the earlier of progressive disease (PD) as determined by the CAC or death on study. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry [EBMT/IBMTR/ABMTR] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia. ITT population who achieved a PR or CR at the time of analysis.

End point type

Secondary

End point timeframe

Up to 149 weeks; up to data cut-off of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	117	104	77
Units: weeks
median (confidence interval 95%)	121.6 (96 to 99999)	56.1 (52.14 to 64.29)	55.4 (44.14 to 76.14)

Statistical Analysis 1

Statistical analysis description

Duration of Response (DOR) was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

194

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[29]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.348

Confidence interval

level

95%

sides

2-sided

lower limit

0.228

upper limit

0.531

Notes
[29] - The p-value is based on unstratified log rank test of Kaplan Meier curve differences between the treatment groups.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[30]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.419

Confidence interval

level

95%

sides

2-sided

lower limit

0.281

upper limit

0.623

Notes
[30] - The p-value is based on unstratified log rank test of Kaplan Meier curve differences between the treatment groups.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.302 ^[31]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.825

Confidence interval

level

95%

sides

2-sided

lower limit

0.571

upper limit

1.191

Notes
[31] - The p-value is based on unstratified log rank test of Kaplan Meier curve differences between the treatment groups.

Secondary: Kaplan Meier Estimates for Duration of Myeloma Response as determined by the investigators review with a later cut-off date

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End point title

Kaplan Meier Estimates for Duration of Myeloma Response as determined by the investigators review with a later cut-off date

End point description

Duration of myeloma response was defined as the time from the initial response date to the disease progression or death on study, whichever occurred first. PD was based on the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry [EBMT/IBMTR/ABMTR] criteria. PD criteria includes increasing monoclonal paraprotein levels, bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia. Includes participants who achieved at least a CR or PR. There were 2 participants in Arm MPR+R and 3 participants in Arm MPR+p who were assessed by investigators with a response to treatment (CR or PR) but who were excluded from the duration of response analysis because they had no measurable disease at baseline.

End point type

Secondary

End point timeframe

Response assessed every 28 days up to 3 years, then every 56 days; From date of first dose of study drug to 30 April 2013; up to 75 months

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	118	113	84
Units: months
median (confidence interval 95%)	26.5 (19.41 to 35.76)	12.4 (11.18 to 13.85)	12 (9.47 to 14.54)

Statistical Analysis 1

Statistical analysis description

DOR was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[32]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.259

upper limit

0.529

Notes
[32] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Statistical Analysis 2

Statistical analysis description

DOR was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

231

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[33]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.433

Confidence interval

level

95%

sides

2-sided

lower limit

0.307

upper limit

0.612

Notes
[33] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Statistical Analysis 3

Statistical analysis description

DOR was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.344 ^[34]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.857

Confidence interval

level

95%

sides

2-sided

lower limit

0.622

upper limit

1.181

Notes
[34] - The p-value is based on unstratified log rank test of Kaplan-Meier curve differences between the treatment groups.

Secondary: Kaplan Meier Estimates for Time to Next Antimyeloma Therapy

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End point title

Kaplan Meier Estimates for Time to Next Antimyeloma Therapy

End point description

Time to the next antimyeloma therapy was defined as time from randomization to the start of another non-protocol antimyeloma therapy. Subjects who do not receive another anti-myeloma therapy were censored at the last assessment or follow-up visit known to have received no new therapy. ITT was defined as all participants who were randomized, independent of whether they received study treatment or not.

End point type

Secondary

End point timeframe

Up to 75 months; 30 April 2013 cut-off

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: months
median (confidence interval 95%)	28 (22.7 to 39.64)	15.2 (14.08 to 17.5)	15.3 (14.08 to 16.68)

Statistical Analysis 1

Statistical analysis description

Time to next anti-myeloma therapy was compared between treatment arms using the unstratified log-rank test. A Cox proportional hazards model was used to estimate relative risk hazard rate (risk) ratio along with 95% CIs.

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[35]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.413

Confidence interval

level

95%

sides

2-sided

lower limit

0.312

upper limit

0.547

Notes
[35] - The p-value is based on unstratified log rank test of Kaplan Meier curve differences between the treatment groups.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[36]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.495

Confidence interval

level

95%

sides

2-sided

lower limit

0.373

upper limit

0.656

Notes
[36] - The p-value is based on unstratified log rank test of Kaplan Meier curve differences between the treatment groups.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.174 ^[37]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.842

Confidence interval

level

95%

sides

2-sided

lower limit

0.656

upper limit

1.08

Notes
[37] - The p-value is based on unstratified log rank test of Kaplan Meier curve differences between the treatment groups.

Secondary: Number of Subjects with Adverse Events (AEs) During the Induction-Maintenance Period

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End point title

Number of Subjects with Adverse Events (AEs) During the Induction-Maintenance Period

End point description

End point type

Secondary

End point timeframe

Time of first dose of study drug to 30 days after the last dose of study drug plus follow up period; maximum exposure to Lenalidomide/Placebo in MPR + R and and MPp+p = 190 days and MPR + p = 189 days; maximum exposure to Melphalan in any arm was 39 days.

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	150	152	153
Units: subjects
>=1 adverse event (AE)	150	151	153
>=1 CTCAE grade 3-4 AE	139	131	107
>=1 CTCAE grade 5 AE	11	8	7
>=1 serious AE (SAE)	79	66	57
>=1 AE related to Lenaldomide/Placebo	148	145	131
>=1 AE related to Melphalan	140	134	126
>=1AE related to Prednisone	88	94	94
>=1 Grade 3-4 AE related to Lenaldomide/Placebo	132	118	67
>=1 Grade 3-4 AE related to Melphalan	118	110	61
>=1 Grade 3-4 AE related to Prednisone	33	29	21
>=1 Grade 5 AE related to Lenalidomide/Placebo	4	2	2
>=1 Grade 5 AE related to Melphalan	4	1	3
>=1 Grade 5 AE related to Prednisone	1	1	1
>=1 SAE related to Lenalidomide/Placebo	43	34	10
>=1 SAE related to Melphalan	30	24	11
>=1 SAE related to Prednisone	20	16	5
>=1 AE leading to Lenalidomide/Placebo withdrawal	40	26	14
>=1 AE leading to Melphalan withdrawal	20	20	10
>=1 AE leading to Prednisone withdrawal	19	20	10
>=1 AE leading to Lenalidomide/Plac dose reduction	76	70	26
>=1 AE leading to Melphalan dose reduction	46	59	21
>=1 AE leading to Prednisone dose reduction	13	7	6
>=1 AE leading to Lenalidomide/Plac dose interrupt	99	85	52
>=1 AE leading to Melphalan dose interruption	5	2	0
>=1 AE leading to Prednisone dose interruption	25	38	15

No statistical analyses for this end point

Secondary: Number of Subjects with AEs During the Open-Label Extension Phase (OLEP)

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End point title

Number of Subjects with AEs During the Open-Label Extension Phase (OLEP)

End point description

A TEAE is as 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. Dose reduction includes reduction with or without interruption. 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 was defined as all randomized subjects who received at least one dose of study treatment

End point type

Secondary

End point timeframe

Time of first dose of study drug during the OLEP up to 30 days after the last dose of study drug; maximum exposure to Lenalidomide was 1239 days

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	23	53	80
Units: Subjects
>=1 adverse event (AE)	23	50	78
>=1 CTCAE grade 3-4 AE	18	40	73
>=1 CTCAE grade 5 AE	2	10	7
>=1 serious AE (SAE)	11	21	39
>=1 AE related to Lenalidomide	20	47	72
>=1 Grade 3-4 AE related to Lenalidomide	14	37	64
>=1 Grade 5 AE related to Lenalidomide	0	0	3
>=1 SAE related to Lenalidomide	7	5	13
>=1 AE leading to Lenalidomide withdrawal	3	9	14
>=1 AE leading to Lenalidomide dose reduction	8	14	20
>=1 AE leading to Lenalidomide dose interrupt	14	36	51

No statistical analyses for this end point

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Quality of Life Scale

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End point title

Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Quality of Life Scale

End point description

EORTC QLC-C30 is a 30-item questionnaire to assess the quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); two used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to a 0-100 scale; where a higher score indicates a better quality of life. Data up to cycle 19 are presented due to small sample of subjects after cycle 19. ITT population was defined as all subjects who were randomized, independent of whether they received study treatment or not.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16 and 19; Up to 30 April 2013 data cut-off

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=111,119,124)	1.9 ( 26.27 )	6.3 ( 18.29 )	6.1 ( 19.48 )
Cycle 7 - approximately Month 7 (n=96,108,109)	8.3 ( 25.07 )	7.7 ( 22.97 )	4.3 ( 24 )
Cycle 10 -approximately Month 10 (n=85,87,97)	12.2 ( 25.08 )	8.5 ( 24.77 )	6 ( 24.52 )
Cycle 13 - approximately Month 13 (n=70,70,79)	8.6 ( 28.05 )	8.7 ( 24.09 )	5.3 ( 22.41 )
Cycle 16 approximately Month 16 (n=61,51,63)	11.1 ( 24.89 )	7.7 ( 26.07 )	7.9 ( 25.81 )
Cycle 19 approximately Month 16 (n=50,36,43)	5.2 ( 24.73 )	8.8 ( 25.58 )	8.1 ( 23.67 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

= 0.1589 ^[39]

Method

t-test, 2-sided

Confidence interval

Notes
[38] - P-values reported from change from baseline at cycle 4 only
[39] - The p-value is calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

P-value

= 0.1379 ^[41]

Method

t-test, 2-sided

Confidence interval

Notes
[40] - P-values reported from change from baseline at cycle 4 only
[41] - The p-value is calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[42]

P-value

= 0.9399 ^[43]

Method

t-test, 2-sided

Confidence interval

Notes
[42] - P-values reported from change from baseline at cycle 4 only
[43] - The p-value is calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Physical Functioning Scale

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End point title

Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Physical Functioning Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged and transformed to a 0-100 scale where a higher score indicates a better level of physical functioning. Data up to cycle 19 are presented due to small sample of participants after cycle 19. ITT Population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16 and 19; Up to 30 April 2013 data cut-off

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	117	125	129
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=117,125,129)	2 ( 23.78 )	3.9 ( 20.24 )	4.6 ( 18.75 )
Cycle 7 - approximately Month 7 (n= 100, 112,111)	8.4 ( 22.85 )	7.5 ( 22.37 )	3.7 ( 22.02 )
Cycle 10 - approximately Month 10 (n = 89,96,96)	8.3 ( 22.83 )	8.4 ( 25.52 )	5.1 ( 20.42 )
Cycle 13 - approximately Month 13 (n=75, 74, 80)	9 ( 23.71 )	9.6 ( 25.41 )	3.1 ( 19.75 )
Cycle 16 - approximately Month 16 (n=64, 54, 65)	10.3 ( 24.99 )	8.6 ( 23.27 )	0.7 ( 20.6 )
Cycle 19 - approximately Month 19 (n= 53,39,43)	9.9 ( 21.42 )	7.6 ( 22.91 )	7.2 ( 19.65 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

P-value

= 0.3372 ^[45]

Method

t-test, 2-sided

Confidence interval

Notes
[44] - P-values reported from change from baseline at cycle 4 only
[45] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

242

Analysis specification

Pre-specified

Analysis type

superiority ^[46]

P-value

= 0.482 ^[47]

Method

t-test, 2-sided

Confidence interval

Notes
[46] - P-values reported from change from baseline at cycle 4 only
[47] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

superiority ^[48]

P-value

= 0.8006 ^[49]

Method

t-test, 2-sided

Confidence interval

Notes
[48] - P-values reported from change from baseline at cycle 4 only
[49] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Role Functioning Scale

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End point title

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Role Functioning Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to 0-100 scale; a higher score indicates a higher level of role functioning. Data reported up to cycle 16 on role functioning scale. ITT population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13 and 16; up to data cutoff of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=119,127,130)	1.8 ( 33.18 )	3 ( 30.75 )	7.4 ( 26.34 )
Cycle 7 - approximately Month 7 (n=99,112,113)	5.7 ( 35.57 )	8 ( 32.42 )	6.9 ( 31.16 )
Cycle 10 - approximately Month 10 (n=86,95,95)	9.3 ( 35.76 )	7.5 ( 36.29 )	5.6 ( 31.29 )
Cycle 13 - approximately Month 13 (n=74,74,82)	9.7 ( 40.36 )	11.7 ( 33.42 )	5.7 ( 30.68 )
Cycle 16 - approximately Month 16 (n=64,53,63)	12.2 ( 40.09 )	8.5 ( 34.22 )	7.1 ( 31.93 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[50]

P-value

= 0.1391 ^[51]

Method

t-test, 2-sided

Confidence interval

Notes
[50] - P-value provided at Cycle 4 only.
[51] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[52]

P-value

= 0.7702 ^[53]

Method

t-test, 2-sided

Confidence interval

Notes
[52] - P-value provided at Cycle 4 only.
[53] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[54]

P-value

= 0.2167 ^[55]

Method

t-test, 2-sided

Confidence interval

Notes
[54] - P-value reported at Cycle 4 only
[55] - P-value calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Emotional Functioning Scale

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End point title

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Emotional Functioning Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged and transformed to 0-100 scale; a higher score indicates a higher level of emotional functioning. Data reported up to cycle 16 on emotional functioning scale. ITT Population

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; up to data cut off of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=115,125,128)	4.8 ( 25 )	2.7 ( 22.59 )	6.8 ( 18.75 )
Cycle 7 - approximately Month 7 (n=98,111,112)	8.8 ( 24.94 )	4.2 ( 20.38 )	5 ( 21.56 )
Cycle 10 - approximately Month 10 (n=86,92,97)	9 ( 23.28 )	1.6 ( 22.07 )	4.7 ( 22.05 )
Cycle 13 - approximately Month 13 (n=73,73,83)	8.2 ( 24.59 )	1.1 ( 21.78 )	6.6 ( 21.78 )
Cycle 16 - approximately Month 16 (n=63,52,63)	9.9 ( 23.23 )	-0.2 ( 21.57 )	6.9 ( 19.72 )

Statistical Analysis

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.4649 ^[57]

Method

t-test, 2-sided

Confidence interval

Notes
[56] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[57] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[58]

P-value

= 0.5118 ^[59]

Method

t-test, 2-sided

Confidence interval

Notes
[58] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[59] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[60]

P-value

= 0.1188 ^[61]

Method

t-test, 2-sided

Confidence interval

Notes
[60] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[61] - P-value calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Cognitive Functioning Scale

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End point title

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Cognitive Functioning Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to 0-100 scale; higher score indicates a higher level of cognitive functioning. Data reported up to cycle 16 on cognitive functioning scale. ITT population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; Up to data cut-off 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=115,125,128)	0.3 ( 21.51 )	-2 ( 21.33 )	1.3 ( 16.68 )
Cycle 7 - approximately Month 7 (n=98,111,113)	2.9 ( 22.31 )	0.1 ( 17.33 )	0.7 ( 18.42 )
Cycle 10 - approximately Month 10 (n=87,92,97)	1 ( 22.64 )	-4.4 ( 19.89 )	-2.7 ( 20.65 )
Cycle 13 - approximately Month 13 (n=73,73,83)	0 ( 21.34 )	-3 ( 23.78 )	-1.4 ( 17.69 )
Cycle 16 - approximately Month 16 (n=63,52,63)	0.3 ( 22.29 )	-3.5 ( 27.48 )	-4 ( 18.13 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[62]

P-value

= 0.6798 ^[63]

Method

t-test, 2-sided

Confidence interval

Notes
[62] - P-values reported from change from baseline at cycle 4 only
[63] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[64]

P-value

= 0.4081 ^[65]

Method

t-test, 2-sided

Confidence interval

Notes
[64] - P-values reported from change from baseline at cycle 4 only
[65] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[66]

P-value

= 0.17 ^[67]

Method

t-test, 2-sided

Confidence interval

Notes
[66] - P-value provided only at Cycle 4
[67] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Fatigue Scale

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End point title

Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Fatigue Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to a 0-100 scale; a higher score indicates a higher level of fatigue. Data up to cycle 19 are presented due to small sample of participants after cycle 19.

End point type

Secondary

End point timeframe

Baseline (Day 0), Cycles 4, 7, 10, 13, 16 and 19; up to data cut-off 30 April 2013

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	117	125	128
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=117,125,128)	-3 ( 25.65 )	-5.8 ( 24.1 )	-5.1 ( 24.42 )
Cycle 7 - approximately Month 7 (n=100,112,109)	-8.1 ( 23.06 )	-9.2 ( 26.23 )	-6.4 ( 26.97 )
Cycle 10 - approximately Month 10 (n = 88, 86, 95)	-6.7 ( 27.47 )	-7.4 ( 29.6 )	-6.9 ( 28.5 )
Cycle 13 - approximately Month 13 ( n= 74, 74, 79)	-7.7 ( 25.65 )	-11.2 ( 29.91 )	-7.3 ( 27.64 )
Cycle 16 - approximately Month 16 (n = 64, 54, 64)	-10.2 ( 26.83 )	-10.5 ( 28.85 )	-4.3 ( 25.64 )
Cycle 19 - approximately Month 19 (n = 53, 39, 42)	-8.5 ( 29.72 )	-5.4 ( 30.8 )	-9.3 ( 27.85 )

Statistical Analysis

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

245

Analysis specification

Pre-specified

Analysis type

superiority ^[68]

P-value

= 0.5146 ^[69]

Method

t-test, 2-sided

Confidence interval

Notes
[68] - P-values reported from change from baseline at cycle 4 only
[69] - The p-value was calculated based on a pooled t-test comparing two treatment groups.

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

242

Analysis specification

Pre-specified

Analysis type

superiority ^[70]

P-value

= 0.3839 ^[71]

Method

t-test, 2-sided

Confidence interval

Notes
[70] - P-values reported from change from baseline at cycle 4 only
[71] - The p-value was calculated based on a pooled t-test comparing two treatment groups.

Statistical Analysis

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

253

Analysis specification

Pre-specified

Analysis type

superiority ^[72]

P-value

= 0.8192 ^[73]

Method

t-test, 2-sided

Confidence interval

Notes
[72] - P-values reported from change from baseline at cycle 4 only
[73] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Nausea and Vomiting Scale

Top of page

End point title

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Nausea and Vomiting Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to a 0-100 scale; a higher score indicates a higher level of nausea and vomiting. Data reported up to cycle 16 on nausea/vomiting scale. ITT population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; up to data cut off of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=120,127,130)	3.3 ( 19.4 )	-1.3 ( 17.14 )	0 ( 17.36 )
Cycle 7 - approximately Month 7 (n=99,112,112)	0.5 ( 14.57 )	-0.7 ( 19.94 )	0.7 ( 14.73 )
Cycle 10 - approximately Month 10 (n=87,95,97)	1.9 ( 16.75 )	-1.4 ( 19.4 )	0.3 ( 14.23 )
Cycle 13 - approximately Month 13 (n=75,72,83)	0.7 ( 13.55 )	-3 ( 19.65 )	-0.4 ( 12.48 )
Cycle 16 - approximately Month 16 (n=64,52,62)	1 ( 12.9 )	-4.2 ( 18.65 )	-1.3 ( 9.21 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[74]

P-value

= 0.1525 ^[75]

Method

t-test, 2-sided

Confidence interval

Notes
[74] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[75] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[76]

P-value

= 0.0467 ^[77]

Method

t-test, 2-sided

Confidence interval

Notes
[76] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[77] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[78]

P-value

= 0.5428 ^[79]

Method

t-test, 2-sided

Confidence interval

Notes
[78] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[79] - P-value calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Pain Scale

Top of page

End point title

Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Pain Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale ( from1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to a 0-100 scale; a higher score indicates a higher level of pain. Data up to cycle 19 are presented due to small sample of participants after cycle 19. ITT Population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13,16 and 19; up to data cut off 30 April 2013

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	117	125	128
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n= 117, 125, 128)	-13.8 ( 32.77 )	-13.9 ( 33.72 )	-13.3 ( 29.38 )
Cycle 7 - approximately Month 7 ( n=100, 112, 112)	-18.3 ( 36.04 )	-17.9 ( 31.38 )	-11.9 ( 33.37 )
Cycle 10 - approximately Month 10 (n=89, 96, 98)	-17.2 ( 35.13 )	-14.1 ( 37.33 )	-8.7 ( 31.68 )
Cycle 13 - approximately Month 13 (n=74, 74, 80)	-14.4 ( 40.1 )	-14.9 ( 33.28 )	-12.3 ( 27.4 )
Cycle 16 - approximately Month 16 (n=64, 54, 65)	-21.6 ( 32.75 )	-11.1 ( 32.69 )	-12.8 ( 30.87 )
Cycle 19 - approximately Month 19 (n=53, 39, 43)	-19.2 ( 33.87 )	-13.3 ( 36.71 )	-17.8 ( 33.22 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

245

Analysis specification

Pre-specified

Analysis type

superiority ^[80]

P-value

= 0.8932 ^[81]

Method

t-test, 2-sided

Confidence interval

Notes
[80] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[81] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

253

Analysis specification

Pre-specified

Analysis type

superiority ^[82]

P-value

= 0.8838 ^[83]

Method

t-test, 2-sided

Confidence interval

Notes
[82] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[83] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

242

Analysis specification

Pre-specified

Analysis type

superiority ^[84]

P-value

= 0.9911

Method

t-test, 2-sided

Confidence interval

Notes
[84] - P-value included at Cycle 4 (Change from Cycle 4 reported)

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Dyspnoea Scale

Top of page

End point title

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Dyspnoea Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to 0-100 scale; a higher score indicates a higher level of dyspnoea. Data reported up to cycle 16 on dyspnoea scale. ITT Population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; Data as of 11 May 2010 cutoff

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=117,126,126)	-2.6 ( 29.74 )	-6.4 ( 32.04 )	0 ( 23.48 )
Cycle 7 - approximately Month 7 (n=100,110,110)	-1.7 ( 28.18 )	-8.5 ( 32.07 )	2.1 ( 20.82 )
Cycle 10 - approximately Month 10 (n=86,93,96)	-4.3 ( 30.6 )	-4.3 ( 35.87 )	3.8 ( 25.07 )
Cycle 13 - approximately Month 13 (n=73,73,81)	-5 ( 30.26 )	-2.3 ( 30.6 )	0 ( 22.35 )
Cycle 16 - approximately Month 16 (n=62,53,62)	-3.2 ( 29.39 )	-6.3 ( 32.07 )	1.6 ( 22.92 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[85]

P-value

= 0.4556 ^[86]

Method

t-test, 2-sided

Confidence interval

Notes
[85] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[86] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[87]

P-value

= 0.3411 ^[88]

Method

t-test, 2-sided

Confidence interval

Notes
[87] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[88] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[89]

P-value

= 0.0739 ^[90]

Method

t-test, 2-sided

Confidence interval

Notes
[89] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[90] - P-value calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Insomnia Scale

Top of page

End point title

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Insomnia Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to a 0-100 scale; a higher score for a symptom scale like the insomnia scale indicates a higher level of insomnia. Data reported up to cycle 16 on insomnia scale. ITT Population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; Data as of 11 May 2010 cutoff

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=118,124,128)	2 ( 33.56 )	-1.6 ( 31.77 )	-5 ( 27.77 )
Cycle 7 - approximately Month 7 (n=100,109,111)	-1 ( 29.76 )	-6.4 ( 27.02 )	-5.7 ( 32.06 )
Cycle 10 - approximately Month 10 (n=87,94,96)	-5 ( 28.99 )	-2.5 ( 25.04 )	-1.7 ( 32.58 )
Cycle 13 - approximately Month 13 (n=75,73,83)	-4.9 ( 29.86 )	0.9 ( 29.38 )	-6.8 ( 29.8 )
Cycle 16 - approximately Month 16 (n=64,53,63)	-4.7 ( 32.46 )	-0.6 ( 32.36 )	-3.7 ( 31.18 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[91]

P-value

= 0.078 ^[92]

Method

t-test, 2-sided

Confidence interval

Notes
[91] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[92] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[93]

P-value

= 0.3933 ^[94]

Method

t-test, 2-sided

Confidence interval

Notes
[93] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[94] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[95]

P-value

= 0.3749 ^[96]

Method

t-test, 2-sided

Confidence interval

Notes
[95] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[96] - P-value calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Appetite Loss Scale

Top of page

End point title

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Appetite Loss Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to a 0-100 scale; a higher score for a symptom scale like the appetite loss scale indicates a higher level of appetite loss. Data reported up to cycle 16 on appetite loss scale. ITT Population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; up to data cut off of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=119,125,130)	1.7 ( 36.54 )	1.9 ( 34.73 )	-5.6 ( 25.96 )
Cycle 7 - approximately Month 7 (n=99,111,111)	-3.7 ( 33.64 )	-5.7 ( 31.75 )	-5.7 ( 27.66 )
Cycle 10 - approximately Month 10 (n=87,93,96)	-5 ( 33.15 )	-5.4 ( 29.2 )	-8 ( 29.32 )
Cycle 13 - approximately Month 13 (n=75,72,83)	-6.2 ( 36.23 )	-8.8 ( 30.13 )	-4.8 ( 32.15 )
Cycle 16 - approximately Month 16 (n=64,52,63)	-7.8 ( 36.01 )	-16 ( 35.24 )	-6.4 ( 28.62 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[97]

P-value

= 0.0678 ^[98]

Method

t-test, 2-sided

Confidence interval

Notes
[97] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[98] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[99]

P-value

= 0.9674 ^[100]

Method

t-test, 2-sided

Confidence interval

Notes
[99] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[100] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[101]

P-value

= 0.0511 ^[102]

Method

t-test, 2-sided

Confidence interval

Notes
[101] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[102] - P-value calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Constipation Scale

Top of page

End point title

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Constipation Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to 0-100 scale; a higher score for a symptom scale like the constipation scale indicates a higher level of constipation. Data reported up to cycle 16 on constipation scale. ITT Population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; up to data cut off of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=114,124,128)	-1.8 ( 34.31 )	4.8 ( 30.86 )	-4.9 ( 27.45 )
Cycle 7 - approximately Month 7 (n=96,111,112)	-3.5 ( 36.35 )	0.6 ( 30.14 )	-2.7 ( 31.05 )
Cycle 10 - approximately Month 10 (n=86,93,97)	-5 ( 34.88 )	-1.1 ( 28.43 )	-1.7 ( 26.95 )
Cycle 13 - approximately Month 13 (n=73,73,81)	-5 ( 31.27 )	-2.7 ( 28.74 )	-3.3 ( 29.16 )
Cycle 16 - approximately Month 16 (n=63,51,62)	-1.6 ( 31.36 )	-5.2 ( 30.82 )	-2.2 ( 32.44 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[103]

P-value

= 0.4226 ^[104]

Method

t-test, 2-sided

Confidence interval

Notes
[103] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[104] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[105]

P-value

= 0.1198 ^[106]

Method

t-test, 2-sided

Confidence interval

Notes
[105] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[106] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[107]

P-value

= 0.0083 ^[108]

Method

t-test, 2-sided

Confidence interval

Notes
[107] - P-value included at Cycle 4 (Change from Cycle 4 reported):
[108] - P-value calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Diarrhoea Scale

Top of page

End point title

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Diarrhoea Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to a 0-100 scale; a higher score for a symptom scale like the diarrhea scale indicates a higher level of diarrhea. Data reported up to cycle 16 on diarrhea scale. ITT Population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; up to data cut off of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=115,125,124)	2.3 ( 28.85 )	1.9 ( 24.06 )	3.2 ( 25.65 )
Cycle 7 - approximately Month 7 (n=98,109,112)	3.4 ( 25.54 )	-1.2 ( 23.09 )	0.9 ( 22.13 )
Cycle 10 - approximately Month 10 (n=87,92,95)	1.1 ( 22.98 )	1.4 ( 20.91 )	0 ( 21.19 )
Cycle 13 - approximately Month 13 (n=73,73,80)	5.5 ( 30.43 )	-1.4 ( 18.78 )	0.8 ( 18.35 )
Cycle 16 - approximately Month 16 (n=63,52,61)	10.6 ( 35.83 )	1.3 ( 19.75 )	0.5 ( 17.74 )

Statistical Analysis

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[109]

P-value

= 0.7984 ^[110]

Method

t-test, 2-sided

Confidence interval

Notes
[109] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[110] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[111]

P-value

= 0.8936 ^[112]

Method

t-test, 2-sided

Confidence interval

Notes
[111] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[112] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[113]

P-value

= 0.6665 ^[114]

Method

t-test, 2-sided

Confidence interval

Notes
[113] - P-value included at Cycle 4 (Change from Cycle 4 reported):
[114] - P-value calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Financial Difficulties Scale

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End point title

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Financial Difficulties Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged, and transformed to a 0-100 scale; a higher score for a problem scale like the financial problems scale indicates a higher level of financial problems. Data reported up to cycle 16 on financial problems scale.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; up to data cut off of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=111,123,125)	2.4 ( 24.91 )	-1.1 ( 19.06 )	-2.9 ( 18.93 )
Cycle 7 - approximately Month 7 (n=94,111,112)	2.1 ( 23.85 )	-0.6 ( 28.07 )	-2.1 ( 22.5 )
Cycle 10 - approximately Month 10 (n=84,92,97)	6 ( 21.44 )	0.7 ( 28.81 )	-1.7 ( 19.47 )
Cycle 13 - approximately Month 13 (n=70,72,83)	4.8 ( 21.45 )	-0.5 ( 28.8 )	-4 ( 26.75 )
Cycle 16 - approximately Month 16 (n=61,52,63)	1.6 ( 20.58 )	-0.6 ( 35.24 )	-5.3 ( 30.06 )

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[115]

P-value

= 0.0636 ^[116]

Method

t-test, 2-sided

Confidence interval

Notes
[115] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[116] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[117]

P-value

= 0.228 ^[118]

Method

t-test, 2-sided

Confidence interval

Notes
[117] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[118] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[119]

P-value

= 0.4443 ^[120]

Method

t-test, 2-sided

Confidence interval

Notes
[119] - P-value included at Cycle 4 (Change from Cycle 4 reported):
[120] - P-value calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in 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 to Cycles 4, 7, 10, 13, 16 and 19 in 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). Data up to cycle 19 are presented due to small sample of participants after cycle 19. ITT Population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16 and 19; up to data cut off of 30 April 2013

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	110	119	126
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=110, 119, 126)	-8.4 ( 19.53 )	-8.8 ( 19.23 )	-5.5 ( 15.79 )
Cycle 7 - approximately Month 7 (n=96, 109, 111)	-9.4 ( 20.94 )	-10.4 ( 22.38 )	-6.2 ( 20.82 )
Cycle 10 - approximately Month 10 (n=86, 92,96)	-8.5 ( 22.44 )	-6 ( 24.47 )	-4.6 ( 19.57 )
Cycle 13 - approximately Month 13 (n=72, 73, 79)	-7.1 ( 25.89 )	-8.9 ( 25.12 )	-6.5 ( 21.58 )
Cycle 16 - approximately Month 16 (n=62, 52, 63)	-10.6 ( 23.69 )	-6.9 ( 25.92 )	-3.8 ( 20.63 )
Cycle 19 - approximately Month 19 (n=51, 37, 43)	-12.4 ( 23.9 )	-7.3 ( 28.46 )	-3.8 ( 23.58 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

236

Analysis specification

Pre-specified

Analysis type

superiority ^[121]

P-value

= 0.2007 ^[122]

Method

t-test, 2-sided

Confidence interval

Notes
[121] - P-values reported from change from baseline at cycle 4 only
[122] - The p-value was calculated based on a pooled t-test comparing two treatment groups.

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority ^[123]

P-value

= 0.903 ^[124]

Method

t-test, 2-sided

Confidence interval

Notes
[123] - P-values reported from change from baseline at cycle 4 only
[124] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

245

Analysis specification

Pre-specified

Analysis type

superiority ^[125]

P-value

= 0.1468 ^[126]

Method

t-test, 2-sided

Confidence interval

Notes
[125] - P-values reported from change from baseline at cycle 4 only
[126] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) In Side Effects of Treatment Scale

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End point title

Change From Baseline to Cycles 4, 7, 10, 13, 16 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) In Side Effects of Treatment Scale

End point description

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. 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. Data up to cycle 19 are presented due to small sample of participants after cycle 19. ITT Population

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; Up to data cut-off of 30 April 2013

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	110	118	124
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=110, 118, 124)	1.1 ( 13.32 )	-0.1 ( 13.26 )	0.4 ( 12.52 )
Cycle 7 - approximately Month 7 (n=95, 108, 110)	0.5 ( 15.34 )	-1.2 ( 14.1 )	1.8 ( 13 )
Cycle 10 - approximately Month 10 (n=86, 90, 95)	-1.7 ( 14.22 )	-0.1 ( 16.2 )	0.9 ( 13.3 )
Cycle 13 - approximately Month 13 (n=72, 72, 78)	-3.9 ( 15.53 )	-1.4 ( 14.69 )	0.3 ( 12.78 )
Cycle 16 - approximately Month 16 (n=62, 51, 62)	-2.3 ( 14.62 )	-2.7 ( 14.01 )	-1.3 ( 11.19 )
Cycle 19 - approximately Month 19 (n=51, 36, 42)	-3.2 ( 14.84 )	-0.6 ( 15.16 )	-0.3 ( 15.55 )

Statistical Analysis

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

234

Analysis specification

Pre-specified

Analysis type

superiority ^[127]

P-value

= 0.6977 ^[128]

Method

t-test, 2-sided

Confidence interval

Notes
[127] - P-values reported from change from baseline at cycle 4 only
[128] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

228

Analysis specification

Pre-specified

Analysis type

superiority ^[129]

P-value

= 0.5072 ^[130]

Method

t-test, 2-sided

Confidence interval

Notes
[129] - P-values reported from change from baseline at cycle 4 only
[130] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

242

Analysis specification

Pre-specified

Analysis type

superiority ^[131]

P-value

= 0.7572 ^[132]

Method

t-test, 2-sided

Confidence interval

Notes
[131] - P-values reported from change from baseline at cycle 4 only
[132] - The p-value was calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) In Future Perspective Scale

Top of page

End point title

End point description

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. 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. Data reported up to cycle 16 for the future perspective scale. ITT Population.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; up to data cut off of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=112,121,124)	4.7 ( 23.74 )	4.3 ( 23.56 )	7.6 ( 22.38 )
Cycle 7 - approximately Month 7 (n=93,108,112)	14.6 ( 24.45 )	7.7 ( 23.86 )	9.8 ( 20.62 )
Cycle 10 - approximately Month 10 (n=83,88,97)	17.3 ( 27.84 )	6.6 ( 22.4 )	14.5 ( 21.73 )
Cycle 13 - approximately Month 13 (n=71,73,81)	17.3 ( 27.15 )	6.3 ( 23.78 )	11.9 ( 24.67 )
Cycle 16 - approximately Month 16 (n=62,52,62)	18.5 ( 25.3 )	7.7 ( 28.49 )	14.4 ( 26.62 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[133]

P-value

= 0.3351 ^[134]

Method

t-test, 2-sided

Confidence interval

Notes
[133] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[134] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[135]

P-value

= 0.8982 ^[136]

Method

t-test, 2-sided

Confidence interval

Notes
[135] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[136] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[137]

P-value

= 0.2624 ^[138]

Method

t-test, 2-sided

Confidence interval

Notes
[137] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[138] - P-value calculated based on a pooled t-test comparing two treatment groups

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) In Body Image Scale

Top of page

End point title

End point description

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. 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. Data presented up to cycle 16 for body image scale. ITT Population

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13, 16; up to data cut off of 11 May 2010

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=110,117,119)	2.1 ( 35.36 )	-0.3 ( 37.27 )	4.5 ( 25.65 )
Cycle 7 - approximately Month 7 (n=88,104,108)	3.8 ( 33.32 )	2.6 ( 37.94 )	5.2 ( 27.78 )
Cycle 10 - approximately Month 10 (n=79,83,94)	7.6 ( 33.32 )	-4 ( 43.69 )	3.9 ( 26.72 )
Cycle 13 - approximately Month 13 (n=68,72,79)	1 ( 31.01 )	-0.5 ( 44.23 )	5.1 ( 32.51 )
Cycle 16 - approximately Month 16 (n=59,52,61)	3.4 ( 32.58 )	6.4 ( 41.25 )	2.7 ( 28.08 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[139]

P-value

= 0.5618 ^[140]

Method

t-test, 2-sided

Confidence interval

Notes
[139] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[140] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPR+p

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority ^[141]

P-value

= 0.6189 ^[142]

Method

t-test, 2-sided

Confidence interval

Notes
[141] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[142] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[143]

P-value

= 0.2532 ^[144]

Method

t-test, 2-sided

Confidence interval

Notes
[143] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[144] - P-value calculated based on a pooled t-test comparing two treatment groups

Secondary: Percentage of participants who received anti-myeloma salvage therapy at the time of progressive disease

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End point title

Percentage of participants who received anti-myeloma salvage therapy at the time of progressive disease

End point description

Anti-myeloma therapies administered during the course of the study included bortezomib, glucocorticoids, lenalidomide, thalidomide, alkylating agents and other antineoplastic agents.

End point type

Secondary

End point timeframe

Following first line therapy including OLEP treatment up to final cut-off date of 17 May 2016; 111 months

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	152	153	154
Units: percentage of subjects
number (not applicable)	57.9	81.7	83.8

No statistical analyses for this end point

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Subjects with Cancer (EORTC QLQ-C30) Social Functioning Scale

Top of page

End point title

Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Subjects with Cancer (EORTC QLQ-C30) Social Functioning Scale

End point description

EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer subjects. Most questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (from 1 'Very Poor' to 7 'Excellent'). Scores were averaged and transformed to a 0-100 scale, with a higher score indicating a better level of social functioning.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 4, 7, 10, 13 and 16

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	115	115	127
Units: units on a scale
arithmetic mean (standard deviation)
Cycle 4 - approximately Month 4 (n=115, 125, 127)	5.1 ( 35.05 )	0.3 ( 26.6 )	6 ( 22.78 )
Cycle 7 - approximately Month 7 (n=98, 111, 112)	8.3 ( 33.87 )	4.4 ( 24.48 )	6.1 ( 26.57 )
Cycle 10 - approximately Month 10 (n=87, 92, 97)	10.9 ( 34.27 )	4.5 ( 29.87 )	4.1 ( 27.22 )
Cycle 13 - approximately Month 13 (n=72, 73, 83)	11.8 ( 32.91 )	7.5 ( 29.8 )	6.2 ( 27.63 )
Cycle 16 - approximately Month 16 (n=63, 52, 63)	13.2 ( 33.35 )	6.1 ( 30.79 )	9.8 ( 28.66 )

Statistical Analysis 1

Comparison groups

Induction + Maintenance Phase: MPR+R v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

242

Analysis specification

Pre-specified

Analysis type

superiority ^[145]

P-value

= 0.798 ^[146]

Method

t-test, 2-sided

Confidence interval

Notes
[145] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[146] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 2

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPR+R

Number of subjects included in analysis

230

Analysis specification

Pre-specified

Analysis type

superiority ^[147]

P-value

= 0.2305 ^[148]

Method

t-test, 2-sided

Confidence interval

Notes
[147] - P-value included at Cycle 4 (Change from Cycle 4 reported)
[148] - P-value calculated based on a pooled t-test comparing two treatment groups

Statistical Analysis 3

Statistical analysis description

P-value included at Cycle 4 (Change from Cycle 4 reported)

Comparison groups

Induction + Maintenance Phase: MPR+p v Induction + Maintenance Phase: MPp+p

Number of subjects included in analysis

242

Analysis specification

Pre-specified

Analysis type

superiority ^[149]

P-value

= 0.0654

Method

t-test, 2-sided

Confidence interval

Notes
[149] - P-value calculated based on a pooled t-test comparing two treatment groups

Other pre-specified: Percentage of participants with second primary malignancies during the entire course of the trial

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End point title

Percentage of participants with second primary malignancies during the entire course of the trial

End point description

Second primary malignancies were monitored as events of interest and reported as serious adverse events throughout the course of the trial. Safety population includes participants who took at least one dose of study drug.

End point type

Other pre-specified

End point timeframe

Date of first dose of study drug through the end of the follow-up period; up to 111 months

End point values	Induction + Maintenance Phase: MPR+R	Induction + Maintenance Phase: MPR+p	Induction + Maintenance Phase: MPp+p
Number of subjects analysed	150	152	153
Units: Percentage of subjects
number (not applicable)
Hematologic malignancies	6	5.3	1.3
Solid tumors	4.7	7.9	2.6
Invasive second primary malignancies	10.7	12.5	3.9
Non-invasive second primary malignancies	3.3	3.9	5.2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first dose of study drug through to 30 days after the last dose

Adverse event reporting additional description

During the induction-maintenance period there was a maximum exposure to Lenalidomide/Placebo in MPR + R and MPp+p = 190 days and MPR + p = 189 days; maximum exposure to Melphalan in any arm was 39 days. During the OLEP period there was a maximum exposure to Lenalidomide was 1239 days.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

10.0

Reporting group title

Induction + Maintenance MPR+R

Reporting group description

Reporting group title

Induction + Maintenance MPR+p

Reporting group description

Reporting group title

Induction + Maintenance MPp+p

Reporting group description

Reporting group title

Open-Label Extension MPR+R

Reporting group description

For subjects who were treated with MPR+R and experienced PD during the induction or maintenance treatment periods, were given the option to be treated with lenalidomide 25 mg PO QD on Days 1 to 21 of each 28-day cycle with or without dexamethasone 40 mg PO QD on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle at the discretion of the investigator.

Reporting group title

Open-Label Extension MPR+p

Reporting group description

For subjects who were treated with MPR+p and experienced PD during the induction or maintenance treatment periods, were given the option to be treated with lenalidomide 25 mg PO QD on Days 1 to 21 of each 28-day cycle with or without dexamethasone 40 mg PO QD on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle at the discretion of the investigator.

Reporting group title

Open-Label Extension MPp+p

Reporting group description

For subjects who were treated with MPp+p and experienced PD during the induction or maintenance treatment periods, were given the option to be treated with lenalidomide 25 mg PO QD on Days 1 to 21 of each 28-day cycle with or without dexamethasone 40 mg PO QD on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle at the discretion of the investigator.

Serious adverse events	Induction + Maintenance MPR+R	Induction + Maintenance MPR+p	Induction + Maintenance MPp+p	Open-Label Extension MPR+R	Open-Label Extension MPR+p	Open-Label Extension MPp+p
Total subjects affected by serious adverse events
subjects affected / exposed	79 / 150 (52.67%)	66 / 152 (43.42%)	57 / 153 (37.25%)	11 / 23 (47.83%)	21 / 53 (39.62%)	39 / 80 (48.75%)
number of deaths (all causes)	11	8	7	2	10	7
number of deaths resulting from adverse events	4	2	3	0	0	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACUTE MYELOID LEUKAEMIA
subjects affected / exposed	4 / 150 (2.67%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 4	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BASAL CELL CARCINOMA
subjects affected / exposed	1 / 150 (0.67%)	1 / 152 (0.66%)	1 / 153 (0.65%)	1 / 23 (4.35%)	0 / 53 (0.00%)	3 / 80 (3.75%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	1 / 1	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BOWEN'S DISEASE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BREAST CANCER
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHIAL CARCINOMA
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
COLON CANCER
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
KERATOACANTHOMA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LENTIGO MALIGNA STAGE UNSPECIFIED
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LEUKAEMIA PLASMACYTIC
subjects affected / exposed	0 / 150 (0.00%)	2 / 152 (1.32%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2
LIGHT CHAIN DISEASE
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LUNG NEOPLASM MALIGNANT
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
MULTIPLE MYELOMA
subjects affected / exposed	0 / 150 (0.00%)	3 / 152 (1.97%)	2 / 153 (1.31%)	1 / 23 (4.35%)	2 / 53 (3.77%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 2	0 / 1	0 / 2	0 / 0
MYELODYSPLASTIC SYNDROME
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NASAL CAVITY CANCER
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PLASMACYTOMA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PROSTATE CANCER
subjects affected / exposed	1 / 150 (0.67%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RECTAL CANCER
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RECTAL CANCER METASTATIC
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL CELL CARCINOMA STAGE I
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA OF SKIN
subjects affected / exposed	1 / 150 (0.67%)	1 / 152 (0.66%)	0 / 153 (0.00%)	1 / 23 (4.35%)	0 / 53 (0.00%)	3 / 80 (3.75%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	1 / 1	0 / 0	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
T-CELL TYPE ACUTE LEUKAEMIA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
AORTIC DISSECTION
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIOVASCULAR INSUFFICIENCY
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CIRCULATORY COLLAPSE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
DEEP VEIN THROMBOSIS
subjects affected / exposed	1 / 150 (0.67%)	6 / 152 (3.95%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	2 / 2	6 / 7	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERTENSION
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	2 / 153 (1.31%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERIPHERAL ISCHAEMIA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
THROMBOSIS
subjects affected / exposed	2 / 150 (1.33%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VASCULITIS
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VENOUS THROMBOSIS
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	0 / 150 (0.00%)	2 / 152 (1.32%)	1 / 153 (0.65%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHEST DISCOMFORT
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHEST PAIN
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHILLS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEATH
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
FACE OEDEMA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FATIGUE
subjects affected / exposed	4 / 150 (2.67%)	2 / 152 (1.32%)	1 / 153 (0.65%)	2 / 23 (8.70%)	2 / 53 (3.77%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	3 / 4	1 / 2	0 / 1	2 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	2 / 150 (1.33%)	1 / 152 (0.66%)	2 / 153 (1.31%)	0 / 23 (0.00%)	0 / 53 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	1 / 2	1 / 1	1 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
MALAISE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MULTI-ORGAN FAILURE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
NON-CARDIAC CHEST PAIN
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OEDEMA PERIPHERAL
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	2 / 153 (1.31%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PAIN
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	8 / 150 (5.33%)	2 / 152 (1.32%)	7 / 153 (4.58%)	0 / 23 (0.00%)	2 / 53 (3.77%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	4 / 8	0 / 2	2 / 8	0 / 0	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUDDEN CARDIAC DEATH
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
HYPERSENSITIVITY
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
BENIGN PROSTATIC HYPERPLASIA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	2 / 153 (1.31%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ACUTE PULMONARY OEDEMA
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHOSPASM
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	2 / 150 (1.33%)	3 / 152 (1.97%)	2 / 153 (1.31%)	0 / 23 (0.00%)	1 / 53 (1.89%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	1 / 3	1 / 3	0 / 2	0 / 0	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	0 / 150 (0.00%)	2 / 152 (1.32%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA ASPIRATION
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PRODUCTIVE COUGH
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	2 / 150 (1.33%)	3 / 152 (1.97%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	2 / 2	4 / 4	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
PULMONARY HAEMORRHAGE
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY FAILURE
subjects affected / exposed	2 / 150 (1.33%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	2 / 53 (3.77%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
WHEEZING
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
DELIRIUM
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEPRESSION
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DISORIENTATION
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INSOMNIA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PSYCHOTIC DISORDER DUE TO A GENERAL MEDICAL CONDITION
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
MONOCLONAL IMMUNOGLOBULIN PRESENT
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
ACCIDENTAL OVERDOSE
subjects affected / exposed	1 / 150 (0.67%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FALL
subjects affected / exposed	0 / 150 (0.00%)	2 / 152 (1.32%)	2 / 153 (1.31%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEMORAL NECK FRACTURE
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	2 / 53 (3.77%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEMUR FRACTURE
subjects affected / exposed	0 / 150 (0.00%)	2 / 152 (1.32%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HEAD INJURY
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HIP FRACTURE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HUMERUS FRACTURE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SPINAL COMPRESSION FRACTURE
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SPINAL FRACTURE
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STERNAL FRACTURE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	2 / 153 (1.31%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TENDON RUPTURE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
THERAPEUTIC AGENT TOXICITY
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
THORACIC VERTEBRAL FRACTURE
subjects affected / exposed	1 / 150 (0.67%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TRAUMATIC FRACTURE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
ACUTE CORONARY SYNDROME
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANGINA PECTORIS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	3 / 153 (1.96%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANGINA UNSTABLE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ATRIAL FIBRILLATION
subjects affected / exposed	1 / 150 (0.67%)	3 / 152 (1.97%)	5 / 153 (3.27%)	0 / 23 (0.00%)	1 / 53 (1.89%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	1 / 1	0 / 3	1 / 6	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ATRIAL FLUTTER
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ATRIOVENTRICULAR BLOCK
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRADYCARDIA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	2 / 153 (1.31%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
CARDIAC ARREST
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC DISORDER
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC FAILURE
subjects affected / exposed	3 / 150 (2.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	1 / 23 (4.35%)	2 / 53 (3.77%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
CARDIAC FAILURE CHRONIC
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC FAILURE CONGESTIVE
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIOGENIC SHOCK
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
CORONARY ARTERY DISEASE
subjects affected / exposed	1 / 150 (0.67%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CORONARY ARTERY OCCLUSION
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MYOCARDIAL INFARCTION
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MYOCARDIAL ISCHAEMIA
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PALPITATIONS
subjects affected / exposed	2 / 150 (1.33%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 3	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RIGHT VENTRICULAR FAILURE
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SINUS TACHYCARDIA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TACHYARRHYTHMIA
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
APHASIA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRAIN OEDEMA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
CEREBRAL HAEMORRHAGE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
CEREBRAL ISCHAEMIA
subjects affected / exposed	1 / 150 (0.67%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COGNITIVE DISORDER
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CONVULSION
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIABETIC COMA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIZZINESS
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HEMIPARESIS
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ISCHAEMIC STROKE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
METABOLIC ENCEPHALOPATHY
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEUROPATHY PERIPHERAL
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NYSTAGMUS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PARALYSIS
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PARKINSON'S DISEASE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
POST HERPETIC NEURALGIA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PRESYNCOPE
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SCIATICA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUBARACHNOID HAEMORRHAGE
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	2 / 150 (1.33%)	2 / 152 (1.32%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SYNCOPE VASOVAGAL
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TRANSIENT ISCHAEMIC ATTACK
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	6 / 150 (4.00%)	8 / 152 (5.26%)	2 / 153 (1.31%)	2 / 23 (8.70%)	3 / 53 (5.66%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	5 / 6	6 / 10	0 / 2	3 / 3	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	9 / 150 (6.00%)	2 / 152 (1.32%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	9 / 9	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMOLYTIC ANAEMIA
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LEUKOPENIA
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	6 / 150 (4.00%)	4 / 152 (2.63%)	1 / 153 (0.65%)	0 / 23 (0.00%)	1 / 53 (1.89%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	5 / 6	3 / 5	1 / 1	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PANCYTOPENIA
subjects affected / exposed	1 / 150 (0.67%)	2 / 152 (1.32%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	3 / 150 (2.00%)	4 / 152 (2.63%)	1 / 153 (0.65%)	1 / 23 (4.35%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	2 / 3	2 / 4	1 / 1	1 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
CATARACT
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIABETIC RETINOPATHY
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GLAUCOMA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RETINAL DETACHMENT
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL DISCOMFORT
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN UPPER
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ABDOMINAL STRANGULATED HERNIA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COLITIS
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	2 / 150 (1.33%)	3 / 152 (1.97%)	1 / 153 (0.65%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 3	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	3 / 150 (2.00%)	1 / 152 (0.66%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	1 / 3	0 / 1	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DYSPHAGIA
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRITIS ATROPHIC
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRITIS HAEMORRHAGIC
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMORRHOIDAL HAEMORRHAGE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ILEUS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INGUINAL HERNIA
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MELAENA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	3 / 150 (2.00%)	2 / 152 (1.32%)	2 / 153 (1.31%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	2 / 3	1 / 2	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PANCREATIC MASS
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RECTAL HAEMORRHAGE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VOMITING
subjects affected / exposed	4 / 150 (2.67%)	1 / 152 (0.66%)	3 / 153 (1.96%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	2 / 5	0 / 1	1 / 3	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
BILIARY COLIC
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHOLESTASIS
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HEPATITIS TOXIC
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
ACTINIC KERATOSIS
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANGIOEDEMA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BLISTER
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DERMATITIS EXFOLIATIVE
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DRUG ERUPTION
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ERYTHEMA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RASH
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URTICARIA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
DYSURIA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEPHROPATHY
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEPHROTIC SYNDROME
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL AMYLOIDOSIS
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	0 / 150 (0.00%)	3 / 152 (1.97%)	2 / 153 (1.31%)	0 / 23 (0.00%)	1 / 53 (1.89%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL FAILURE ACUTE
subjects affected / exposed	1 / 150 (0.67%)	3 / 152 (1.97%)	4 / 153 (2.61%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 3	0 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0	0 / 0
URINARY RETENTION
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	1 / 150 (0.67%)	2 / 152 (1.32%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ARTHRITIS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ARTHROPATHY
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BACK PAIN
subjects affected / exposed	2 / 150 (1.33%)	1 / 152 (0.66%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BONE LESION
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BONE PAIN
subjects affected / exposed	5 / 150 (3.33%)	2 / 152 (1.32%)	6 / 153 (3.92%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 7	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GOUTY ARTHRITIS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INTERVERTEBRAL DISC DISORDER
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MUSCLE HAEMORRHAGE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MUSCULOSKELETAL PAIN
subjects affected / exposed	2 / 150 (1.33%)	1 / 152 (0.66%)	1 / 153 (0.65%)	1 / 23 (4.35%)	1 / 53 (1.89%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MYOSITIS
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OSTEOARTHRITIS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PAIN IN EXTREMITY
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PATHOLOGICAL FRACTURE
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
APPENDICITIS
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ARTHRITIS INFECTIVE
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	1 / 150 (0.67%)	2 / 152 (1.32%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHITIS BACTERIAL
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHOPNEUMONIA
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CAMPYLOBACTER GASTROENTERITIS
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CAMPYLOBACTER INFECTION
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARBUNCLE
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM COLITIS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE COLITIS
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CRYPTOCOCCOSIS
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CYSTITIS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIVERTICULITIS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ERYSIPELAS
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA INFECTION
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA SEPSIS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS NORWALK VIRUS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HERPES SIMPLEX
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HERPES ZOSTER
subjects affected / exposed	1 / 150 (0.67%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFECTION
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LOBAR PNEUMONIA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
MENINGITIS
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
ORAL CANDIDIASIS
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	6 / 150 (4.00%)	8 / 152 (5.26%)	8 / 153 (5.23%)	0 / 23 (0.00%)	3 / 53 (5.66%)	6 / 80 (7.50%)
occurrences causally related to treatment / all	5 / 7	6 / 9	3 / 9	0 / 0	0 / 3	4 / 6
deaths causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 2	1 / 1
PNEUMONIA PNEUMOCOCCAL
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA STAPHYLOCOCCAL
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
POST PROCEDURAL INFECTION
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PSEUDOMEMBRANOUS COLITIS
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PYELONEPHRITIS CHRONIC
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
SEPSIS
subjects affected / exposed	1 / 150 (0.67%)	3 / 152 (1.97%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	1 / 1	1 / 3	0 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
SEPTIC SHOCK
subjects affected / exposed	1 / 150 (0.67%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
SINUSITIS
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STREPTOCOCCAL BACTERAEMIA
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STREPTOCOCCAL SEPSIS
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	2 / 150 (1.33%)	0 / 152 (0.00%)	3 / 153 (1.96%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VIRAL UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
WOUND INFECTION
subjects affected / exposed	0 / 150 (0.00%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
ANOREXIA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEHYDRATION
subjects affected / exposed	2 / 150 (1.33%)	1 / 152 (0.66%)	0 / 153 (0.00%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIABETES MELLITUS
subjects affected / exposed	1 / 150 (0.67%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIABETES MELLITUS INADEQUATE CONTROL
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERCALCAEMIA
subjects affected / exposed	2 / 150 (1.33%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERGLYCAEMIA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERKALAEMIA
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	1 / 153 (0.65%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOCALCAEMIA
subjects affected / exposed	2 / 150 (1.33%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOGLYCAEMIA
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOKALAEMIA
subjects affected / exposed	2 / 150 (1.33%)	1 / 152 (0.66%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ORAL INTAKE REDUCED
subjects affected / exposed	1 / 150 (0.67%)	0 / 152 (0.00%)	0 / 153 (0.00%)	0 / 23 (0.00%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Induction + Maintenance MPR+R	Induction + Maintenance MPR+p	Induction + Maintenance MPp+p	Open-Label Extension MPR+R	Open-Label Extension MPR+p	Open-Label Extension MPp+p
Total subjects affected by non serious adverse events
subjects affected / exposed	150 / 150 (100.00%)	150 / 152 (98.68%)	150 / 153 (98.04%)	21 / 23 (91.30%)	48 / 53 (90.57%)	76 / 80 (95.00%)
Vascular disorders
DEEP VEIN THROMBOSIS
subjects affected / exposed	4 / 150 (2.67%)	9 / 152 (5.92%)	1 / 153 (0.65%)	2 / 23 (8.70%)	1 / 53 (1.89%)	4 / 80 (5.00%)
occurrences all number	4	12	1	2	2	4
HYPERTENSION
subjects affected / exposed	8 / 150 (5.33%)	9 / 152 (5.92%)	13 / 153 (8.50%)	3 / 23 (13.04%)	2 / 53 (3.77%)	2 / 80 (2.50%)
occurrences all number	9	10	24	5	6	2
HYPOTENSION
subjects affected / exposed	10 / 150 (6.67%)	4 / 152 (2.63%)	10 / 153 (6.54%)	0 / 23 (0.00%)	0 / 53 (0.00%)	3 / 80 (3.75%)
occurrences all number	13	4	10	0	0	3
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	34 / 150 (22.67%)	22 / 152 (14.47%)	24 / 153 (15.69%)	4 / 23 (17.39%)	6 / 53 (11.32%)	9 / 80 (11.25%)
occurrences all number	80	37	38	5	18	32
FATIGUE
subjects affected / exposed	52 / 150 (34.67%)	53 / 152 (34.87%)	59 / 153 (38.56%)	6 / 23 (26.09%)	15 / 53 (28.30%)	23 / 80 (28.75%)
occurrences all number	151	105	107	8	29	53
MALAISE
subjects affected / exposed	2 / 150 (1.33%)	1 / 152 (0.66%)	4 / 153 (2.61%)	0 / 23 (0.00%)	4 / 53 (7.55%)	2 / 80 (2.50%)
occurrences all number	4	4	4	0	6	2
OEDEMA
subjects affected / exposed	6 / 150 (4.00%)	11 / 152 (7.24%)	5 / 153 (3.27%)	0 / 23 (0.00%)	1 / 53 (1.89%)	2 / 80 (2.50%)
occurrences all number	11	13	9	0	1	5
OEDEMA PERIPHERAL
subjects affected / exposed	31 / 150 (20.67%)	38 / 152 (25.00%)	29 / 153 (18.95%)	1 / 23 (4.35%)	9 / 53 (16.98%)	21 / 80 (26.25%)
occurrences all number	52	63	49	1	15	33
PYREXIA
subjects affected / exposed	34 / 150 (22.67%)	40 / 152 (26.32%)	32 / 153 (20.92%)	3 / 23 (13.04%)	7 / 53 (13.21%)	10 / 80 (12.50%)
occurrences all number	54	65	39	6	12	14
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	36 / 150 (24.00%)	29 / 152 (19.08%)	22 / 153 (14.38%)	1 / 23 (4.35%)	5 / 53 (9.43%)	12 / 80 (15.00%)
occurrences all number	52	35	30	1	5	16
DYSPHONIA
subjects affected / exposed	4 / 150 (2.67%)	4 / 152 (2.63%)	5 / 153 (3.27%)	0 / 23 (0.00%)	1 / 53 (1.89%)	5 / 80 (6.25%)
occurrences all number	4	4	6	0	1	5
DYSPNOEA
subjects affected / exposed	22 / 150 (14.67%)	14 / 152 (9.21%)	19 / 153 (12.42%)	1 / 23 (4.35%)	8 / 53 (15.09%)	10 / 80 (12.50%)
occurrences all number	36	19	23	2	11	16
DYSPNOEA EXERTIONAL
subjects affected / exposed	4 / 150 (2.67%)	3 / 152 (1.97%)	3 / 153 (1.96%)	0 / 23 (0.00%)	5 / 53 (9.43%)	2 / 80 (2.50%)
occurrences all number	6	4	6	0	7	3
EPISTAXIS
subjects affected / exposed	9 / 150 (6.00%)	7 / 152 (4.61%)	11 / 153 (7.19%)	3 / 23 (13.04%)	3 / 53 (5.66%)	2 / 80 (2.50%)
occurrences all number	25	10	16	3	4	3
PHARYNGOLARYNGEAL PAIN
subjects affected / exposed	6 / 150 (4.00%)	10 / 152 (6.58%)	9 / 153 (5.88%)	0 / 23 (0.00%)	2 / 53 (3.77%)	4 / 80 (5.00%)
occurrences all number	9	11	11	0	5	6
Psychiatric disorders
AGITATION
subjects affected / exposed	3 / 150 (2.00%)	4 / 152 (2.63%)	0 / 153 (0.00%)	0 / 23 (0.00%)	3 / 53 (5.66%)	3 / 80 (3.75%)
occurrences all number	3	5	0	0	3	4
ANXIETY
subjects affected / exposed	3 / 150 (2.00%)	5 / 152 (3.29%)	1 / 153 (0.65%)	0 / 23 (0.00%)	3 / 53 (5.66%)	2 / 80 (2.50%)
occurrences all number	3	6	1	0	3	2
DEPRESSION
subjects affected / exposed	9 / 150 (6.00%)	18 / 152 (11.84%)	10 / 153 (6.54%)	1 / 23 (4.35%)	3 / 53 (5.66%)	4 / 80 (5.00%)
occurrences all number	13	19	10	1	6	4
INSOMNIA
subjects affected / exposed	17 / 150 (11.33%)	22 / 152 (14.47%)	22 / 153 (14.38%)	5 / 23 (21.74%)	3 / 53 (5.66%)	11 / 80 (13.75%)
occurrences all number	18	25	35	6	6	12
Investigations
BLOOD ALKALINE PHOSPHATASE INCREASED
subjects affected / exposed	7 / 150 (4.67%)	11 / 152 (7.24%)	5 / 153 (3.27%)	1 / 23 (4.35%)	3 / 53 (5.66%)	0 / 80 (0.00%)
occurrences all number	13	23	8	1	9	0
BLOOD CREATININE INCREASED
subjects affected / exposed	16 / 150 (10.67%)	6 / 152 (3.95%)	17 / 153 (11.11%)	0 / 23 (0.00%)	1 / 53 (1.89%)	4 / 80 (5.00%)
occurrences all number	35	7	37	0	1	6
C-REACTIVE PROTEIN INCREASED
subjects affected / exposed	4 / 150 (2.67%)	8 / 152 (5.26%)	2 / 153 (1.31%)	1 / 23 (4.35%)	1 / 53 (1.89%)	3 / 80 (3.75%)
occurrences all number	7	13	2	1	1	9
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed	1 / 150 (0.67%)	5 / 152 (3.29%)	0 / 153 (0.00%)	0 / 23 (0.00%)	4 / 53 (7.55%)	0 / 80 (0.00%)
occurrences all number	5	11	0	0	8	0
WEIGHT DECREASED
subjects affected / exposed	9 / 150 (6.00%)	14 / 152 (9.21%)	9 / 153 (5.88%)	0 / 23 (0.00%)	0 / 53 (0.00%)	6 / 80 (7.50%)
occurrences all number	11	19	11	0	0	7
Injury, poisoning and procedural complications
FALL
subjects affected / exposed	4 / 150 (2.67%)	6 / 152 (3.95%)	11 / 153 (7.19%)	0 / 23 (0.00%)	4 / 53 (7.55%)	2 / 80 (2.50%)
occurrences all number	6	9	12	0	6	2
Cardiac disorders
BRADYCARDIA
subjects affected / exposed	0 / 150 (0.00%)	2 / 152 (1.32%)	1 / 153 (0.65%)	0 / 23 (0.00%)	4 / 53 (7.55%)	2 / 80 (2.50%)
occurrences all number	0	2	1	0	5	2
Nervous system disorders
DIZZINESS
subjects affected / exposed	16 / 150 (10.67%)	21 / 152 (13.82%)	16 / 153 (10.46%)	1 / 23 (4.35%)	4 / 53 (7.55%)	10 / 80 (12.50%)
occurrences all number	24	22	21	1	6	13
DYSGEUSIA
subjects affected / exposed	6 / 150 (4.00%)	10 / 152 (6.58%)	7 / 153 (4.58%)	0 / 23 (0.00%)	3 / 53 (5.66%)	3 / 80 (3.75%)
occurrences all number	9	13	7	0	3	11
HEADACHE
subjects affected / exposed	12 / 150 (8.00%)	16 / 152 (10.53%)	22 / 153 (14.38%)	0 / 23 (0.00%)	3 / 53 (5.66%)	4 / 80 (5.00%)
occurrences all number	35	29	22	0	5	5
PARAESTHESIA
subjects affected / exposed	15 / 150 (10.00%)	10 / 152 (6.58%)	6 / 153 (3.92%)	1 / 23 (4.35%)	3 / 53 (5.66%)	1 / 80 (1.25%)
occurrences all number	20	18	8	6	3	1
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	12 / 150 (8.00%)	10 / 152 (6.58%)	5 / 153 (3.27%)	0 / 23 (0.00%)	6 / 53 (11.32%)	2 / 80 (2.50%)
occurrences all number	18	13	11	0	7	6
SCIATICA
subjects affected / exposed	5 / 150 (3.33%)	2 / 152 (1.32%)	4 / 153 (2.61%)	0 / 23 (0.00%)	1 / 53 (1.89%)	4 / 80 (5.00%)
occurrences all number	5	2	6	0	1	6
TREMOR
subjects affected / exposed	9 / 150 (6.00%)	4 / 152 (2.63%)	6 / 153 (3.92%)	1 / 23 (4.35%)	0 / 53 (0.00%)	6 / 80 (7.50%)
occurrences all number	11	4	6	1	0	7
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	106 / 150 (70.67%)	96 / 152 (63.16%)	83 / 153 (54.25%)	11 / 23 (47.83%)	21 / 53 (39.62%)	41 / 80 (51.25%)
occurrences all number	506	374	313	24	57	126
LEUKOPENIA
subjects affected / exposed	54 / 150 (36.00%)	59 / 152 (38.82%)	50 / 153 (32.68%)	7 / 23 (30.43%)	22 / 53 (41.51%)	27 / 80 (33.75%)
occurrences all number	499	461	249	23	80	129
LYMPHOPENIA
subjects affected / exposed	2 / 150 (1.33%)	4 / 152 (2.63%)	4 / 153 (2.61%)	1 / 23 (4.35%)	1 / 53 (1.89%)	5 / 80 (6.25%)
occurrences all number	42	6	33	6	1	19
NEUTROPENIA
subjects affected / exposed	124 / 150 (82.67%)	118 / 152 (77.63%)	79 / 153 (51.63%)	14 / 23 (60.87%)	38 / 53 (71.70%)	57 / 80 (71.25%)
occurrences all number	1093	837	409	36	185	268
THROMBOCYTOPENIA
subjects affected / exposed	105 / 150 (70.00%)	104 / 152 (68.42%)	69 / 153 (45.10%)	13 / 23 (56.52%)	25 / 53 (47.17%)	33 / 80 (41.25%)
occurrences all number	598	558	285	26	60	96
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	15 / 150 (10.00%)	10 / 152 (6.58%)	14 / 153 (9.15%)	0 / 23 (0.00%)	4 / 53 (7.55%)	8 / 80 (10.00%)
occurrences all number	26	13	25	0	4	9
Eye disorders
CATARACT
subjects affected / exposed	3 / 150 (2.00%)	1 / 152 (0.66%)	2 / 153 (1.31%)	0 / 23 (0.00%)	3 / 53 (5.66%)	3 / 80 (3.75%)
occurrences all number	4	1	2	0	4	3
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	18 / 150 (12.00%)	9 / 152 (5.92%)	7 / 153 (4.58%)	1 / 23 (4.35%)	2 / 53 (3.77%)	3 / 80 (3.75%)
occurrences all number	31	9	8	1	3	7
ABDOMINAL PAIN UPPER
subjects affected / exposed	15 / 150 (10.00%)	7 / 152 (4.61%)	13 / 153 (8.50%)	1 / 23 (4.35%)	3 / 53 (5.66%)	2 / 80 (2.50%)
occurrences all number	24	9	21	1	4	2
CONSTIPATION
subjects affected / exposed	50 / 150 (33.33%)	39 / 152 (25.66%)	38 / 153 (24.84%)	3 / 23 (13.04%)	9 / 53 (16.98%)	21 / 80 (26.25%)
occurrences all number	86	70	58	4	15	40
DIARRHOEA
subjects affected / exposed	50 / 150 (33.33%)	37 / 152 (24.34%)	39 / 153 (25.49%)	5 / 23 (21.74%)	9 / 53 (16.98%)	19 / 80 (23.75%)
occurrences all number	164	65	52	9	33	28
DRY MOUTH
subjects affected / exposed	13 / 150 (8.67%)	8 / 152 (5.26%)	5 / 153 (3.27%)	0 / 23 (0.00%)	2 / 53 (3.77%)	2 / 80 (2.50%)
occurrences all number	15	9	7	0	2	3
DYSPEPSIA
subjects affected / exposed	14 / 150 (9.33%)	7 / 152 (4.61%)	8 / 153 (5.23%)	1 / 23 (4.35%)	1 / 53 (1.89%)	1 / 80 (1.25%)
occurrences all number	20	7	10	1	1	1
NAUSEA
subjects affected / exposed	40 / 150 (26.67%)	40 / 152 (26.32%)	54 / 153 (35.29%)	4 / 23 (17.39%)	4 / 53 (7.55%)	8 / 80 (10.00%)
occurrences all number	73	69	99	5	7	9
VOMITING
subjects affected / exposed	18 / 150 (12.00%)	19 / 152 (12.50%)	21 / 153 (13.73%)	1 / 23 (4.35%)	2 / 53 (3.77%)	4 / 80 (5.00%)
occurrences all number	28	28	34	2	2	5
Skin and subcutaneous tissue disorders
ALOPECIA
subjects affected / exposed	4 / 150 (2.67%)	3 / 152 (1.97%)	8 / 153 (5.23%)	1 / 23 (4.35%)	0 / 53 (0.00%)	0 / 80 (0.00%)
occurrences all number	4	4	9	1	0	0
DRY SKIN
subjects affected / exposed	8 / 150 (5.33%)	3 / 152 (1.97%)	10 / 153 (6.54%)	0 / 23 (0.00%)	1 / 53 (1.89%)	4 / 80 (5.00%)
occurrences all number	9	3	12	0	1	4
HYPERHIDROSIS
subjects affected / exposed	9 / 150 (6.00%)	6 / 152 (3.95%)	8 / 153 (5.23%)	0 / 23 (0.00%)	3 / 53 (5.66%)	1 / 80 (1.25%)
occurrences all number	12	7	9	0	6	1
NIGHT SWEATS
subjects affected / exposed	5 / 150 (3.33%)	9 / 152 (5.92%)	6 / 153 (3.92%)	0 / 23 (0.00%)	0 / 53 (0.00%)	3 / 80 (3.75%)
occurrences all number	9	11	11	0	0	3
PRURITUS
subjects affected / exposed	16 / 150 (10.67%)	12 / 152 (7.89%)	10 / 153 (6.54%)	0 / 23 (0.00%)	5 / 53 (9.43%)	5 / 80 (6.25%)
occurrences all number	25	15	11	0	8	5
RASH
subjects affected / exposed	31 / 150 (20.67%)	43 / 152 (28.29%)	13 / 153 (8.50%)	0 / 23 (0.00%)	2 / 53 (3.77%)	16 / 80 (20.00%)
occurrences all number	61	64	14	0	2	27
Renal and urinary disorders
PROTEINURIA
subjects affected / exposed	4 / 150 (2.67%)	8 / 152 (5.26%)	7 / 153 (4.58%)	1 / 23 (4.35%)	3 / 53 (5.66%)	3 / 80 (3.75%)
occurrences all number	14	17	14	3	5	4
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	17 / 150 (11.33%)	21 / 152 (13.82%)	17 / 153 (11.11%)	0 / 23 (0.00%)	4 / 53 (7.55%)	7 / 80 (8.75%)
occurrences all number	20	31	24	0	5	9
BACK PAIN
subjects affected / exposed	24 / 150 (16.00%)	20 / 152 (13.16%)	35 / 153 (22.88%)	1 / 23 (4.35%)	5 / 53 (9.43%)	13 / 80 (16.25%)
occurrences all number	31	28	45	1	9	16
BONE PAIN
subjects affected / exposed	50 / 150 (33.33%)	47 / 152 (30.92%)	51 / 153 (33.33%)	5 / 23 (21.74%)	13 / 53 (24.53%)	20 / 80 (25.00%)
occurrences all number	118	82	87	6	18	33
MUSCLE SPASMS
subjects affected / exposed	19 / 150 (12.67%)	18 / 152 (11.84%)	10 / 153 (6.54%)	0 / 23 (0.00%)	6 / 53 (11.32%)	15 / 80 (18.75%)
occurrences all number	35	39	10	0	10	20
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	12 / 150 (8.00%)	9 / 152 (5.92%)	5 / 153 (3.27%)	0 / 23 (0.00%)	2 / 53 (3.77%)	2 / 80 (2.50%)
occurrences all number	13	12	6	0	2	2
MUSCULOSKELETAL PAIN
subjects affected / exposed	25 / 150 (16.67%)	18 / 152 (11.84%)	21 / 153 (13.73%)	1 / 23 (4.35%)	8 / 53 (15.09%)	7 / 80 (8.75%)
occurrences all number	47	25	40	1	14	10
MYALGIA
subjects affected / exposed	5 / 150 (3.33%)	10 / 152 (6.58%)	3 / 153 (1.96%)	3 / 23 (13.04%)	1 / 53 (1.89%)	3 / 80 (3.75%)
occurrences all number	6	16	3	3	1	5
NECK PAIN
subjects affected / exposed	7 / 150 (4.67%)	2 / 152 (1.32%)	7 / 153 (4.58%)	0 / 23 (0.00%)	3 / 53 (5.66%)	1 / 80 (1.25%)
occurrences all number	8	2	10	0	5	1
OSTEOARTHRITIS
subjects affected / exposed	1 / 150 (0.67%)	3 / 152 (1.97%)	6 / 153 (3.92%)	0 / 23 (0.00%)	3 / 53 (5.66%)	0 / 80 (0.00%)
occurrences all number	1	4	6	0	3	0
PAIN IN EXTREMITY
subjects affected / exposed	14 / 150 (9.33%)	9 / 152 (5.92%)	13 / 153 (8.50%)	0 / 23 (0.00%)	2 / 53 (3.77%)	4 / 80 (5.00%)
occurrences all number	20	15	18	0	2	4
Infections and infestations
BRONCHITIS
subjects affected / exposed	19 / 150 (12.67%)	17 / 152 (11.18%)	12 / 153 (7.84%)	2 / 23 (8.70%)	6 / 53 (11.32%)	6 / 80 (7.50%)
occurrences all number	35	22	16	3	6	7
CYSTITIS
subjects affected / exposed	6 / 150 (4.00%)	7 / 152 (4.61%)	8 / 153 (5.23%)	0 / 23 (0.00%)	0 / 53 (0.00%)	1 / 80 (1.25%)
occurrences all number	13	8	15	0	0	1
HERPES ZOSTER
subjects affected / exposed	0 / 150 (0.00%)	3 / 152 (1.97%)	8 / 153 (5.23%)	0 / 23 (0.00%)	1 / 53 (1.89%)	2 / 80 (2.50%)
occurrences all number	0	3	8	0	1	2
INFLUENZA
subjects affected / exposed	6 / 150 (4.00%)	5 / 152 (3.29%)	3 / 153 (1.96%)	0 / 23 (0.00%)	3 / 53 (5.66%)	6 / 80 (7.50%)
occurrences all number	6	5	3	0	3	7
NASOPHARYNGITIS
subjects affected / exposed	30 / 150 (20.00%)	22 / 152 (14.47%)	26 / 153 (16.99%)	2 / 23 (8.70%)	6 / 53 (11.32%)	10 / 80 (12.50%)
occurrences all number	49	38	36	4	11	17
ORAL HERPES
subjects affected / exposed	8 / 150 (5.33%)	6 / 152 (3.95%)	6 / 153 (3.92%)	0 / 23 (0.00%)	0 / 53 (0.00%)	3 / 80 (3.75%)
occurrences all number	8	7	6	0	0	17
PNEUMONIA
subjects affected / exposed	4 / 150 (2.67%)	6 / 152 (3.95%)	7 / 153 (4.58%)	1 / 23 (4.35%)	2 / 53 (3.77%)	6 / 80 (7.50%)
occurrences all number	4	6	7	1	2	6
RESPIRATORY TRACT INFECTION
subjects affected / exposed	10 / 150 (6.67%)	6 / 152 (3.95%)	3 / 153 (1.96%)	2 / 23 (8.70%)	1 / 53 (1.89%)	4 / 80 (5.00%)
occurrences all number	12	8	3	2	5	5
RESPIRATORY TRACT INFECTION VIRAL
subjects affected / exposed	0 / 150 (0.00%)	0 / 152 (0.00%)	0 / 153 (0.00%)	1 / 23 (4.35%)	3 / 53 (5.66%)	0 / 80 (0.00%)
occurrences all number	0	0	0	1	3	0
RHINITIS
subjects affected / exposed	9 / 150 (6.00%)	5 / 152 (3.29%)	6 / 153 (3.92%)	1 / 23 (4.35%)	2 / 53 (3.77%)	0 / 80 (0.00%)
occurrences all number	13	10	6	1	3	0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	20 / 150 (13.33%)	20 / 152 (13.16%)	15 / 153 (9.80%)	0 / 23 (0.00%)	3 / 53 (5.66%)	7 / 80 (8.75%)
occurrences all number	30	27	21	0	15	30
URINARY TRACT INFECTION
subjects affected / exposed	17 / 150 (11.33%)	13 / 152 (8.55%)	12 / 153 (7.84%)	1 / 23 (4.35%)	5 / 53 (9.43%)	3 / 80 (3.75%)
occurrences all number	24	18	14	1	6	7
VIRAL INFECTION
subjects affected / exposed	7 / 150 (4.67%)	2 / 152 (1.32%)	1 / 153 (0.65%)	0 / 23 (0.00%)	3 / 53 (5.66%)	0 / 80 (0.00%)
occurrences all number	7	2	1	0	3	0
Metabolism and nutrition disorders
ANOREXIA
subjects affected / exposed	24 / 150 (16.00%)	36 / 152 (23.68%)	23 / 153 (15.03%)	0 / 23 (0.00%)	8 / 53 (15.09%)	8 / 80 (10.00%)
occurrences all number	40	54	28	0	11	9
HYPERGLYCAEMIA
subjects affected / exposed	11 / 150 (7.33%)	11 / 152 (7.24%)	18 / 153 (11.76%)	0 / 23 (0.00%)	1 / 53 (1.89%)	7 / 80 (8.75%)
occurrences all number	45	42	51	0	1	15
HYPERURICAEMIA
subjects affected / exposed	10 / 150 (6.67%)	5 / 152 (3.29%)	6 / 153 (3.92%)	1 / 23 (4.35%)	1 / 53 (1.89%)	0 / 80 (0.00%)
occurrences all number	14	9	9	1	1	0
HYPOCALCAEMIA
subjects affected / exposed	14 / 150 (9.33%)	9 / 152 (5.92%)	10 / 153 (6.54%)	2 / 23 (8.70%)	0 / 53 (0.00%)	6 / 80 (7.50%)
occurrences all number	18	20	26	2	0	10
HYPOKALAEMIA
subjects affected / exposed	19 / 150 (12.67%)	11 / 152 (7.24%)	6 / 153 (3.92%)	0 / 23 (0.00%)	2 / 53 (3.77%)	4 / 80 (5.00%)
occurrences all number	24	20	6	0	2	5

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Were there any global substantial amendments to the protocol? Yes

21 Apr 2008

1. Clarified Myeloma Response Determination Criteria for progressive disease for subjects who did not achieve CR 2. Clarified procedural changes to best reflect clinical practice 3. Added language for the Lenalidomide Pregnancy Prevention Risk Management Plan 4. Added contact information for Central Laboratory for Cytogenetics 5. Updated address of Celgene emergency contact and Celgene personnel 6. Corrected prior administrative errors

27 Jan 2009

1. Clarified the conditions around interim analysis at 50% information 2. Added another interim analysis at 70% information

04 Jan 2010

1. Described changes in the study design and the procedures to be followed after unblinding for subjects in the different treatment arms; 2. described the change of treatment for subjects in the different treatment arms after unblinding (Subjects in Arm MPR+R could continue lenalidomide maintenance as open label therapy, those in Arms MPR+p and MPp+p were to stop treatment with placebo); 3. Clarified procedures to follow for emergency unblinding during the induction + maintenance phase;described the study drug given during the induct+maintenance periods; 4. Clarified supplies of melphalan and prednisone will be commercial and how they will be labeled; 5. Clarified the dosing regimens to follow after unblinding; clarified dose reduction steps for lenalidomide during the induction and maintenance periods after unblinding; 6. Clarified dose modification guidelines for hematologic toxicity during the induction and maintenance periods after unblinding; 7. Clarified the antithrombotic therapy to be used during the induct+maint periods after unblinding; 8. Clarified on when efficacy, safety, and other assessments should be performed; 9. Described the assessments to be performed during the observation phase (subjects in Arms MPR+p and MPp+p entered into the observation phase following unblinding);10. Provided for more frequent follow-up OS and subsequent antimyeloma treatment regimens for subjects in the follow-up phase; 11. Clarified storage of the study drug; clarified the requirement for a repeat bone marrow aspiration to confirm a CR per EBMT criteria; 12. Clarified the collection of M-protein data; 13. Clarified definition of the efficacy-evaluable population; 14. Provided further clarification for analysis of the PFS; 15. Clarified that “50% information” and “70% information” can only be approximate, since the actual number of events may change slightly as a result of adjudication review and further data cleaning; 16. Updated study contact information

10 Feb 2011

1. Modified the requirements of the follow-up phase to ensure that subjects who discontinued study therapy for any reason other than disease progression (even if they went on to receive next-line therapy) continued to be followed until disease progression, including the survival follow-up phase 2. Required that Secondary primary malignancies (SPMs) be treated as serious adverse events (SAEs) and reported throughout the study duration, including the survival follow-up phase 3. Added a central review of all hematologic SPMs 4. Updated study contact information

11 Oct 2011

1. In addition to the SPM reporting requirements and hematologic SPM central review requirements outlined in Amendment 4, for subjects with any SPM (solid tumors and hematologic malignancies), Amendment 5 also mandated submission of diagnostic reports (eg, pathology reports ) from tumor biopsy samples collected at the SPM diagnosis to Celgene or a designee for secondary confirmation. 2. Added the collection of samples for exploratory biomarker studies, in agreement with health authorities (EMA and FDA), to assess subjects for possible molecular risk factors and to examine whether there is any correlation of molecular and genetic risk factors with the potential development of SPMs during and after lenalidomide treatment 3. Updated study contact information 4. Recorded staffing changes and added new central laboratory contacts for sample storage and exploratory laboratory studies

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/23242595
http://www.ncbi.nlm.nih.gov/pubmed/22571200

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Baseline characteristics

Baseline characteristics

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Primary: Kaplan Meier Estimates of Progression-free Survival (PFS) Based on the Response Assessment by the Central Adjudication Committee (CAC) and Food and Drug Administration (FDA) Censoring Rules

Primary: Kaplan Meier Estimates of Progression-free Survival (PFS) Based on the Response Assessment by the Central Adjudication Committee (CAC) and Food and Drug Administration (FDA) Censoring Rules

Primary: Kaplan Meier Estimates of Progression-free Survival Time (PFS) Based on European Medicines Agency (EMA) Guidelines Based on the Response Assessment by the CAC

Primary: Kaplan Meier Estimates of Progression-free Survival Time (PFS) Based on European Medicines Agency (EMA) Guidelines Based on the Response Assessment by the CAC

Primary: Kaplan Meier Estimates of Progression-free Survival (PFS) from Start of Maintenance Therapy Period Based on the Response Assessment by the Central Adjudication Committee (CAC)

Primary: Kaplan Meier Estimates of Progression-free Survival (PFS) from Start of Maintenance Therapy Period Based on the Response Assessment by the Central Adjudication Committee (CAC)

Primary: Kaplan Meier Estimates of Progression-free Survival (PFS) from Start of Maintenance Therapy Period Based Investigator Assessment at a Later Cut-off date of 30 April 2013

Primary: Kaplan Meier Estimates of Progression-free Survival (PFS) from Start of Maintenance Therapy Period Based Investigator Assessment at a Later Cut-off date of 30 April 2013

Primary: Kaplan Meier Estimates of PFS Time Based on the Investigator Response Assessment at a later cut off date

Primary: Kaplan Meier Estimates of PFS Time Based on the Investigator Response Assessment at a later cut off date

Secondary: Kaplan Meier Estimates of Overall Survival (OS) Based on the Investigator Response Assessment

Secondary: Kaplan Meier Estimates of Overall Survival (OS) Based on the Investigator Response Assessment

Secondary: Kaplan Meier Estimates of Time to Progression (TTP) Based on Response Assessment by the Central Adjudication Committee (CAC)

Secondary: Kaplan Meier Estimates of Time to Progression (TTP) Based on Response Assessment by the Central Adjudication Committee (CAC)

Secondary: Kaplan Meier Estimates of Time to Progression (TTP) Based on the Investigator Assessment with a later cut-off date

Secondary: Kaplan Meier Estimates of Time to Progression (TTP) Based on the Investigator Assessment with a later cut-off date

Secondary: Percentage of subjects in Disease Response Categories Representing Their Best Response During the Double-blind Treatment Period

Secondary: Percentage of subjects in Disease Response Categories Representing Their Best Response During the Double-blind Treatment Period

Secondary: Percentage of Participants in Disease Response Categories Representing Their Best Response During the Treatment Period (Induction plus maintenance) based on the investigators assessment

Secondary: Percentage of Participants in Disease Response Categories Representing Their Best Response During the Treatment Period (Induction plus maintenance) based on the investigators assessment

Secondary: Time to First Response

Secondary: Time to First Response

Secondary: Time to First Response based On a later cut-off date

Secondary: Time to First Response based On a later cut-off date

Secondary: Kaplan Meier Estimates for Duration of Response as Determined by the Central Adjudication Committee (CAC)

Secondary: Kaplan Meier Estimates for Duration of Response as Determined by the Central Adjudication Committee (CAC)

Secondary: Kaplan Meier Estimates for Duration of Myeloma Response as determined by the investigators review with a later cut-off date

Secondary: Kaplan Meier Estimates for Duration of Myeloma Response as determined by the investigators review with a later cut-off date

Secondary: Kaplan Meier Estimates for Time to Next Antimyeloma Therapy

Secondary: Kaplan Meier Estimates for Time to Next Antimyeloma Therapy

Secondary: Number of Subjects with Adverse Events (AEs) During the Induction-Maintenance Period

Secondary: Number of Subjects with Adverse Events (AEs) During the Induction-Maintenance Period

Secondary: Number of Subjects with AEs During the Open-Label Extension Phase (OLEP)

Secondary: Number of Subjects with AEs During the Open-Label Extension Phase (OLEP)

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Quality of Life Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Quality of Life Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Physical Functioning Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Physical Functioning Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Role Functioning Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Role Functioning Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Emotional Functioning Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Emotional Functioning Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Cognitive Functioning Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Cognitive Functioning Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Fatigue Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Fatigue Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Nausea and Vomiting Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Nausea and Vomiting Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Pain Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Pain Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Dyspnoea Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Dyspnoea Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Insomnia Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Insomnia Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Appetite Loss Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Appetite Loss Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Constipation Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Constipation Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Diarrhoea Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Diarrhoea Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Financial Difficulties Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13 and 16 in European Organization for Research and Treatment of Cancer Questionnaire for Patients With Cancer (EORTC QLQ-C30) Financial Difficulties Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 and 19 in 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 to Cycles 4, 7, 10, 13, 16 and 19 in 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 to Cycles 4, 7, 10, 13, 16 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) In Side Effects of Treatment Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) In Side Effects of Treatment Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) In Future Perspective Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) In Future Perspective Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) In Body Image Scale

Secondary: Change From Baseline to Cycles 4, 7, 10, 13, 16 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) In Body Image Scale

Secondary: Percentage of participants who received anti-myeloma salvage therapy at the time of progressive disease