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Clinical Trial Results:
Study of Daratumumab in Combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) in the First Line Treatment of Transplant Eligible Subjects with Newly Diagnosed Multiple Myeloma

Summary
EudraCT number	2014-004781-15
Trial protocol	NL FR BE
Global end of trial date	01 Sep 2023

Results information
Results version number	v1(current)
This version publication date	31 Jul 2025
First version publication date	31 Jul 2025
Other versions
Summary report(s)	2014-004781-15_Additional results_30June2025

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

IFM2015-01/HO131/54767414MMY3006

ISRCTN number

US NCT number

NCT02541383

WHO universal trial number (UTN)

Sponsor organisation name

Intergroupe Francophone du Myelome (IFM)

Sponsor organisation address

75 avenue Parmentier, Paris, France,

Public contact

Chief Executive Officer, Intergroupe Francophone du Myelome (IFM), IFMclinicaltrials@myelome.fr

Scientific contact

Chief Executive Officer, Intergroupe Francophone du Myelome (IFM), IFMclinicaltrials@myelome.fr

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

01 Sep 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Sep 2023

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to evaluate if the addition of daratumumab to Bortezomib, Thalidomide and Dexamethasone will increase the stringent complete response rate after consolidation therapy (part 1) and increase the progression free survival after daratumumab maintenance therapy (part 2) in transplant eligible participants with previously untreated Multiple Myeloma.

Protection of trial subjects

The protocol, protocol amendments, Informed Consent Form (ICF), Investigator’s Brochure, and other relevant documents (eg, advertisements) were submitted to an Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) by the investigator and reviewed and approved by the IRB/IEC before the study was initiated. Any amendments to the protocol required IRB/IEC approval before implementation of changes made. As applicable according to local regulations, the protocol and all protocol amendments were reviewed and approved by each pertinent Competent Authority. This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice (GCP) and applicable regulatory requirements. Participants or their legally acceptable representatives provided their written consent to participate in the study after having been informed about the nature and purpose of the study, participation/termination conditions, and risks and benefits of treatment. Informed consent was obtained during the Screening Phase prior to enrollment. A copy of the ICF(s) was provided to the participant or the participant’s legally acceptable representative. Personal data from participants enrolled in this study were limited to those data necessary to investigate the efficacy, safety, quality, and utility of the investigational study intervention(s) used in this study and were collected and processed with adequate precautions to ensure confidentiality and compliance with applicable data privacy protection laws and regulations. An Independent Data Monitoring Committee (IDMC) reviewed safety data after 100 subjects had completed consolidation therapy. Subsequently, the IDMC was to review safety data at regular intervals during the study (ie, every 6 months).

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Sep 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 89

Country: Number of subjects enrolled

France: 854

Country: Number of subjects enrolled

Netherlands: 142

Worldwide total number of subjects

1085

EEA total number of subjects

1085

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)

1004

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Planned: 1080 subjects (540/arm) for first randomization (induction) Actual: 1085 subjects randomized in the first randomization.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

VTd only

Arm description

All patients randomized to the VTd group (Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 (even those who didn't receive any study treatment), not re-randomized in maintenance phase.

Arm type

Active comparator

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 1.3 mg/m2 bortezomib as a subcutaneaous injection twice a week (Days 1, 4, 8, and 11) for four 28-day induction cycles (Cycles 1 to 4), and two consolidation cycles (Cycles 5 and 6), with an option to change the schedule from twice a week to once a week, should toxicity be encountered. Cycles remained 28 days in length regardless of injection interval.

Investigational medicinal product name

Thalidomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Thalidomide was administered Per Os at 100 mg daily for 4 x28 days induction cycles and 2 x 28 days consolidation cycles. Thalidomide had to be taken as a single dose at bedtime, to reduce the impact of somnolence. Thalidomide could be taken with or without food. Breaking or dividing thalidomide was strongly discouraged.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

DVTd only

Arm description

All patients randomized to the DVTd group (Daratumumab, Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 (even those who didn't receive any study treatment), not re-randomized in maintenance phase.

Arm type

Experimental

Investigational medicinal product name

Daratumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Investigational medicinal product name

Thalidomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection, Tablet

Routes of administration

Intravenous use, Oral use

Dosage and administration details

Dexamethasone was administered at 40 mg during Cycles 1 and 2 on Days 1-2, Days 8-9, Days 15-16 and Days 22-23. In Cycles 3 and 4, dexamethasone was administered at 40 mg on Days 1-2 and 20 mg on Days 8-9 and Days 15-16. Dexamethasone 20 mg was administered in Cycles 5 and 6 on Days 1-2, Days 8-9 and Days 15-16. Dexamethasone tablets was to be taken with or immediately after a meal or snack, preferably in the morning On daratumumab infusion days, in the induction/consolidation phase, dexamethasone could be administered intravenously 1 hour before the daratumumab infusion. On days when daratumumab was not administered, dexamethasone was administered Per Os.

VTd-OBS

Arm description

All patients randomized to the VTd group (Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 (even those who didn't receive any study treatment), re-randomized to observation

Arm type

Part1:Active comparator - Part2:No Intervention

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Investigational medicinal product name

Thalidomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

VTd-DARA

Arm description

All patients randomized to the VTd group (Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 (even those who didn't receive any study treatment), re-randomized to daratumumab monotherapy

Arm type

Part1:Active comparator - Part2:Experimental

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Investigational medicinal product name

Thalidomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Daratumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Following second randomization, subjects assigned to the daratumumab maintenance arm received daratumumab (16mg/kg) once every 8 weeks until documented disease progression (limited to a maximum duration of 2 years).

DVTd-OBS

Arm description

Arm type

Part1:Experimental - Part2:No Intervention

Investigational medicinal product name

Daratumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Investigational medicinal product name

Thalidomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection, Tablet

Routes of administration

Intravenous use, Oral use

Dosage and administration details

Dexamethasone was administered at 40 mg during Cycles 1 and 2 on Days 1-2, Days 8-9, Days 15-16 and Days 22-23. In Cycles 3 and 4, dexamethasone was administered at 40 mg on Days 1-2 and 20 mg on Days 8-9 and Days 15-16. Dexamethasone 20 mg was administered in Cycles 5 and 6 on Days 1-2, Days 8-9 and Days 15-16. Dexamethasone tablets was to be taken with or immediately after a meal or snack, preferably in the morning. On daratumumab infusion days, in the induction/consolidation phase, dexamethasone could be administered intravenously 1 hour before the daratumumab infusion. On days when daratumumab was not administered, dexamethasone was administered Per Os.

DVTd-DARA

Arm description

Arm type

Part1:Experimental - Part2:Experimental

Investigational medicinal product name

Daratumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Daratumumab (16mg/kg) was administered by intravenous (IV) infusion once every week for 8 weeks (VTD induction Cycle 1-2), then every 2 weeks for the 2 remaining induction cycles and the 2 consolidation cycles. Following second randomization, subjects assigned to the daratumumab maintenance arm received daratumumab (16mg/kg) once every 8 weeks until documented disease progression (limited to a maximum duration of 2 years).

Investigational medicinal product name

Bortezomib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Investigational medicinal product name

Thalidomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection, Tablet

Routes of administration

Intravenous use, Oral use

Dosage and administration details

Dexamethasone was administered at 40 mg during Cycles 1 and 2 on Days 1-2, Days 8-9, Days 15-16 and Days 22-23. In Cycles 3 and 4, dexamethasone was administered at 40 mg on Days 1-2 and 20 mg on Days 8-9 and Days 15-16. Dexamethasone 20 mg was administered in Cycles 5 and 6 on Days 1-2, Days 8-9 and Days 15-16. Dexamethasone tablets was to be taken with or immediately after a meal or snack, preferably in the morning. On daratumumab infusion days, in the induction/consolidation phase, dexamethasone could be administered intravenously 1 hour before the daratumumab infusion. On days when daratumumab was not administered, dexamethasone was administered Per Os.

Number of subjects in period 1	VTd only	DVTd only	VTd-OBS	VTd-DARA	DVTd-OBS	DVTd-DARA
Started	114	85	215	213	229	229
Completed	53	38	165	170	205	204
Not completed	61	47	50	43	24	25
Adverse event, serious fatal	50	37	48	41	21	25
Sponsor's decision	1	1	-	-	-	-
Consent withdrawn by subject	5	6	1	1	-	-
Lost to follow-up	5	3	1	1	3	-

Baseline characteristics

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Reporting group title

VTd only

Reporting group description

Reporting group title

DVTd only

Reporting group description

Reporting group title

VTd-OBS

Reporting group description

All patients randomized to the VTd group (Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 (even those who didn't receive any study treatment), re-randomized to observation

Reporting group title

VTd-DARA

Reporting group description

Reporting group title

DVTd-OBS

Reporting group description

Reporting group title

DVTd-DARA

Reporting group description

Reporting group values	VTd only	DVTd only	VTd-OBS	VTd-DARA	DVTd-OBS	DVTd-DARA	Total
Number of subjects	114	85	215	213	229	229	1085
Title for AgeCategorical
Units: subjects
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	105	77	200	194	216	212	1004
From 65 to 84 years	9	8	15	19	13	17	81
85 years and over	0	0	0	0	0	0	0
Title for AgeContinuous
Units: years
arithmetic mean (standard deviation)	57.7 ( 6.36 )	57.8 ( 7.5 )	56 ( 6.96 )	56.3 ( 7.38 )	56.8 ( 6.83 )	56.4 ( 6.79 )	-
Title for Gender
Units: subjects
Female	42	37	94	87	96	94	450
Male	72	48	121	126	133	135	635
Baseline ISS Stage
The International Staging System (ISS) for Multiple Myeloma was established by the International Myeloma Working Group (IMWG) in 2005. Sβ2M = Serum β2 microglobulin. Stage I is defined by Sβ2M < 3.5 mg/L and serum albumin ≥ 3.5 g/dL - Stage II is defined by Sβ2M < 3.5 mg/L and serum albumin < 3.5 g/dL; or Sβ2M ≥ 3.5 mg/L and < 5.5 mg/L, irrespective of serum albumin – Stage Ill is defined by Sβ2M ≥ 5.5 mg/L. Stage I is considered to have a better prognosis and stage Ill a worse prognosis.
Units: Subjects
Stage I	47	25	88	93	83	96	432
Stage II	52	41	96	85	118	96	488
Stage III	15	19	31	35	28	37	165
Baseline Type of Myeloma
Multiple myeloma has different types of monoclonal proteins. These types are based on the immunoglobulin (protein) produced by the myeloma cell and they are identified by immunofixation method. The five types of heavy protein chains are G, A, D, E, and M. The two types of light protein chains are kappa (Κ) and lambda (λ). The myeloma cells may secrete heavy and light protein chains (i.e. lgG Kappa) but also only light protein chains. Row "Biclonal" = the myeloma cells (plasmocytes) produce two immunoglobulins with heavy chains. Row"negative immunofixation" = absence of monoclonal proteins
Units: Subjects
Biclonal	1	2	10	8	5	5	31
IgA	15	14	46	43	36	37	191
IgD	3	1	3	7	2	2	18
IgG	79	54	126	128	159	138	684
IgM	0	0	1	1	0	1	3
Kappa	11	9	17	18	17	27	99
Lambda	3	5	10	7	8	17	50
Negative Immunofixation	2	0	2	1	2	2	9
Presence of diffuse myeloma-related osteopenia
Units: Subjects
No	100	76	197	194	203	208	978
Yes	14	9	18	17	25	19	102
Missing	0	0	0	2	1	2	5
Presence of evaluable bone marrow assessment
Units: Subjects
No	3	0	3	3	4	6	19
Yes	111	85	212	210	225	223	1066
Bone marrow cellularity
A sample of bone marrow aspirate was analyzed to count the cells and assess the cellular richness
Units: Subjects
Hypercellular	30	28	62	63	62	46	291
Normocellular	52	31	78	93	101	112	467
Moderately cellular	24	19	50	42	41	47	223
Severely acellular	5	3	13	5	14	10	50
Indeterminate	1	3	8	8	6	8	34
Missing	2	1	4	2	5	6	20
Time since initial diagnosis to randomization
Units: months
arithmetic mean (standard deviation)	1.6 ( 2.65 )	1.3 ( 0.96 )	1.2 ( 0.86 )	1.2 ( 0.87 )	1.2 ( 1.08 )	1.2 ( 0.95 )	-

End points

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Reporting group title

VTd only

Reporting group description

Reporting group title

DVTd only

Reporting group description

Reporting group title

VTd-OBS

Reporting group description

All patients randomized to the VTd group (Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 (even those who didn't receive any study treatment), re-randomized to observation

Reporting group title

VTd-DARA

Reporting group description

Reporting group title

DVTd-OBS

Reporting group description

Reporting group title

DVTd-DARA

Reporting group description

Subject analysis set title

Set VTd Part 1

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects allocated to the treatment "Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTd)" at the randomization 1 (part 1) Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTd): Part 1: 4 Cycles of Bortezomib, Thalidomide and Dexamethasone induction therapy, followed by Autologous Stem Cell Transplantation, followed by 2 cycles of Bortezomib, Thalidomide and Dexamethasone consolidation

Subject analysis set title

Set VTd-Dara Part 1

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects allocated to the treatment "Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) plus daratumumab" at the randomization 1 (part 1). Bortezomib, Thalidomide, Dexamethasone (VTd) + daratumumab: Part 1: 4 Cycles of Bortezomib, Thalidomide and Dexamethasone plus daratumumab 16mg/kg induction therapy, followed by Autologous Stem Cell Transplantation, followed by 2 cycles of Bortezomib, Thalidomide and Dexamethasone plus daratumumab 16 mg/kg consolidation

Subject analysis set title

Set OBS Part 2

Subject analysis set type

Intention-to-treat

Subject analysis set description

OBS = observation All subjects randomized to the Observation group (no intervention) at randomization 2 for the maintenance phase (Part 2) whatever the treatment allocated at randomization 1

Subject analysis set title

Set DARA Part 2

Subject analysis set type

Intention-to-treat

Subject analysis set description

DARA = Daratumumab All subjects randomized to the Daratumumab group at randomization 2 for the maintenance phase (Part 2), even those who didn't receive any treatment dose, and whatever the treatment allocated at randomization 1. Daratumumab 16mg/kg every 8 weeks for 2 years.

Subject analysis set title

Set VTd Part 1 up to End of Study

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomized to the VTd group (Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 whether they subsequently had randomization 2 or not, even those who didn't receive any treatment dose.

Subject analysis set title

Set VTd-Dara Part 1 up to End of Study

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomized to the DVTd group (Daratumumab in combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 whether they subsequently had randomization 2 or not, even those who didn't receive any treatment dose.

Primary: Post-Consolidation Stringent Complete Response (sCR) Rate

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End point title

Post-Consolidation Stringent Complete Response (sCR) Rate

End point description

Post-consolidation sCR rate is defined as the percentage of ITT subjects who achieved or maintained sCR status within 30 days of Day 100 post Autologous Stem Cell Transplant (ASCT). The sCR status is assessed using the computerized algorithm according to IMWG response criteria, and must be achieved on or prior to start of subsequent therapies. Subjects must not die or progress by Day 100 post ASCT. According to the IMWG consensus recommendations for multiple myeloma treatment response criteria from 2006, the stringent complete response (sCR) was defined by a negative immunofixation on the serum and urine, and a disappearance of any soft tissue plasmacytomas, and < 5% plasma cells in bone marrow, plus normal free-light chain ratio and the absence of clonal bone marrow plasma cells by immunohistochemistry, immunofluorescence or 2- to 4- color flow cytometry.

End point type

Primary

End point timeframe

At day 100 post Autologous Stem Cell Transplant (ASCT), up to 114 days post ASCT

End point values	Set VTd Part 1	Set VTd-Dara Part 1
Number of subjects analysed	542	543
Units: Subjects	110	157

Post-Consolidation sCR Rate

Statistical analysis description

sCR = Stringent Complete Response

Comparison groups

Set VTd Part 1 v Set VTd-Dara Part 1

Number of subjects included in analysis

1085

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

1.21

upper limit

2.12

Adverse events

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Timeframe for reporting adverse events

AEs that started during the study treatment until 30 days after the last dose of study treatment, approximately 59 months, except for secondary malignancies and deaths followed until the end of the study.

Adverse event reporting additional description

For subjects randomized to Observation arm in the Maintenance Phase, AE were collected for 2 years after the second randomization, or upon disease progression, withdrawal of consent, death or start of new anticancer therapy (whichever occured first in the Maintenance Phase), even though no study drug was administered.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

VTd - Part 1

Reporting group description

All subjects randomized to the VTd group (Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 (whether they subsequently had randomization 2 or not) and who received at least one dose of study treatment. Reported SAEs/AEs correspond to those considered treatment emergent (TEAE) to Part 1 only, from the first dose of study treatment to randomization 2 or subsequent therapy (ST) initiation (whichever occurred first), or after randomization 2 if TEAE related to the Part 1 treatment. It includes deaths occurred from randomization 1 to the end of the study.

Reporting group title

DVTd - Part 1

Reporting group description

All subjects randomized to the DVTd group (Daratumumab in combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 (whether they subsequently had randomization 2 or not) and who received at least one dose of study treatment. Reported SAEs/AEs correspond to those considered treatment emergent (TEAE) to Part 1 only, from the first dose of study treatment to randomization 2 or subsequent therapy (ST) initiation (whichever occurred first), or after randomization 2 if TEAE related to the Part 1 treatment. It includes deaths that occurred from randomization 1 to the end of the study.

Reporting group title

VTd-OBS - Part 2

Reporting group description

All subjects randomized to the VTd group (Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 and to observation group (OBS) at randomization 2. Reporting of SAEs/AEs from randomization 2 for 2 years or until disease progression, withdrawal of consent, death or initiation of subsequent therapy (whichever occurred first), even though no study drug was administered during maintenance phase. It includes deaths that occurred from randomization 2 to the end of the study. That means that all deaths reported in this group are also reported in the VTd - Part 1 group.

Reporting group title

VTd-DARA - Part 2

Reporting group description

All subjects randomized to the VTd group (Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 and to daratumumab group (DARA) at randomization 2. Reported SAEs/AEs correspond to those considered treatment emergent (TEAE) to Part 2 from randomization 2 up to 30 days after the last dose of study treatment or subsequent therapy (ST) initiation (whichever occurred first). It includes deaths that occurred from randomization 2 to the end of the study. That means that all deaths reported in this group are also reported in the VTd - Part 1 group.

Reporting group title

DVTd-OBS - Part 2

Reporting group description

All subjects randomized to the DVTd group (Daratumumab in combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 and to observation group (OBS) at randomization 2. Reporting of SAEs/AEs from randomization 2 for 2 years or until disease progression, withdrawal of consent, death or initiation of subsequent therapy (whichever occurred first), even though no study drug was administered during maintenance phase. It includes deaths that occurred from randomization 2 to the end of the study. That means that all deaths reported in this group are also reported in the DVTd - Part 1 group.

Reporting group title

DVTd-DARA - Part 2

Reporting group description

All subjects randomized to the DVTd group (Daratumumab in combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone) at randomization 1 and to daratumumab group (DARA) at randomization 2. Reported SAEs/AEs correspond to those considered treatment emergent (TEAE) to Part 2 from randomization 2 up to 30 days after the last dose of study treatment or subsequent therapy (ST) initiation (whichever occurred first). It includes deaths that occurred from randomization 2 to the end of the study. That means that all deaths reported in this group are also reported in the DVTd - Part 1 group.

Serious adverse events	VTd - Part 1	DVTd - Part 1	VTd-OBS - Part 2	VTd-DARA - Part 2	DVTd-OBS - Part 2	DVTd-DARA - Part 2
Total subjects affected by serious adverse events
subjects affected / exposed	261 / 538 (48.51%)	264 / 536 (49.25%)	35 / 215 (16.28%)	58 / 211 (27.49%)	50 / 229 (21.83%)	43 / 229 (18.78%)
number of deaths (all causes)	138	81	48	41	21	25
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Myeloid Leukaemia
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Adenocarcinoma of Colon
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Blastic Plasmacytoid Dendritic Cell Neoplasia
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Bladder Cancer Recurrent
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Bladder Cancer
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Basal Cell Carcinoma
subjects affected / exposed	2 / 538 (0.37%)	2 / 536 (0.37%)	2 / 215 (0.93%)	2 / 211 (0.95%)	0 / 229 (0.00%)	2 / 229 (0.87%)
occurrences causally related to treatment / all	1 / 2	0 / 2	0 / 2	1 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaplastic Thyroid Cancer
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Bowen's Disease
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Invasive Ductal Breast Carcinoma
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Intraductal Proliferative Breast Lesion
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Gastrointestinal Tract Adenoma
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Cancer Pain
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Breast Cancer
subjects affected / exposed	0 / 538 (0.00%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 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
Lip Squamous Cell Carcinoma
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Natural Killer-Cell Lymphoblastic Lymphoma
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Myelodysplastic Syndrome
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Malignant Melanoma
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Lung Cancer Metastatic
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung Adenocarcinoma
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal Oncocytoma
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Prostate Cancer
subjects affected / exposed	2 / 538 (0.37%)	1 / 536 (0.19%)	0 / 215 (0.00%)	2 / 211 (0.95%)	1 / 229 (0.44%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	1 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Plasma Cell Myeloma
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pituitary Tumour Benign
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Squamous Cell Carcinoma of Skin
subjects affected / exposed	1 / 538 (0.19%)	2 / 536 (0.37%)	1 / 215 (0.47%)	2 / 211 (0.95%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 1	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Papillary Thyroid Cancer
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
T-Cell Lymphoma
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Thyroid Cancer
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Vascular disorders
Arteritis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Deep Vein Thrombosis
subjects affected / exposed	7 / 538 (1.30%)	3 / 536 (0.56%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 7	0 / 3	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
Hypertension
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	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	1 / 538 (0.19%)	2 / 536 (0.37%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	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
Orthostatic Hypotension
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Peripheral Artery Thrombosis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Peripheral Ischaemia
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Vena Cava Thrombosis
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Thrombophlebitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Phlebitis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Venous Thrombosis
subjects affected / exposed	1 / 538 (0.19%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 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
General disorders and administration site conditions
Chest Discomfort
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Asthenia
subjects affected / exposed	3 / 538 (0.56%)	3 / 536 (0.56%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	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
Chest Pain
subjects affected / exposed	3 / 538 (0.56%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 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
Hernia
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Hyperthermia
subjects affected / exposed	2 / 538 (0.37%)	3 / 536 (0.56%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	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	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Death
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
General Physical Health Deterioration
subjects affected / exposed	3 / 538 (0.56%)	6 / 536 (1.12%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 6	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
Influenza Like Illness
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inflammation
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Malaise
subjects affected / exposed	1 / 538 (0.19%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	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
Medical Device Site Joint Pain
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Mucosal Inflammation
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Oedema Peripheral
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Non-Cardiac Chest Pain
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Sudden Death
subjects affected / exposed	2 / 538 (0.37%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	22 / 538 (4.09%)	15 / 536 (2.80%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	2 / 229 (0.87%)
occurrences causally related to treatment / all	0 / 23	3 / 16	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic Shock
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Sarcoidosis
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Hypersensitivity
subjects affected / exposed	2 / 538 (0.37%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 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
Reproductive system and breast disorders
Endometrial Hyperplasia
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Erectile Dysfunction
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Genital Prolapse
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Prostatitis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Uterine Cervical Metaplasia
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Distress Syndrome
subjects affected / exposed	0 / 538 (0.00%)	3 / 536 (0.56%)	1 / 215 (0.47%)	1 / 211 (0.47%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute Pulmonary Oedema
subjects affected / exposed	1 / 538 (0.19%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Acute Respiratory Failure
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Asthma
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumopathy
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Bronchospasm
subjects affected / exposed	0 / 538 (0.00%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	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
Chronic Obstructive Pulmonary Disease
subjects affected / exposed	0 / 538 (0.00%)	3 / 536 (0.56%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 4	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
Dyspnoea
subjects affected / exposed	4 / 538 (0.74%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 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
Eosinophilic Pneumonia
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Dyspnoea Exertional
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 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
Idiopathic Interstitial Pneumonia
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Interstitial Lung Disease
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Lung Disorder
subjects affected / exposed	6 / 538 (1.12%)	10 / 536 (1.87%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 6	5 / 10	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
Pharyngeal Oedema
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pneumonia Aspiration
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pneumonitis
subjects affected / exposed	2 / 538 (0.37%)	5 / 536 (0.93%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 5	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
Pulmonary Embolism
subjects affected / exposed	20 / 538 (3.72%)	8 / 536 (1.49%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 20	1 / 8	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Distress
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Respiratory Failure
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Sinus Polyp
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Abnormal Behaviour
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Depression
subjects affected / exposed	4 / 538 (0.74%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 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
Delusional Disorder, Unspecified Type
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Confusional State
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Anxiety Disorder
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Anxiety
subjects affected / exposed	0 / 538 (0.00%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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
Major Depression
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Suicide Attempt
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Mental Disorder
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Product issues
Device Breakage
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Investigations
Hepatic Enzyme Abnormal
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
General Physical Condition Abnormal
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Blood Creatinine Increased
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Injury, poisoning and procedural complications
Blood Stem Cell Harvest Failure
subjects affected / exposed	0 / 538 (0.00%)	3 / 536 (0.56%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 3	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
Femur Fracture
subjects affected / exposed	2 / 538 (0.37%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Femoral Neck Fracture
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Burns Second Degree
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Forearm Fracture
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Fractured Sacrum
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Fracture
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Hand Fracture
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Hip Fracture
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Humerus Fracture
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infusion Related Reaction
subjects affected / exposed	0 / 538 (0.00%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Jaw Fracture
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Lumbar Vertebral Fracture
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	1 / 211 (0.47%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pelvic Fracture
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Perirenal Haematoma
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Product Preparation Error
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Post Procedural Complication
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Rib Fracture
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Spinal Fracture
subjects affected / exposed	3 / 538 (0.56%)	2 / 536 (0.37%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 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
Spinal Compression Fracture
subjects affected / exposed	5 / 538 (0.93%)	3 / 536 (0.56%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 3	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
Tendon Rupture
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Upper Limb Fracture
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Toxicity to Various Agents
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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
Thoracic Vertebral Fracture
subjects affected / exposed	3 / 538 (0.56%)	0 / 536 (0.00%)	2 / 215 (0.93%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 4	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
Wrist Fracture
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Congenital, familial and genetic disorders
Fanconi Syndrome
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cardiac disorders
Angina Pectoris
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Acute Coronary Syndrome
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Atrial Tachycardia
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Atrial Flutter
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Atrial Fibrillation
subjects affected / exposed	6 / 538 (1.12%)	1 / 536 (0.19%)	0 / 215 (0.00%)	2 / 211 (0.95%)	1 / 229 (0.44%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular Block
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Arrhythmia Supraventricular
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cardiac Arrest
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cardiac Amyloidosis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Cardiac Failure
subjects affected / exposed	5 / 538 (0.93%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 5	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
Cardiac Failure Acute
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cardiac Failure Congestive
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Coronary Artery Disease
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Coronary Artery Stenosis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Mitral Valve Prolapse
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Myocardial Infarction
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Paroxysmal Arrhythmia
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Myocarditis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Myocardial Ischaemia
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Pericardial Effusion
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pericarditis
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Sinus Tachycardia
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Supraventricular Tachycardia
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Tachycardia
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Ventricular Fibrillation
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Nervous system disorders
Acute Motor-Sensory Axonal Neuropathy
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Amnestic Disorder
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Autonomic Neuropathy
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cerebellar Haematoma
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cerebral Haemorrhage
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cerebrovascular Accident
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cervicobrachial Syndrome
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Encephalopathy
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Epidural Lipomatosis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Headache
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Hemiparaesthesia
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Hemiparesis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Neuropathy Peripheral
subjects affected / exposed	1 / 538 (0.19%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 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
Neuralgia
subjects affected / exposed	2 / 538 (0.37%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Ischaemic Stroke
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Paraesthesia
subjects affected / exposed	2 / 538 (0.37%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Paraparesis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Peripheral Motor Neuropathy
subjects affected / exposed	2 / 538 (0.37%)	2 / 536 (0.37%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 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
Peripheral Sensorimotor Neuropathy
subjects affected / exposed	2 / 538 (0.37%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 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
Peripheral Sensory Neuropathy
subjects affected / exposed	16 / 538 (2.97%)	11 / 536 (2.05%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 16	0 / 11	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
Polyneuropathy
subjects affected / exposed	4 / 538 (0.74%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 5	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
Posterior Reversible Encephalopathy Syndrome
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Spinal Cord Compression
subjects affected / exposed	5 / 538 (0.93%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 6	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
Seizure
subjects affected / exposed	2 / 538 (0.37%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Sciatica
subjects affected / exposed	2 / 538 (0.37%)	0 / 536 (0.00%)	1 / 215 (0.47%)	1 / 211 (0.47%)	1 / 229 (0.44%)	2 / 229 (0.87%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Status Epilepticus
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Syncope
subjects affected / exposed	1 / 538 (0.19%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 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
Transient Ischaemic Attack
subjects affected / exposed	1 / 538 (0.19%)	2 / 536 (0.37%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	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
Transient Global Amnesia
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Blood and lymphatic system disorders
Agranulocytosis
alternative assessment type: Systematic
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Eosinophilia
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Anaemia
subjects affected / exposed	0 / 538 (0.00%)	3 / 536 (0.56%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	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
Febrile Bone Marrow Aplasia
subjects affected / exposed	12 / 538 (2.23%)	7 / 536 (1.31%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 12	0 / 7	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
Febrile Neutropenia
subjects affected / exposed	16 / 538 (2.97%)	12 / 536 (2.24%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	1 / 16	3 / 12	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
Haemolytic Uraemic Syndrome
subjects affected / exposed	2 / 538 (0.37%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Lymphopenia
subjects affected / exposed	3 / 538 (0.56%)	7 / 536 (1.31%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 3	5 / 10	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	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Histiocytosis Haematophagic
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	2 / 211 (0.95%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	2 / 2	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	8 / 538 (1.49%)	22 / 536 (4.10%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 12	12 / 22	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
Pancytopenia
subjects affected / exposed	0 / 538 (0.00%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 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
Thrombotic Microangiopathy
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Thrombocytopenia
subjects affected / exposed	4 / 538 (0.74%)	12 / 536 (2.24%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 4	2 / 12	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
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Blepharitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Retinal Detachment
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Vision Blurred
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Uveitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal Fistula
subjects affected / exposed	0 / 538 (0.00%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 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
Abdominal Pain Upper
subjects affected / exposed	1 / 538 (0.19%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 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
Colitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Colitis Ischaemic
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Diverticular Perforation
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Diarrhoea
subjects affected / exposed	2 / 538 (0.37%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Constipation
subjects affected / exposed	3 / 538 (0.56%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 4	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
Colitis Ulcerative
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Diverticulum Intestinal Haemorrhagic
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Duodenal Obstruction
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Dysphagia
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Faecaloma
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Hernial Eventration
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Inflammatory Bowel Disease
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Mallory-Weiss Syndrome
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Large Intestine Perforation
subjects affected / exposed	3 / 538 (0.56%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 4	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
Intestinal Obstruction
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Inguinal Hernia
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Nausea
subjects affected / exposed	6 / 538 (1.12%)	6 / 536 (1.12%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 6	1 / 6	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic Colitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pancreatic Cyst
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pancreatitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Pancreatitis Acute
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Pneumoperitoneum
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Proctitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Rectal Haemorrhage
subjects affected / exposed	0 / 538 (0.00%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 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
Umbilical Hernia
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Stomatitis
subjects affected / exposed	5 / 538 (0.93%)	4 / 536 (0.75%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 4	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 Gastrointestinal Haemorrhage
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Vomiting
subjects affected / exposed	3 / 538 (0.56%)	6 / 536 (1.12%)	0 / 215 (0.00%)	2 / 211 (0.95%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 3	1 / 6	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 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
Cholecystitis Acute
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Hepatic Failure
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cholelithiasis
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Hepatocellular Injury
subjects affected / exposed	0 / 538 (0.00%)	3 / 536 (0.56%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 3	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
Hepatomegaly
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Acute Generalised Exanthematous Pustulosis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Drug Reaction with Eosinophilia and Systemic Symptoms
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Toxic Skin Eruption
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Rash Maculo-Papular
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Rash
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Urticaria
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Renal and urinary disorders
Cystitis Haemorrhagic
subjects affected / exposed	2 / 538 (0.37%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Chronic Kidney Disease
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Acute Kidney Injury
subjects affected / exposed	3 / 538 (0.56%)	3 / 536 (0.56%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	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
Myeloma Cast Nephropathy
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Renal Colic
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	1 / 215 (0.47%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Bladder Haemorrhage
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Renal Tubular Necrosis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Renal Impairment
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Renal Failure
subjects affected / exposed	3 / 538 (0.56%)	1 / 536 (0.19%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 3	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
Endocrine disorders
Hyperparathyroidism
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Musculoskeletal and connective tissue disorders
Gouty Arthritis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Bone Pain
subjects affected / exposed	4 / 538 (0.74%)	3 / 536 (0.56%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 4	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
Back Pain
subjects affected / exposed	9 / 538 (1.67%)	9 / 536 (1.68%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 9	0 / 10	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
Arthralgia
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Osteolysis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Osteoarthritis
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	2 / 215 (0.93%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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
Musculoskeletal Pain
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Intervertebral Disc Protrusion
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	2 / 215 (0.93%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Osteonecrosis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 1	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 / 0	0 / 0
Intervertebral Disc Compression
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Rhabdomyolysis
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Spinal Pain
subjects affected / exposed	3 / 538 (0.56%)	2 / 536 (0.37%)	0 / 215 (0.00%)	1 / 211 (0.47%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis of Jaw
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Infections and infestations
Anal Abscess
subjects affected / exposed	3 / 538 (0.56%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Bartholinitis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Appendicitis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Arthritis Bacterial
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Bacterial Sepsis
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Bacterial Pyelonephritis
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Bronchiolitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Bronchitis
subjects affected / exposed	1 / 538 (0.19%)	7 / 536 (1.31%)	0 / 215 (0.00%)	2 / 211 (0.95%)	1 / 229 (0.44%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 1	3 / 7	0 / 0	0 / 2	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic Sinusitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Cellulitis Staphylococcal
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Bronchopulmonary Aspergillosis
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Clostridium Difficile Infection
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cystitis
alternative assessment type: Systematic
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Clostridium Difficile Colitis
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Clostridium Colitis
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Clostridial Infection
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Device Related Sepsis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cytomegalovirus Gastroenteritis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cytomegalovirus Infection
subjects affected / exposed	0 / 538 (0.00%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cytomegalovirus Oesophagitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Dermo-Hypodermitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Eczema Infected
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Ear Infection
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Diverticulitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Encephalitis
subjects affected / exposed	0 / 538 (0.00%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	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
Endocarditis Staphylococcal
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Escherichia Bacteraemia
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Erysipelas
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Epstein-Barr Virus Infection
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Enterococcal Infection
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Escherichia Sepsis
subjects affected / exposed	3 / 538 (0.56%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 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
Fungal Oesophagitis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Gastroenteritis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Gastroenteritis Salmonella
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Gastroenteritis Viral
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Hepatitis E
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infectious Colitis
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Infection
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Herpes Zoster Meningitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Infective Thrombosis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Influenza
subjects affected / exposed	3 / 538 (0.56%)	4 / 536 (0.75%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	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
Intervertebral Discitis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Intestinal Sepsis
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Legionella Infection
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Localised Infection
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Lower Respiratory Tract Infection Viral
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Lung Infection
subjects affected / exposed	2 / 538 (0.37%)	5 / 536 (0.93%)	3 / 215 (1.40%)	3 / 211 (1.42%)	4 / 229 (1.75%)	3 / 229 (1.31%)
occurrences causally related to treatment / all	0 / 2	4 / 6	0 / 3	1 / 3	1 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Parotitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Metapneumovirus Infection
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	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
Meningitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pneumocystis Jirovecii Infection
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pneumococcal Sepsis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Peritonitis
subjects affected / exposed	3 / 538 (0.56%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pneumocystis Jirovecii Pneumonia
subjects affected / exposed	4 / 538 (0.74%)	0 / 536 (0.00%)	1 / 215 (0.47%)	2 / 211 (0.95%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia Fungal
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pneumonia
subjects affected / exposed	9 / 538 (1.67%)	21 / 536 (3.92%)	2 / 215 (0.93%)	4 / 211 (1.90%)	4 / 229 (1.75%)	7 / 229 (3.06%)
occurrences causally related to treatment / all	0 / 9	11 / 24	0 / 2	3 / 4	1 / 4	6 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia Acinetobacter
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pneumonia Bacterial
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	2 / 211 (0.95%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia Escherichia
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pneumonia Haemophilus
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pneumonia Influenzal
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Pneumonia Legionella
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Pneumonia Parainfluenzae Viral
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pneumonia Pneumococcal
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia Pseudomonal
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pneumonia Respiratory Syncytial Viral
subjects affected / exposed	0 / 538 (0.00%)	2 / 536 (0.37%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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
Pneumonia Viral
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Pulmonary Sepsis
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Pyelonephritis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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 Syncytial Virus Infection
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Sepsis
subjects affected / exposed	11 / 538 (2.04%)	7 / 536 (1.31%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 11	1 / 7	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
Salmonella Sepsis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Rhinitis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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 Viral
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (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
Respiratory Tract Infection
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
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
Staphylococcal Infection
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Spinal Cord Infection
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Skin Bacterial Infection
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Sinusitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Septic Shock
subjects affected / exposed	2 / 538 (0.37%)	4 / 536 (0.75%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Staphylococcal Sepsis
subjects affected / exposed	3 / 538 (0.56%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 3	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 Bacteraemia
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Streptococcal Endocarditis
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Streptococcal Infection
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Subcutaneous Abscess
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	1 / 211 (0.47%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Upper Respiratory Tract Infection
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Systemic Mycosis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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
Thrombophlebitis Septic
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Urinary Tract Infection
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Urosepsis
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Varicella
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	1 / 229 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varicella Zoster Virus Infection
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	1 / 211 (0.47%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral Diarrhoea
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	1 / 229 (0.44%)	0 / 229 (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
Viral Infection
subjects affected / exposed	2 / 538 (0.37%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Viral Rhinitis
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Cell Death
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Electrolyte Imbalance
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Diabetic Metabolic Decompensation
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Diabetes Mellitus
subjects affected / exposed	3 / 538 (0.56%)	3 / 536 (0.56%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	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	1 / 538 (0.19%)	4 / 536 (0.75%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	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
Fluid Overload
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Decreased Appetite
subjects affected / exposed	1 / 538 (0.19%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Gout
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Fluid Retention
subjects affected / exposed	2 / 538 (0.37%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Hypercalcaemia
subjects affected / exposed	0 / 538 (0.00%)	2 / 536 (0.37%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 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
Hyponatraemia
subjects affected / exposed	0 / 538 (0.00%)	1 / 536 (0.19%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences causally related to treatment / all	0 / 0	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
Hypokalaemia
subjects affected / exposed	0 / 538 (0.00%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	2 / 229 (0.87%)	0 / 229 (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 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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
Tumour Lysis Syndrome
subjects affected / exposed	1 / 538 (0.19%)	0 / 536 (0.00%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (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	VTd - Part 1	DVTd - Part 1	VTd-OBS - Part 2	VTd-DARA - Part 2	DVTd-OBS - Part 2	DVTd-DARA - Part 2
Total subjects affected by non serious adverse events
subjects affected / exposed	529 / 538 (98.33%)	534 / 536 (99.63%)	170 / 215 (79.07%)	194 / 211 (91.94%)	198 / 229 (86.46%)	205 / 229 (89.52%)
Vascular disorders
Hypertension
subjects affected / exposed	30 / 538 (5.58%)	51 / 536 (9.51%)	4 / 215 (1.86%)	18 / 211 (8.53%)	13 / 229 (5.68%)	10 / 229 (4.37%)
occurrences all number	35	95	5	23	26	15
General disorders and administration site conditions
Injection Site Erythema
subjects affected / exposed	28 / 538 (5.20%)	31 / 536 (5.78%)	0 / 215 (0.00%)	0 / 211 (0.00%)	0 / 229 (0.00%)	0 / 229 (0.00%)
occurrences all number	33	32	0	0	0	0
Influenza Like Illness
subjects affected / exposed	30 / 538 (5.58%)	34 / 536 (6.34%)	20 / 215 (9.30%)	21 / 211 (9.95%)	29 / 229 (12.66%)	32 / 229 (13.97%)
occurrences all number	30	39	21	22	37	37
Fatigue
subjects affected / exposed	85 / 538 (15.80%)	75 / 536 (13.99%)	9 / 215 (4.19%)	14 / 211 (6.64%)	17 / 229 (7.42%)	16 / 229 (6.99%)
occurrences all number	117	106	9	17	21	20
Chills
subjects affected / exposed	22 / 538 (4.09%)	47 / 536 (8.77%)	1 / 215 (0.47%)	8 / 211 (3.79%)	1 / 229 (0.44%)	0 / 229 (0.00%)
occurrences all number	22	53	1	8	1	0
Asthenia
subjects affected / exposed	159 / 538 (29.55%)	176 / 536 (32.84%)	27 / 215 (12.56%)	35 / 211 (16.59%)	26 / 229 (11.35%)	26 / 229 (11.35%)
occurrences all number	190	241	33	43	28	31
Malaise
subjects affected / exposed	25 / 538 (4.65%)	35 / 536 (6.53%)	4 / 215 (1.86%)	6 / 211 (2.84%)	3 / 229 (1.31%)	2 / 229 (0.87%)
occurrences all number	34	37	4	6	3	2
Oedema Peripheral
subjects affected / exposed	154 / 538 (28.62%)	166 / 536 (30.97%)	8 / 215 (3.72%)	9 / 211 (4.27%)	9 / 229 (3.93%)	13 / 229 (5.68%)
occurrences all number	206	228	10	9	12	17
Pyrexia
subjects affected / exposed	104 / 538 (19.33%)	133 / 536 (24.81%)	7 / 215 (3.26%)	20 / 211 (9.48%)	17 / 229 (7.42%)	18 / 229 (7.86%)
occurrences all number	128	188	10	26	21	25
Immune system disorders
Hypogammaglobulinaemia
subjects affected / exposed	29 / 538 (5.39%)	48 / 536 (8.96%)	7 / 215 (3.26%)	30 / 211 (14.22%)	9 / 229 (3.93%)	30 / 229 (13.10%)
occurrences all number	30	50	8	31	9	30
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	63 / 538 (11.71%)	78 / 536 (14.55%)	2 / 215 (0.93%)	20 / 211 (9.48%)	6 / 229 (2.62%)	9 / 229 (3.93%)
occurrences all number	71	88	2	21	6	10
Cough
subjects affected / exposed	52 / 538 (9.67%)	90 / 536 (16.79%)	19 / 215 (8.84%)	41 / 211 (19.43%)	23 / 229 (10.04%)	39 / 229 (17.03%)
occurrences all number	57	109	20	54	27	54
Dyspnoea Exertional
subjects affected / exposed	25 / 538 (4.65%)	27 / 536 (5.04%)	5 / 215 (2.33%)	3 / 211 (1.42%)	6 / 229 (2.62%)	5 / 229 (2.18%)
occurrences all number	29	31	5	3	6	5
Rhinorrhoea
subjects affected / exposed	23 / 538 (4.28%)	45 / 536 (8.40%)	6 / 215 (2.79%)	21 / 211 (9.95%)	10 / 229 (4.37%)	14 / 229 (6.11%)
occurrences all number	25	48	7	22	12	15
Psychiatric disorders
Insomnia
subjects affected / exposed	81 / 538 (15.06%)	64 / 536 (11.94%)	5 / 215 (2.33%)	8 / 211 (3.79%)	5 / 229 (2.18%)	9 / 229 (3.93%)
occurrences all number	91	68	5	9	5	9
Anxiety
subjects affected / exposed	47 / 538 (8.74%)	61 / 536 (11.38%)	3 / 215 (1.40%)	4 / 211 (1.90%)	6 / 229 (2.62%)	3 / 229 (1.31%)
occurrences all number	51	75	4	4	6	3
Investigations
Weight Decreased
subjects affected / exposed	39 / 538 (7.25%)	38 / 536 (7.09%)	1 / 215 (0.47%)	3 / 211 (1.42%)	3 / 229 (1.31%)	4 / 229 (1.75%)
occurrences all number	40	45	1	3	3	4
Nervous system disorders
Dizziness
subjects affected / exposed	32 / 538 (5.95%)	36 / 536 (6.72%)	1 / 215 (0.47%)	2 / 211 (0.95%)	4 / 229 (1.75%)	5 / 229 (2.18%)
occurrences all number	36	42	1	2	5	5
Paraesthesia
subjects affected / exposed	114 / 538 (21.19%)	127 / 536 (23.69%)	4 / 215 (1.86%)	21 / 211 (9.95%)	10 / 229 (4.37%)	15 / 229 (6.55%)
occurrences all number	161	195	4	31	10	18
Headache
subjects affected / exposed	42 / 538 (7.81%)	44 / 536 (8.21%)	5 / 215 (2.33%)	10 / 211 (4.74%)	8 / 229 (3.49%)	6 / 229 (2.62%)
occurrences all number	45	50	6	11	17	6
Dysgeusia
subjects affected / exposed	34 / 538 (6.32%)	50 / 536 (9.33%)	1 / 215 (0.47%)	1 / 211 (0.47%)	1 / 229 (0.44%)	1 / 229 (0.44%)
occurrences all number	37	53	2	1	1	1
Peripheral Sensory Neuropathy
subjects affected / exposed	340 / 538 (63.20%)	325 / 536 (60.63%)	24 / 215 (11.16%)	31 / 211 (14.69%)	27 / 229 (11.79%)	39 / 229 (17.03%)
occurrences all number	718	721	35	42	40	53
Tremor
subjects affected / exposed	58 / 538 (10.78%)	72 / 536 (13.43%)	0 / 215 (0.00%)	2 / 211 (0.95%)	0 / 229 (0.00%)	2 / 229 (0.87%)
occurrences all number	65	88	0	2	0	2
Blood and lymphatic system disorders
Febrile Neutropenia
alternative assessment type: Systematic
subjects affected / exposed	13 / 538 (2.42%)	27 / 536 (5.04%)	1 / 215 (0.47%)	0 / 211 (0.00%)	0 / 229 (0.00%)	1 / 229 (0.44%)
occurrences all number	13	29	1	0	0	1
Anaemia
subjects affected / exposed	78 / 538 (14.50%)	74 / 536 (13.81%)	7 / 215 (3.26%)	8 / 211 (3.79%)	4 / 229 (1.75%)	2 / 229 (0.87%)
occurrences all number	130	118	7	13	9	2
Neutropenia
subjects affected / exposed	83 / 538 (15.43%)	149 / 536 (27.80%)	6 / 215 (2.79%)	7 / 211 (3.32%)	4 / 229 (1.75%)	5 / 229 (2.18%)
occurrences all number	150	281	15	10	4	6
Lymphopenia
subjects affected / exposed	65 / 538 (12.08%)	106 / 536 (19.78%)	5 / 215 (2.33%)	14 / 211 (6.64%)	12 / 229 (5.24%)	19 / 229 (8.30%)
occurrences all number	211	355	9	35	26	32
Leukopenia
subjects affected / exposed	16 / 538 (2.97%)	30 / 536 (5.60%)	1 / 215 (0.47%)	1 / 211 (0.47%)	1 / 229 (0.44%)	1 / 229 (0.44%)
occurrences all number	23	45	1	1	1	1
Thrombocytopenia
subjects affected / exposed	72 / 538 (13.38%)	109 / 536 (20.34%)	4 / 215 (1.86%)	7 / 211 (3.32%)	4 / 229 (1.75%)	10 / 229 (4.37%)
occurrences all number	123	225	8	11	6	15
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	43 / 538 (7.99%)	40 / 536 (7.46%)	6 / 215 (2.79%)	5 / 211 (2.37%)	5 / 229 (2.18%)	6 / 229 (2.62%)
occurrences all number	45	44	6	5	5	6
Eye disorders
Vision Blurred
subjects affected / exposed	31 / 538 (5.76%)	23 / 536 (4.29%)	1 / 215 (0.47%)	1 / 211 (0.47%)	1 / 229 (0.44%)	2 / 229 (0.87%)
occurrences all number	32	24	1	1	1	2
Gastrointestinal disorders
Constipation
subjects affected / exposed	255 / 538 (47.40%)	271 / 536 (50.56%)	2 / 215 (0.93%)	10 / 211 (4.74%)	6 / 229 (2.62%)	7 / 229 (3.06%)
occurrences all number	315	366	2	11	7	7
Diarrhoea
subjects affected / exposed	92 / 538 (17.10%)	105 / 536 (19.59%)	10 / 215 (4.65%)	33 / 211 (15.64%)	16 / 229 (6.99%)	25 / 229 (10.92%)
occurrences all number	106	124	12	40	20	27
Abdominal Pain Upper
subjects affected / exposed	28 / 538 (5.20%)	31 / 536 (5.78%)	5 / 215 (2.33%)	5 / 211 (2.37%)	5 / 229 (2.18%)	8 / 229 (3.49%)
occurrences all number	28	34	6	5	6	11
Abdominal Pain
subjects affected / exposed	22 / 538 (4.09%)	36 / 536 (6.72%)	4 / 215 (1.86%)	7 / 211 (3.32%)	4 / 229 (1.75%)	7 / 229 (3.06%)
occurrences all number	25	37	4	8	4	8
Dry Mouth
subjects affected / exposed	20 / 538 (3.72%)	27 / 536 (5.04%)	2 / 215 (0.93%)	0 / 211 (0.00%)	1 / 229 (0.44%)	1 / 229 (0.44%)
occurrences all number	20	28	2	0	1	1
Nausea
subjects affected / exposed	129 / 538 (23.98%)	159 / 536 (29.66%)	2 / 215 (0.93%)	33 / 211 (15.64%)	4 / 229 (1.75%)	10 / 229 (4.37%)
occurrences all number	160	209	2	34	4	10
Stomatitis
subjects affected / exposed	102 / 538 (18.96%)	93 / 536 (17.35%)	1 / 215 (0.47%)	0 / 211 (0.00%)	2 / 229 (0.87%)	2 / 229 (0.87%)
occurrences all number	107	104	1	0	2	2
Vomiting
subjects affected / exposed	50 / 538 (9.29%)	83 / 536 (15.49%)	2 / 215 (0.93%)	31 / 211 (14.69%)	3 / 229 (1.31%)	8 / 229 (3.49%)
occurrences all number	65	106	2	33	3	9
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	7 / 538 (1.30%)	18 / 536 (3.36%)	4 / 215 (1.86%)	11 / 211 (5.21%)	4 / 229 (1.75%)	7 / 229 (3.06%)
occurrences all number	7	22	4	11	5	8
Erythema
subjects affected / exposed	50 / 538 (9.29%)	61 / 536 (11.38%)	1 / 215 (0.47%)	14 / 211 (6.64%)	1 / 229 (0.44%)	7 / 229 (3.06%)
occurrences all number	60	81	1	14	1	8
Pruritus
subjects affected / exposed	17 / 538 (3.16%)	25 / 536 (4.66%)	2 / 215 (0.93%)	17 / 211 (8.06%)	6 / 229 (2.62%)	7 / 229 (3.06%)
occurrences all number	17	29	2	17	8	7
Rash
subjects affected / exposed	64 / 538 (11.90%)	80 / 536 (14.93%)	4 / 215 (1.86%)	17 / 211 (8.06%)	7 / 229 (3.06%)	8 / 229 (3.49%)
occurrences all number	74	95	5	18	7	10
Dry Skin
subjects affected / exposed	35 / 538 (6.51%)	29 / 536 (5.41%)	2 / 215 (0.93%)	4 / 211 (1.90%)	6 / 229 (2.62%)	5 / 229 (2.18%)
occurrences all number	37	30	2	4	6	6
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	48 / 538 (8.92%)	49 / 536 (9.14%)	32 / 215 (14.88%)	19 / 211 (9.00%)	31 / 229 (13.54%)	26 / 229 (11.35%)
occurrences all number	58	62	37	22	37	29
Arthralgia
subjects affected / exposed	28 / 538 (5.20%)	26 / 536 (4.85%)	24 / 215 (11.16%)	20 / 211 (9.48%)	27 / 229 (11.79%)	31 / 229 (13.54%)
occurrences all number	32	26	29	24	32	33
Bone Pain
subjects affected / exposed	82 / 538 (15.24%)	68 / 536 (12.69%)	18 / 215 (8.37%)	24 / 211 (11.37%)	14 / 229 (6.11%)	19 / 229 (8.30%)
occurrences all number	97	84	21	29	16	21
Musculoskeletal Pain
subjects affected / exposed	9 / 538 (1.67%)	17 / 536 (3.17%)	6 / 215 (2.79%)	8 / 211 (3.79%)	16 / 229 (6.99%)	11 / 229 (4.80%)
occurrences all number	10	18	6	9	16	11
Myalgia
subjects affected / exposed	34 / 538 (6.32%)	40 / 536 (7.46%)	7 / 215 (3.26%)	11 / 211 (5.21%)	8 / 229 (3.49%)	20 / 229 (8.73%)
occurrences all number	38	43	7	14	8	26
Pain in Extremity
subjects affected / exposed	44 / 538 (8.18%)	36 / 536 (6.72%)	3 / 215 (1.40%)	9 / 211 (4.27%)	11 / 229 (4.80%)	17 / 229 (7.42%)
occurrences all number	52	38	4	10	11	18
Muscle Spasms
subjects affected / exposed	38 / 538 (7.06%)	33 / 536 (6.16%)	10 / 215 (4.65%)	15 / 211 (7.11%)	3 / 229 (1.31%)	9 / 229 (3.93%)
occurrences all number	40	39	11	19	3	11
Infections and infestations
Nasopharyngitis
subjects affected / exposed	33 / 538 (6.13%)	60 / 536 (11.19%)	20 / 215 (9.30%)	37 / 211 (17.54%)	29 / 229 (12.66%)	39 / 229 (17.03%)
occurrences all number	42	69	29	54	36	56
Herpes Zoster
subjects affected / exposed	21 / 538 (3.90%)	27 / 536 (5.04%)	26 / 215 (12.09%)	14 / 211 (6.64%)	39 / 229 (17.03%)	17 / 229 (7.42%)
occurrences all number	23	28	27	14	40	18
Pneumonia
subjects affected / exposed	18 / 538 (3.35%)	19 / 536 (3.54%)	6 / 215 (2.79%)	7 / 211 (3.32%)	8 / 229 (3.49%)	12 / 229 (5.24%)
occurrences all number	23	19	7	8	8	15
Bronchitis
subjects affected / exposed	79 / 538 (14.68%)	107 / 536 (19.96%)	71 / 215 (33.02%)	77 / 211 (36.49%)	63 / 229 (27.51%)	93 / 229 (40.61%)
occurrences all number	94	136	100	126	102	151
Gastroenteritis
subjects affected / exposed	5 / 538 (0.93%)	15 / 536 (2.80%)	13 / 215 (6.05%)	16 / 211 (7.58%)	16 / 229 (6.99%)	22 / 229 (9.61%)
occurrences all number	5	15	15	16	21	23
Rhinitis
subjects affected / exposed	19 / 538 (3.53%)	34 / 536 (6.34%)	9 / 215 (4.19%)	19 / 211 (9.00%)	13 / 229 (5.68%)	20 / 229 (8.73%)
occurrences all number	19	36	10	24	14	26
Upper Respiratory Tract Infection
subjects affected / exposed	20 / 538 (3.72%)	40 / 536 (7.46%)	9 / 215 (4.19%)	29 / 211 (13.74%)	27 / 229 (11.79%)	35 / 229 (15.28%)
occurrences all number	22	57	18	34	43	50
Sinusitis
subjects affected / exposed	17 / 538 (3.16%)	20 / 536 (3.73%)	15 / 215 (6.98%)	18 / 211 (8.53%)	9 / 229 (3.93%)	13 / 229 (5.68%)
occurrences all number	19	25	19	21	10	21
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	36 / 538 (6.69%)	39 / 536 (7.28%)	2 / 215 (0.93%)	1 / 211 (0.47%)	3 / 229 (1.31%)	6 / 229 (2.62%)
occurrences all number	37	43	2	1	3	6
Hypokalaemia
subjects affected / exposed	23 / 538 (4.28%)	31 / 536 (5.78%)	1 / 215 (0.47%)	1 / 211 (0.47%)	2 / 229 (0.87%)	1 / 229 (0.44%)
occurrences all number	34	42	1	1	5	1

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Were there any global substantial amendments to the protocol? Yes

24 Aug 2015

Amendment 1 - Inclusion/exclusion criteria updated to include specific CRAB criteria (CRAB=calcium elevation, renal insufficiency, anemia and bone abnormalities), include free light chain for quantification of immunoglobulin D (IgD), and allow for controlled arrhythmias and vertebroplasty - Other changes including alignment with daratumumab standard protocol wording, updated missing text and adding further text clarification to allow better understanding of the protocol design and requirements

21 Mar 2016

Amendment 2 - Exclusion criteria updated to exclude solitary plasmacytoma - Other changes to ensure better differentiation between the induction/ASCT/consolidation and maintenance phases of the study and the respective Time & Events schedule to allow better understanding of the assessments. In addition, further updates to align with the International Myeloma Working Group (IMWG) publications and recommendations

05 Jul 2019

Amendment 3 - Precisions and clarifications added regarding End of Treatment (EOT) Visit and Follow-Up (FU) visits (Pre-Progressive Disease/Progressive Disease/Survival) procedures - Addition of Infusion Related-Reaction (IRR) definition - Update of safety information in line with Investigator Brochure (IB) update (IB15 and its addendum 1) - Addition of recommendations already communicated to sites for Part I for harmonization purposes - Clarification regarding procedure in case of suspected daratumumab interference on Serum M-Protein ElectroPhoresis (SPEP) and immunofixation (IFE) - Clarification for recording the response to treatment - Clarification for recording any new malignancy event as an Serious Adverse Event (SAE) - Clarifications regarding SAE declaration circuit - Changes in formulation/structure for accuracy and better understanding of protocol procedures - New Minimal Residual Disease (MRD) assessments during Pre-Progression Follow-up - Changes in bisphosphonate therapy recommendations - Change of IFM Director

14 Jan 2021

Amendment 4 - Modification of Pre-PD FU visit frequency ( PD=Progressive Disease;FU=Follow-Up) - Independent Data Monitoring Committee (IDMC) meetings not needed after the unblinding of the data - The interim analysis for Progression-Free Survival (PFS) met the predefined boundary and turned into the final analysis of Part 2 for PFS. Change in monitoring strategy: risk-based approach with remote quality control of data/risk-based monitoring - Addition of analyses of screening aliquots using Next Generation Sequencing (NGS) methodology

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/31171419
http://www.ncbi.nlm.nih.gov/pubmed/34529931
http://www.ncbi.nlm.nih.gov/pubmed/38889735

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Clinical Trial Results:
Study of Daratumumab in Combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) in the First Line Treatment of Transplant Eligible Subjects with Newly Diagnosed Multiple Myeloma

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Clinical Trial Results: Study of Daratumumab in Combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) in the First Line Treatment of Transplant Eligible Subjects with Newly Diagnosed Multiple Myeloma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Post-Consolidation Stringent Complete Response (sCR) Rate

Primary: Post-Consolidation Stringent Complete Response (sCR) Rate

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Study of Daratumumab in Combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) in the First Line Treatment of Transplant Eligible Subjects with Newly Diagnosed Multiple Myeloma