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Clinical Trial Results:
A PHASE III STUDY OF VELCADE (BORTEZOMIB) THALIDOMIDE DEXAMETHASONE (VTD) VERSUS VELCADE (BORTEZOMIB) CYCLOPHOSPHAMIDE DEXAMETHASONE (VCD) AS AN INDUCTION TREATMENT PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA.

Summary
EudraCT number	2013-003174-27
Trial protocol	FR
Global end of trial date	12 Aug 2015

Results information
Results version number	v1(current)
This version publication date	09 Aug 2022
First version publication date	09 Aug 2022
Other versions

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

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Trial information

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Sponsor protocol code

RC13-0284

ISRCTN number

US NCT number

NCT01971658

WHO universal trial number (UTN)

Sponsor organisation name

CHU de Nantes

Sponsor organisation address

5 allée de l'Ile Gloriette, Nantes, France, 44 093

Public contact

Département Promotion, CHU de Nantes, 033 253482835, Bp-prom-regl@chu-nantes.fr

Scientific contact

Département Promotion, CHU de Nantes, 033 253482835, Bp-prom-regl@chu-nantes.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

18 May 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Aug 2015

Global end of trial reached?

Yes

Global end of trial date

12 Aug 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study is to compare the VGPR rate achieved with four courses of VTD with that achieved with four courses of VCD

Protection of trial subjects

- Prophylaxis of opportunistic infections: Bactrim Forte, oral enicillin or macrolide (for cases of penicillin allergy), Acyclovir or Valacyclovir (for antiviral prophylaxis) - Bisphosphonate (for bone lesions or osteopaenia), according to centre policy - Recombinant erythropoietin (if haemoglobin levels <11g/dL), according to centre policy

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Nov 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 358

Worldwide total number of subjects

358

EEA total number of subjects

358

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)

333

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

358 patients were included from 06/11/2013 to 18/02/2015 in 58 French centers / 60 open. 340 patients were randomized arm VCD 170 ans arm VTD 170 patients

Screening details

inclusion criteria - Patients newly diagnosed with symptomatic Multiple Myeloma patient, must have measurable disease by serum M-protein ≥ 10 g/L and/or urine M-protein ≥200mg/day or Serum Free Light Chain MM (Freelite)

Number of subjects started

358

Number of subjects completed

340

Reason: Number of subjects

patient not having the inclusion criteria: 18

Period 1 title

essais global (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

ARM VCD

Arm description

For arm B: 1- Induction therapy : 4 cycles of VCD Each cycle : 21 days Each cycle comprises: o Cyclophosphamide 500 mg/m²/d, PO D1, 8, 15 o Velcade® 1.3 mg/m²/d, SC D1, 4, 8 and 11 o Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12

Arm type

Active comparator

Investigational medicinal product name

Velcade

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

1.3 mg/m² subcutaneously on Days 1, 4, 8, and 11, followed by a 10-day rest period (Days 12 to 21)

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Endoxan

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

CYCLOPHOSPHAMIDE 500 mg/m² orally on Days 1, 8 and 15

Investigational medicinal product name

Dexaméthasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Buccal tablet

Routes of administration

Oral use

Dosage and administration details

DEXAMETHASONE 40 mg/day orally on Days 1-4 and 9-12

ARM VTD

Arm description

For arm A: Induction therapy : 4 cycles of VTD Each cycle : 21 days Each cycle comprises: o Thalidomide® 100 mg/d, PO D1 to J21 o Velcade® 1.3 mg/m²/d, SC D1, 4, 8 and 11 o Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12

Arm type

Active comparator

Investigational medicinal product name

Thalidomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg/day orally on days 1 to 21

Investigational medicinal product name

Velcade

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

1.3 mg/m² subcutaneously on Days 1, 4, 8, and 11, followed by a 10-day rest period (Days 12 to 21)

Investigational medicinal product name

Dexaméthasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Buccal tablet

Routes of administration

Oral use

Dosage and administration details

DEXAMETHASONE 40 mg/day orally on Days 1 to 4 and 9 to 12

Number of subjects in period 1 ^[1]	ARM VCD	ARM VTD
Started	170	170
Completed	154	157
Not completed	16	13
Physician decision	6	1
Consent withdrawn by subject	-	1
death	3	2
progression	-	3
Adverse event, non-fatal	3	5
Progreseion	1	-
Protocol deviation	3	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 358 people were included in the Research and 340 randomized

Baseline characteristics

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Reporting group title

ARM VCD

Reporting group description

Reporting group title

ARM VTD

Reporting group description

Reporting group values	ARM VCD	ARM VTD	Total
Number of subjects	170	170	340
Age categorical
Units: Subjects
Adults (18-64 years)	155	161	316
From 65-84 years	15	9	24
Age continuous
Units: years
median (full range (min-max))	60 (26 to 65)	59 (34 to 65)	-
Gender categorical
Units: Subjects
Female	61	67	128
Male	109	103	212

End points

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Reporting group title

ARM VCD

Reporting group description

Reporting group title

ARM VTD

Reporting group description

Primary: Compare the VGPR rate

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End point title

Compare the VGPR rate

End point description

The primary efficacy endpoint is VGPR rate obtained with VTD or VTC at the end of induction phase based on ITT population. This analysis will use the Cochran-Mantel-Haenszel chi-square test, adjusted for the stratification factors. The 2-sided 95% confidence intervals for the response rate for each treatment group, the 2-sided 95% confidence interval for the difference in response rate between the two groups, and the p-value will be presented.

End point type

Primary

End point timeframe

5 months

End point values	ARM VCD	ARM VTD
Number of subjects analysed	169	169
Units: percentage
number (not applicable)	56.2	66.3

Compare the VGPR rate

Statistical analysis description

Comparison groups

ARM VTD v ARM VCD

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.05 ^[2]

Method

Khi² Cochran-Mantel-Haenszel

Confidence interval

Notes
[1] - In the ITT population, 66.3% of patients in the VTD arm achieved at least one VGPR versus 56.2% in the VCD arm (P=0.05). The difference in VGRR rate (primary objective) between the VTD and VCD arms was 10.1% (95% CI, 1% to 18%) In the PP per-protocol analysis, the VGPR rate was also significantly higher in the VTD arm (70.7% vs 60.4%, P 0.05, difference 10.3%, 95% CI 2% to 21%).
[2] - In the ITT population p=0.05 In the PP per-protocol analysis P=0.05

Secondary: Quality of stem cell collection

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End point title

Quality of stem cell collection

End point description

Stem cell collection, starting 1 week after cycle 3: cyclophosphamide 3 g/m² followed by G-CSF (5 μg/kg/day)

End point type

Secondary

End point timeframe

3 cycle

End point values	ARM VCD	ARM VTD
Number of subjects analysed	155	159
Units: 10X6 cellules / kg
number (not applicable)	9.2	10.7

Stem cell collection

Comparison groups

ARM VTD v ARM VCD

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.05 ^[3]

Method

Cochran-Mantel-Haenszel chisquare test,

Confidence interval

Notes
[3] - Le nombre médian de CD34+ collecté étaient de 10.7 X 106 cellules / kg dans le bras VTD versus 9.2 X 106 cellule/kg dans le bras VCD (P=0.05).

Adverse events

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Timeframe for reporting adverse events

5 cycles

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

ARM VCD

Reporting group description

Reporting group title

ARM VTD

Reporting group description

Serious adverse events	ARM VCD	ARM VTD
Total subjects affected by serious adverse events
subjects affected / exposed	63 / 167 (37.72%)	61 / 167 (36.53%)
number of deaths (all causes)	3	2
number of deaths resulting from adverse events	3	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Refractory anaemia with an excess of blasts
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant pleural effusion
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic neoplasm
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parathyroid tumour benign
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Plasma cell myeloma
subjects affected / exposed	2 / 167 (1.20%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombophlebitis superficial
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cryoglobulinaemia
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Parathyroidectomy
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injection site erythema
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oral administration complication
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	3 / 167 (1.80%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 167 (1.80%)	4 / 167 (2.40%)
occurrences causally related to treatment / all	2 / 3	4 / 4
deaths causally related to treatment / all	0 / 0	1 / 1
Bronchial obstruction
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pleural effusion
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
mania
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Lipase increased
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal myelogram abnormal
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Drug administration error
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Medication error
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug dose omission
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inappropriate schedule of drug administration
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Incorrect dose administered
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Incorrect drug administration duration
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intentional product misuse
subjects affected / exposed	2 / 167 (1.20%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax traumatic
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural complication
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Cardiac failure
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive heart disease
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebellar syndrome
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coma
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Extrapyramidal disorder
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	2 / 167 (1.20%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral sensorimotor neuropathy
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brown-Sequard syndrome
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperaesthesia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle contractions involuntary
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral motor neuropathy
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	2 / 167 (1.20%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile bone marrow aplasia
subjects affected / exposed	7 / 167 (4.19%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	7 / 7	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	4 / 167 (2.40%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombotic microangiopathy
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal necrosis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal toxicity
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumoperitoneum
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatocellular injury
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Acute generalised exanthematous pustulosis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toxic skin eruption
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Cystitis haemorrhagic
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	5 / 167 (2.99%)	3 / 167 (1.80%)
occurrences causally related to treatment / all	2 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Sternal fracture
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bacterial sepsis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	4 / 167 (2.40%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Colonic abscess
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumocystis jiroveci pneumonia
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia escherichia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia haemophilus
subjects affected / exposed	3 / 167 (1.80%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia pneumococcal
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatitis Escherichia coli
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 167 (1.20%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	3 / 167 (1.80%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	2 / 3	1 / 2
deaths causally related to treatment / all	2 / 2	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stenotrophomonas infection
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombophlebitis septic
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	9 / 167 (5.39%)	2 / 167 (1.20%)
occurrences causally related to treatment / all	8 / 9	2 / 2
deaths causally related to treatment / all	1 / 1	0 / 0
Anal fistula infection
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 167 (0.00%)	3 / 167 (1.80%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gout
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercreatinaemia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	ARM VCD	ARM VTD
Total subjects affected by non serious adverse events
subjects affected / exposed	167 / 167 (100.00%)	167 / 167 (100.00%)
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Flushing
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Hypertension
subjects affected / exposed	4 / 167 (2.40%)	7 / 167 (4.19%)
occurrences all number	4	8
Hot flush
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Hypotension
subjects affected / exposed	2 / 167 (1.20%)	1 / 167 (0.60%)
occurrences all number	2	1
Orthostatic hypotension
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences all number	2	0
Phlebitis superficial
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Thrombosis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Venous thrombosis
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	2
Surgical and medical procedures
Cementoplasty
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Oophorectomy
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Tooth extraction
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Vertebroplasty
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Phlebitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	43 / 167 (25.75%)	35 / 167 (20.96%)
occurrences all number	49	38
Chest discomfort
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Chest pain
subjects affected / exposed	5 / 167 (2.99%)	5 / 167 (2.99%)
occurrences all number	5	5
Chills
subjects affected / exposed	3 / 167 (1.80%)	2 / 167 (1.20%)
occurrences all number	3	2
Face oedema
subjects affected / exposed	0 / 167 (0.00%)	3 / 167 (1.80%)
occurrences all number	0	3
Fatigue
subjects affected / exposed	1 / 167 (0.60%)	3 / 167 (1.80%)
occurrences all number	1	3
Feeling jittery
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
General physical health deterioration
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Hyperthermia
subjects affected / exposed	2 / 167 (1.20%)	3 / 167 (1.80%)
occurrences all number	2	3
Inflammation
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Influenza like illness
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Injection site erythema
subjects affected / exposed	2 / 167 (1.20%)	1 / 167 (0.60%)
occurrences all number	2	1
Injection site haemorrhage
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Injection site reaction
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Local swelling
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Localised oedema
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Malaise
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Mucosal dryness
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Mucosal inflammation
subjects affected / exposed	2 / 167 (1.20%)	2 / 167 (1.20%)
occurrences all number	2	2
Mucositis
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences all number	2	0
Non-cardiac chest pain
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Oedema
subjects affected / exposed	2 / 167 (1.20%)	3 / 167 (1.80%)
occurrences all number	2	3
Oedema peripheral
subjects affected / exposed	18 / 167 (10.78%)	31 / 167 (18.56%)
occurrences all number	20	34
Pain
subjects affected / exposed	2 / 167 (1.20%)	6 / 167 (3.59%)
occurrences all number	2	6
Pyrexia
subjects affected / exposed	18 / 167 (10.78%)	11 / 167 (6.59%)
occurrences all number	19	11
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 167 (0.00%)	3 / 167 (1.80%)
occurrences all number	0	3
Hypersensitivity
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Seasonal allergy
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Reproductive system and breast disorders
Acquired phimosis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Benign prostatic hyperplasia
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Vulvovaginal discomfort
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Asthmatic crisis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Bronchospasm
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Cough
subjects affected / exposed	11 / 167 (6.59%)	9 / 167 (5.39%)
occurrences all number	11	9
Dysphonia
subjects affected / exposed	4 / 167 (2.40%)	0 / 167 (0.00%)
occurrences all number	4	0
Dyspnoea
subjects affected / exposed	6 / 167 (3.59%)	8 / 167 (4.79%)
occurrences all number	7	10
Dyspnoea exertional
subjects affected / exposed	3 / 167 (1.80%)	2 / 167 (1.20%)
occurrences all number	3	2
Epistaxis
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Hiccups
subjects affected / exposed	4 / 167 (2.40%)	3 / 167 (1.80%)
occurrences all number	4	3
Oropharyngeal pain
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Pleurisy
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Productive cough
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Pulmonary hypertension
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Pulmonary embolism
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Respiratory failure
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Rhinorrhoea
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Tachypnoea
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Wheezing
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Psychiatric disorders
Aggression
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
affective disorder
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Anxiety
subjects affected / exposed	9 / 167 (5.39%)	12 / 167 (7.19%)
occurrences all number	9	12
Confusional state
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Depression
subjects affected / exposed	3 / 167 (1.80%)	3 / 167 (1.80%)
occurrences all number	3	3
Hallucination, visual
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
hyperexcitation
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
hypomania
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Insomnia
subjects affected / exposed	10 / 167 (5.99%)	7 / 167 (4.19%)
occurrences all number	11	8
Mood altered
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
nervousness
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Nightmare
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Sleep disorder
subjects affected / exposed	5 / 167 (2.99%)	3 / 167 (1.80%)
occurrences all number	5	3
Logorrhoea
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Psychiatric symptom
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Investigations
Lymphocyte count decreased
subjects affected / exposed	2 / 167 (1.20%)	1 / 167 (0.60%)
occurrences all number	3	1
Neutrophil count decreased
subjects affected / exposed	6 / 167 (3.59%)	7 / 167 (4.19%)
occurrences all number	8	7
Platelet count decreased
subjects affected / exposed	2 / 167 (1.20%)	1 / 167 (0.60%)
occurrences all number	2	1
White blood cell count decreased
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Angina pectoris
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Alanine aminotransferase decreased
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Alanine aminotransferase increased
subjects affected / exposed	0 / 167 (0.00%)	4 / 167 (2.40%)
occurrences all number	0	4
Aspartate aminotransferase decreased
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Aspartate aminotransferase increased
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 167 (0.00%)	3 / 167 (1.80%)
occurrences all number	0	5
Blood creatinine increased
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Blood phosphorus decreased
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences all number	2	0
C-reactive protein increased
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Staphylococcus test positive
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Weight decreased
subjects affected / exposed	5 / 167 (2.99%)	1 / 167 (0.60%)
occurrences all number	5	1
Weight increased
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Injury, poisoning and procedural complications
fall
subjects affected / exposed	2 / 167 (1.20%)	2 / 167 (1.20%)
occurrences all number	2	2
Intentional product misuse
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Fracture
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Subcutaneous haematoma
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Tooth fracture
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Bradycardia
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Palpitations
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Tachycardia
subjects affected / exposed	1 / 167 (0.60%)	4 / 167 (2.40%)
occurrences all number	1	4
Sinus tachycardia
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Nervous system disorders
Chest pain
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Ageusia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Cognitive disorder
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Dizziness
subjects affected / exposed	2 / 167 (1.20%)	4 / 167 (2.40%)
occurrences all number	2	4
Dysaesthesia
subjects affected / exposed	4 / 167 (2.40%)	3 / 167 (1.80%)
occurrences all number	4	3
Dysgeusia
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Extrapyramidal disorder
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Headache
subjects affected / exposed	13 / 167 (7.78%)	9 / 167 (5.39%)
occurrences all number	14	10
Hypoaesthesia
subjects affected / exposed	3 / 167 (1.80%)	3 / 167 (1.80%)
occurrences all number	3	3
Migraine
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Neuralgia
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Neuropathy peripheral
subjects affected / exposed	40 / 167 (23.95%)	63 / 167 (37.72%)
occurrences all number	51	82
Neurotoxicity
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Optic neuritis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Paraesthesia
subjects affected / exposed	18 / 167 (10.78%)	25 / 167 (14.97%)
occurrences all number	18	28
Peripheral motor neuropathy
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Peripheral nerve palsy
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Peripheral sensorimotor neuropathy
subjects affected / exposed	0 / 167 (0.00%)	3 / 167 (1.80%)
occurrences all number	0	6
Polyneuropathy
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Presyncope
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Radicular syndrome
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Sciatica
subjects affected / exposed	4 / 167 (2.40%)	1 / 167 (0.60%)
occurrences all number	4	1
Somnolence
subjects affected / exposed	1 / 167 (0.60%)	3 / 167 (1.80%)
occurrences all number	1	3
syncope
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
tremor
subjects affected / exposed	2 / 167 (1.20%)	8 / 167 (4.79%)
occurrences all number	2	9
Agitation
subjects affected / exposed	6 / 167 (3.59%)	3 / 167 (1.80%)
occurrences all number	6	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	26 / 167 (15.57%)	22 / 167 (13.17%)
occurrences all number	37	22
Bone marrow failure
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Febrile bone marrow aplasia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Febrile neutropenia
subjects affected / exposed	4 / 167 (2.40%)	1 / 167 (0.60%)
occurrences all number	4	1
Leukopenia
subjects affected / exposed	12 / 167 (7.19%)	5 / 167 (2.99%)
occurrences all number	16	5
Leukocytosis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Lymphopenia
subjects affected / exposed	53 / 167 (31.74%)	43 / 167 (25.75%)
occurrences all number	135	72
Neutropenia
subjects affected / exposed	42 / 167 (25.15%)	21 / 167 (12.57%)
occurrences all number	72	29
Thrombocytopenia
subjects affected / exposed	19 / 167 (11.38%)	11 / 167 (6.59%)
occurrences all number	30	11
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Tinnitus
subjects affected / exposed	2 / 167 (1.20%)	2 / 167 (1.20%)
occurrences all number	2	2
Vertigo
subjects affected / exposed	3 / 167 (1.80%)	4 / 167 (2.40%)
occurrences all number	3	4
Acute vestibular syndrome
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Ear pain
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
hearing impaired
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Eye disorders
Chalazion
subjects affected / exposed	3 / 167 (1.80%)	1 / 167 (0.60%)
occurrences all number	3	1
Chromatopsia
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Conjunctival haemorrhage
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Eyelid oedema
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Keratitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Uveitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Vision blurred
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Visual acuity reduced
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Visual impairment
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Eye pruritus
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Miosis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Photophobia
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	2 / 167 (1.20%)	1 / 167 (0.60%)
occurrences all number	2	1
Abdominal pain
subjects affected / exposed	4 / 167 (2.40%)	5 / 167 (2.99%)
occurrences all number	4	5
Abdominal pain upper
subjects affected / exposed	7 / 167 (4.19%)	5 / 167 (2.99%)
occurrences all number	7	5
aphthous stomatitis
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Constipation
subjects affected / exposed	35 / 167 (20.96%)	59 / 167 (35.33%)
occurrences all number	39	68
Diarrhoea
subjects affected / exposed	21 / 167 (12.57%)	8 / 167 (4.79%)
occurrences all number	21	8
Dry mouth
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Dysgeusia
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Dyspepsia
subjects affected / exposed	6 / 167 (3.59%)	5 / 167 (2.99%)
occurrences all number	6	5
Diverticulum intestinal
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Duodenogastric reflux
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Flatulence
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Gastrointestinal disorder
subjects affected / exposed	4 / 167 (2.40%)	2 / 167 (1.20%)
occurrences all number	4	2
dysphagia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Eructation
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Gastritis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Gastrointestinal motility disorder
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Impaired gastric emptying
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Intestinal dilatation
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Mouth ulceration
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	2	0
Nausea
subjects affected / exposed	47 / 167 (28.14%)	39 / 167 (23.35%)
occurrences all number	54	43
Oesophagitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Oral discomfort
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Rectal haemorrhage
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Rectal prolapse
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Stomatitis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Vomiting
subjects affected / exposed	16 / 167 (9.58%)	12 / 167 (7.19%)
occurrences all number	18	12
Tongue discolouration
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Tooth demineralisation
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	0 / 167 (0.00%)	6 / 167 (3.59%)
occurrences all number	0	6
Cholelithiasis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Drug-induced liver injury
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	3 / 167 (1.80%)	6 / 167 (3.59%)
occurrences all number	3	6
Decubitus ulcer
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Dermatitis acneiform
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Dermatitis allergic
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Dermatitis contact
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Dry skin
subjects affected / exposed	2 / 167 (1.20%)	3 / 167 (1.80%)
occurrences all number	2	3
Ecchymosis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Eczema
subjects affected / exposed	0 / 167 (0.00%)	3 / 167 (1.80%)
occurrences all number	0	3
Erythema
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Hand dermatitis
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Hidradenitis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Hyperhidrosis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Macule
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Mucocutaneous rash
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Nail disorder
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Night sweats
subjects affected / exposed	2 / 167 (1.20%)	1 / 167 (0.60%)
occurrences all number	2	1
Pruritus
subjects affected / exposed	2 / 167 (1.20%)	4 / 167 (2.40%)
occurrences all number	2	4
Rash
subjects affected / exposed	12 / 167 (7.19%)	14 / 167 (8.38%)
occurrences all number	13	14
Rash maculo-papular
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Rash papular
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Rash pruritic
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Skin disorder
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Skin reaction
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Swelling face
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Toxic skin eruption
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Urticaria
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Bladder discomfort
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Cystitis haemorrhagic
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences all number	2	0
Dysuria
subjects affected / exposed	4 / 167 (2.40%)	1 / 167 (0.60%)
occurrences all number	4	1
Haematuria
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Nocturia
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Oliguria
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Pollakiuria
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences all number	2	0
Proteinuria
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Renal failure
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Urinary incontinence
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Endocrine disorders
Cushingoid
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences all number	2	0
Hyperthyroidism
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Hyperparathyroidism
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 167 (1.20%)	3 / 167 (1.80%)
occurrences all number	2	3
back pain
subjects affected / exposed	25 / 167 (14.97%)	22 / 167 (13.17%)
occurrences all number	25	22
Bone lesion
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Bone pain
subjects affected / exposed	8 / 167 (4.79%)	7 / 167 (4.19%)
occurrences all number	9	7
Enthesopathy
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Groin pain
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Muscle spasms
subjects affected / exposed	3 / 167 (1.80%)	3 / 167 (1.80%)
occurrences all number	3	3
Musculoskeletal chest pain
subjects affected / exposed	4 / 167 (2.40%)	7 / 167 (4.19%)
occurrences all number	4	7
Musculoskeletal discomfort
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences all number	2	0
Myalgia
subjects affected / exposed	5 / 167 (2.99%)	3 / 167 (1.80%)
occurrences all number	5	3
Neck pain
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Osteoporosis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Osteonecrosis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Pain in extremity
subjects affected / exposed	11 / 167 (6.59%)	9 / 167 (5.39%)
occurrences all number	11	11
Pathological fracture
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Spinal osteoarthritis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Spinal pain
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Tendonitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Synovial cyst
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Amnesia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Aphonia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Balance disorder
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Infections and infestations
Acute sinusitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Bacterial prostatitis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
BK virus infection cystitis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Bronchitis
subjects affected / exposed	13 / 167 (7.78%)	17 / 167 (10.18%)
occurrences all number	13	18
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Cellulitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Conjunctivitis
subjects affected / exposed	3 / 167 (1.80%)	1 / 167 (0.60%)
occurrences all number	3	2
Cystitis
subjects affected / exposed	5 / 167 (2.99%)	1 / 167 (0.60%)
occurrences all number	5	1
Cytomegalovirus infection
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Device related infection
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Ear infection viral
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Erysipelas
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	2
Escherichia infection
subjects affected / exposed	0 / 167 (0.00%)	3 / 167 (1.80%)
occurrences all number	0	3
Escherichia vaginitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Folliculitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Fungal skin infection
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences all number	2	0
Gastrointestinal candidiasis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Genital infection fungal
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Hordeolum
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Haemorrhoid infection
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Infected cyst
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
infection
subjects affected / exposed	0 / 167 (0.00%)	3 / 167 (1.80%)
occurrences all number	0	4
infectious colitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Influenza
subjects affected / exposed	4 / 167 (2.40%)	2 / 167 (1.20%)
occurrences all number	4	2
Laryngitis
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Localised infection
subjects affected / exposed	2 / 167 (1.20%)	0 / 167 (0.00%)
occurrences all number	2	0
Lung infection
subjects affected / exposed	3 / 167 (1.80%)	0 / 167 (0.00%)
occurrences all number	3	0
Nasal herpes
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Nasopharyngitis
subjects affected / exposed	4 / 167 (2.40%)	8 / 167 (4.79%)
occurrences all number	4	8
Oral candidiasis
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Oral fungal infection
subjects affected / exposed	1 / 167 (0.60%)	4 / 167 (2.40%)
occurrences all number	1	4
Osteitis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
ophtalmic herpes zoster
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Orchitis
subjects affected / exposed	3 / 167 (1.80%)	0 / 167 (0.00%)
occurrences all number	3	0
Pharyngitis
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Pneumococcal sepsis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Pneumonia
subjects affected / exposed	2 / 167 (1.20%)	2 / 167 (1.20%)
occurrences all number	2	2
PROSTATITIS
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Prostatitis Escherichia coli
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Puncture site infection
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Rhinitis
subjects affected / exposed	2 / 167 (1.20%)	4 / 167 (2.40%)
occurrences all number	2	4
Salmonellosis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Sepsis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Sinusitis
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Staphylococcal bacteraemia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Subcutaneous abscess
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Staphylococcal sepsis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Streptococcal sepsis
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Tongue fungal infection
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Tonsillitis
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Tooth abscess
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Tooth infection
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Upper respiratory tract infection
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Urinary tract infection
subjects affected / exposed	7 / 167 (4.19%)	1 / 167 (0.60%)
occurrences all number	7	1
Vaginal infection
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Thermal burn
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Metabolism and nutrition disorders
Alkalosis
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Appetite disorder
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Cell death
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Decreased appetite
subjects affected / exposed	3 / 167 (1.80%)	4 / 167 (2.40%)
occurrences all number	3	4
Dehydration
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
gout
subjects affected / exposed	1 / 167 (0.60%)	2 / 167 (1.20%)
occurrences all number	1	2
Hypercalcaemia
subjects affected / exposed	0 / 167 (0.00%)	4 / 167 (2.40%)
occurrences all number	0	4
Hyperglycaemia
subjects affected / exposed	2 / 167 (1.20%)	3 / 167 (1.80%)
occurrences all number	2	3
Hyperphagia
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Hypertriglyceridaemia
subjects affected / exposed	0 / 167 (0.00%)	1 / 167 (0.60%)
occurrences all number	0	1
Hyperuricaemia
subjects affected / exposed	1 / 167 (0.60%)	0 / 167 (0.00%)
occurrences all number	1	0
Hypoalbuminaemia
subjects affected / exposed	1 / 167 (0.60%)	1 / 167 (0.60%)
occurrences all number	1	1
Hypocalcaemia
subjects affected / exposed	4 / 167 (2.40%)	0 / 167 (0.00%)
occurrences all number	4	0
Hypokalaemia
subjects affected / exposed	2 / 167 (1.20%)	4 / 167 (2.40%)
occurrences all number	2	4
Hypomagnesemia
subjects affected / exposed	1 / 167 (0.60%)	3 / 167 (1.80%)
occurrences all number	1	3
Hyponatraemia
subjects affected / exposed	0 / 167 (0.00%)	4 / 167 (2.40%)
occurrences all number	0	5
HYPOPHOSPHATEMIE
subjects affected / exposed	2 / 167 (1.20%)	4 / 167 (2.40%)
occurrences all number	2	5
Limb discomfort
subjects affected / exposed	0 / 167 (0.00%)	2 / 167 (1.20%)
occurrences all number	0	2
Musculoskeletal pain
subjects affected / exposed	2 / 167 (1.20%)	5 / 167 (2.99%)
occurrences all number	2	5

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Were there any global substantial amendments to the protocol? Yes

01 Jul 2014

augmentation du nombre de centre, modification critère exclusion inclusion, précision sur le dose de G-CSF, ajout du droit de participer à l'étude AMG 162, précision sur la prise de Velcade en fonction du poids, sur les dispensations de Cyclophosphamide, mise à jour des toxicités du cyclophosphamide, précision sur les examens fait au screeninig, modification des données de rando, précision des délais pour réaliser les examens biologiques, modification de la quantité de sang à prélever pour analyses de cytogénétique et analyses bioschiliques, mise à jour de l'adresse de l'unité génomique de Toulouse

04 Dec 2014

prolongation de la période de recrutement

07 May 2015

prolongation de la période de suivi de l’étude (de 2 mois), changement de l’investigateur principal du centre de Poitiers

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/27002117

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Clinical Trial Results:
A PHASE III STUDY OF VELCADE (BORTEZOMIB) THALIDOMIDE DEXAMETHASONE (VTD) VERSUS VELCADE (BORTEZOMIB) CYCLOPHOSPHAMIDE DEXAMETHASONE (VCD) AS AN INDUCTION TREATMENT PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Compare the VGPR rate

Primary: Compare the VGPR rate

Secondary: Quality of stem cell collection

Secondary: Quality of stem cell collection

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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Clinical trials

Clinical Trial Results: A PHASE III STUDY OF VELCADE (BORTEZOMIB) THALIDOMIDE DEXAMETHASONE (VTD) VERSUS VELCADE (BORTEZOMIB) CYCLOPHOSPHAMIDE DEXAMETHASONE (VCD) AS AN INDUCTION TREATMENT PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Compare the VGPR rate

Primary: Compare the VGPR rate

Secondary: Quality of stem cell collection

Secondary: Quality of stem cell collection

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A PHASE III STUDY OF VELCADE (BORTEZOMIB) THALIDOMIDE DEXAMETHASONE (VTD) VERSUS VELCADE (BORTEZOMIB) CYCLOPHOSPHAMIDE DEXAMETHASONE (VCD) AS AN INDUCTION TREATMENT PRIOR TO AUTOLOGOUS STEM CELL TRANSPLANTATION IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA.