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Clinical Trial Results:
A Phase 2, Multi-Center, Randomized, Double-Blinded, Parallel Group Study of the Safety and Efficacy of Different Lenalidomide (REVLIMID®) Dose Regimens in Subjects With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia

Summary
EudraCT number	2009-009836-54
Trial protocol	GB DE FR SE ES IT
Global end of trial date	04 Sep 2017

Results information
Results version number	v1(current)
This version publication date	16 Sep 2018
First version publication date	16 Sep 2018
Other versions

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

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Trial information

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Sponsor protocol code

CC-5013-CLL-009

ISRCTN number

-

US NCT number

NCT00963105

WHO universal trial number (UTN)

-

Sponsor organisation name

Celgene Corporation

Sponsor organisation address

86 Morris Avenue, Summit, NJ, United States, 07901

Public contact

ClinicalTrialDisclosure, Celgene Corporation, +1 888-260-1599, ClinicalTrialDisclosure@celgene.com

Scientific contact

Jeffery Jones, Celgene Corporation, +1 (908) 673-9686, jejones@celgene.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

04 Sep 2017

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

04 Sep 2017

Was the trial ended prematurely?

No

Main objective of the trial

To evaluate the safety of different lenalidomide dose regimens in subjects with relapsed or refractory B-cell chronic lymphocytic leukemia (CLL).

Protection of trial subjects

This study was conducted in accordance with the guidelines of current Good Clinical Practice including the archiving of essential documents.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

18 Oct 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 2

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

United Kingdom: 15

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Germany: 24

Country: Number of subjects enrolled

Italy: 9

Country: Number of subjects enrolled

Canada: 13

Country: Number of subjects enrolled

United States: 26

Worldwide total number of subjects

104

EEA total number of subjects

65

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

52

From 65 to 84 years

52

85 years and over

0

Subject disposition

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Recruitment details

Participants were randomized at 29 sites from North America and Europe.

Screening details

Participants were randomized (1:1:1) in a double-blind fashion, according to age (< 65 versus ≥ 65 years) and disease status (relapsed versus refractory) to their last purine-analog or bendamustine based prior regimen.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Lenalidomide 5 mg

Arm description

Participants received a starting dose of 5 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Arm type

Experimental

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

CC-5013

Other name

Revlimid®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Administered orally once a day in 28-day cycles.

Lenalidomide 10 mg

Arm description

Participants received a starting dose of 10 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Arm type

Experimental

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

CC-5013

Other name

Revlimid®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Administered orally once a day in 28-day cycles.

Lenalidomide 15 mg

Arm description

Participants received a starting dose of 15 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Arm type

Experimental

Investigational medicinal product name

Lenalidomide

Investigational medicinal product code

CC-5013

Other name

Revlimid®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Administered orally once a day in 28-day cycles.

Number of subjects in period 1	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg
Started	34	35	35
Received Treatment	34	34 ^[1]	35
Completed	34	35	35

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Completed indicate participants who discontinued the study.

Baseline characteristics

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Reporting group title

Lenalidomide 5 mg

Reporting group description

Participants received a starting dose of 5 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Reporting group title

Lenalidomide 10 mg

Reporting group description

Participants received a starting dose of 10 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Reporting group title

Lenalidomide 15 mg

Reporting group description

Participants received a starting dose of 15 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Reporting group values	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg	Total
Number of subjects	34	35	35	104
Age categorical
Units: Subjects
< 65 years	16	19	17	52
≥ 65 years	18	16	18	52
Age continuous
Units: years
arithmetic mean (standard deviation)	64.0 ( 9.46 )	63.3 ( 8.31 )	63.7 ( 7.56 )	-
Gender categorical
Units: Subjects
Female	8	13	11	32
Male	26	22	24	72
Race
Units: Subjects
White	31	30	33	94
Black or African American	2	4	2	8
Other	0	1	0	1
Unknown	1	0	0	1

End points

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Reporting group title

Lenalidomide 5 mg

Reporting group description

Participants received a starting dose of 5 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Reporting group title

Lenalidomide 10 mg

Reporting group description

Participants received a starting dose of 10 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Reporting group title

Lenalidomide 15 mg

Reporting group description

Participants received a starting dose of 15 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Primary: Number of Participants With Treatment-emergent Adverse Events

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End point title

Number of Participants With Treatment-emergent Adverse Events ^[1]

End point description

Adverse events (AEs) were graded for severity by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 with the exceptions of hematologic toxicities and tumor lysis syndrome, according to the following scale: Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life Threatening or disabling AE Grade 5 = Death The investigator determined the relationship of each AE to study drug based on the timing of the AE and whether other medications, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the observed event.

End point type

Primary

End point timeframe

From first dose of study drug to 30 days after the last dose; the maximum duration of treatment was 251, 265, and 267 weeks in the 5 mg, 10 mg, and 15 mg treatment groups respectively.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical comparisons between treatment groups were not conducted in this study.

End point values	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg
Number of subjects analysed	34 ^[2]	34 ^[3]	35 ^[4]
Units: participants
Any adverse events	34	34	35
Treatment-related adverse events (TRAE)	33	34	32
Grade 3/4 adverse events	33	32	34
Treatment-related Grade 3/4 adverse events	31	32	30
Grade 5 adverse events	4	4	3
Treatment-related Grade 5 adverse events	2	2	0
Serious adverse events	24	24	27
Treatment-related serious adverse events	15	13	20
AEs leading to discontinuation of study drug	21	17	16
TRAEs leading to discontinuation of study drug	16	14	13
AEs leading to study drug dose reduction only	8	6	5
AEs leading to study drug dose interruption only	25	24	25
AEs leading to study drug interruption & reduction	18	26	19

Notes
[2] - Randomized participants who received at least one dose of study drug.
[3] - Randomized participants who received at least one dose of study drug.
[4] - Randomized participants who received at least one dose of study drug.

No statistical analyses for this end point

Secondary: Overall Response Rate

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End point title

Overall Response Rate

End point description

Overall response rate was defined as the percentage of participants with a complete response (CR), CR with incomplete bone marrow recovery (CRi) or partial response (PR) during the treatment period. Tumor response was assessed by the investigator according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines for the diagnosis and treatment of CLL, based on laboratory, physical exam, assessment of constitutional symptoms and if appropriate computed tomography (CT) scan findings (to confirm PR or CR/CRi). For confirmed PR or CR/CRi, response had to be maintained for ≥ 8 weeks. Efficacy endpoints were analyzed in the intent-to-treat population which consisted of all randomized participants.

End point type

Secondary

End point timeframe

Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months.

End point values	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg
Number of subjects analysed	34	35	35
Units: percentage of participants
number (not applicable)	47.1	37.1	40.0

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Duration of Response

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End point title

Kaplan-Meier Estimate of Duration of Response

End point description

Duration of response (DOR) was defined as the time from the first visit where PR, CRi, or CR was documented to progressive disease (PD). Duration of response was censored at the last date that the participant was known to be progression-free for participants who had not progressed at the time of analysis or who withdrew consent or were lost to follow-up prior to documentation of progression. "99999" indicates data that could not be estimated due to the low number of events at the time of analysis.

End point type

Secondary

End point timeframe

Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months.

End point values	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg
Number of subjects analysed	16 ^[5]	13 ^[6]	14 ^[7]
Units: weeks
median (confidence interval 95%)	101.1 (60.6 to 239.3)	35.1 (22.0 to 99999)	88.8 (72.1 to 127.3)

Notes
[5] - Randomized participants with an objective response (CR/CRi or PR)
[6] - Randomized participants with an objective response (CR/CRi or PR)
[7] - Randomized participants with an objective response (CR/CRi or PR)

No statistical analyses for this end point

Secondary: Time to Response

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End point title

Time to Response

End point description

Time to response (TTR) was calculated as the time from randomization to the first documented date of response (PR, CRi or CR) based on iwCLL guidelines for participants with an objective response during the treatment period.

End point type

Secondary

End point timeframe

Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months.

End point values	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg
Number of subjects analysed	16 ^[8]	13 ^[9]	14 ^[10]
Units: weeks
median (full range (min-max))	16.9 (12.1 to 74.1)	12.6 (8.4 to 52.1)	12.7 (12.0 to 147.3)

Notes
[8] - Randomized participants with an objective response (CR/CRi or PR)
[9] - Randomized participants with an objective response (CR/CRi or PR)
[10] - Randomized participants with an objective response (CR/CRi or PR)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Time to Progression

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End point title

Kaplan-Meier Estimate of Time to Progression

End point description

Time to progression (TTP) was defined as the time from randomization to the first documented progression. For participants who did not progress during the study, TTP was censored at the last adequate response assessment showing evidence of no disease progression.

End point type

Secondary

End point timeframe

From randomization until the end of the study; maximum time on study was 91 months.

End point values	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg
Number of subjects analysed	34	35	35
Units: weeks
median (confidence interval 95%)	96.3 (20.6 to 251.3)	47.6 (31.9 to 261.1)	66.3 (20.1 to 89.3)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Event-Free Survival

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End point title

Kaplan-Meier Estimate of Event-Free Survival

End point description

Event-free survival (EFS) is the interval between the start of treatment to the first sign of disease progression, or treatment for relapse or death (whichever occurred first). If withdrawal of consent or loss to follow-up occurred before documented progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression.

End point type

Secondary

End point timeframe

From randomization until the end of the study; maximum time on study was 91 months.

End point values	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg
Number of subjects analysed	34	35	35
Units: weeks
median (confidence interval 95%)	25.6 (16.1 to 77.6)	31.9 (21.1 to 47.6)	24.1 (13.4 to 66.3)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Progression Free Survival

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End point title

Kaplan-Meier Estimate of Progression Free Survival

End point description

Progression-free survival (PFS) was calculated as the time from randomization to the first documented progression or death due to any cause during or after the treatment period, whichever occurred first. The progression date was assigned to the earliest time when any progression is observed without prior missing assessments. If withdrawal of consent or loss to follow-up occurred before documented progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression.

End point type

Secondary

End point timeframe

From randomization until the end of the study; maximum time on study was 91 months.

End point values	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg
Number of subjects analysed	34	35	35
Units: weeks
median (confidence interval 95%)	31.4 (16.1 to 96.3)	45.1 (22.4 to 120.1)	66.3 (16.1 to 89.3)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Overall Survival

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End point title

Kaplan-Meier Estimate of Overall Survival

End point description

Overall survival (OS) was defined as the time from randomization to death from any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who had withdrawn consent or were lost to follow-up before death was documented.

End point type

Secondary

End point timeframe

From randomization until the end of the study; maximum time on study was 91 months.

End point values	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg
Number of subjects analysed	34	35	35
Units: weeks
median (confidence interval 95%)	161.0 (64.9 to 209.0)	106.7 (83.4 to 235.7)	154.6 (80.9 to 214.7)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug to 30 days after the last dose; the maximum duration of treatment was 251, 265, and 267 weeks in the 5 mg, 10 mg, and 15 mg treatment groups respectively.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Lenalidomide 5 mg

Reporting group description

Participants received a starting dose of 5 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Reporting group title

Lenalidomide 10 mg

Reporting group description

Participants received a starting dose of 10 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Reporting group title

Lenalidomide 15 mg

Reporting group description

Participants received a starting dose of 15 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug.

Serious adverse events	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg
Total subjects affected by serious adverse events
subjects affected / exposed	24 / 34 (70.59%)	24 / 34 (70.59%)	27 / 35 (77.14%)
number of deaths (all causes)	24	23	26
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACUTE LYMPHOCYTIC LEUKAEMIA
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ADENOCARCINOMA
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ADENOCARCINOMA PANCREAS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
ANAL SQUAMOUS CELL CARCINOMA
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BASAL CELL CARCINOMA
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BOWEN'S DISEASE
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
KERATOACANTHOMA
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG ADENOCARCINOMA
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MALIGNANT PLEURAL EFFUSION
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MENINGIOMA BENIGN
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
METASTATIC SQUAMOUS CELL CARCINOMA
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUROFIBROMA
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OLIGOASTROCYTOMA
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA OF SKIN
subjects affected / exposed	2 / 34 (5.88%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TUMOUR FLARE
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	6 / 35 (17.14%)
occurrences causally related to treatment / all	2 / 2	0 / 0	9 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
DEEP VEIN THROMBOSIS
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERTENSIVE CRISIS
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VENOUS THROMBOSIS LIMB
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEATH
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
DISEASE PROGRESSION
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IMPAIRED HEALING
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PAIN
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	2 / 34 (5.88%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	0 / 2	0 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
DYSPNOEA
subjects affected / exposed	2 / 34 (5.88%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOXIA
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG CONSOLIDATION
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA ASPIRATION
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONITIS
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
PNEUMOTHORAX
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY OEDEMA
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
ALCOHOL POISONING
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FALL
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
ARRHYTHMIA
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CARDIAC TAMPONADE
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
MYOCARDIAL INFARCTION
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
PERICARDIAL EFFUSION
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
CEREBRAL ISCHAEMIA
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIZZINESS
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
AGRANULOCYTOSIS
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANAEMIA
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEBRILE BONE MARROW APLASIA
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	2 / 34 (5.88%)	4 / 34 (11.76%)	4 / 35 (11.43%)
occurrences causally related to treatment / all	3 / 3	2 / 4	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IMMUNE THROMBOCYTOPENIC PURPURA
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LYMPHADENITIS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	1 / 34 (2.94%)	2 / 34 (5.88%)	3 / 35 (8.57%)
occurrences causally related to treatment / all	1 / 1	1 / 2	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPLENIC INFARCTION
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL HERNIA
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN
subjects affected / exposed	0 / 34 (0.00%)	3 / 34 (8.82%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COLITIS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PANCREATITIS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PANCREATITIS ACUTE
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RECTAL HAEMORRHAGE
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VOMITING
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
CHOLECYSTITIS ACUTE
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
ACTINIC KERATOSIS
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EXFOLIATIVE RASH
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUBCUTANEOUS EMPHYSEMA
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
URTICARIA
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEPHROLITHIASIS
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
ARTHRITIS REACTIVE
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BACK PAIN
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COCCYDYNIA
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GROIN PAIN
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
ASPERGILLUS INFECTION
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATYPICAL PNEUMONIA
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BACTERAEMIA
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHOPULMONARY ASPERGILLOSIS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE COLITIS
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE INFECTION
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIVERTICULITIS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EPIDIDYMITIS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EPIGLOTTITIS
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ESCHERICHIA BACTERAEMIA
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ESCHERICHIA SEPSIS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ESCHERICHIA URINARY TRACT INFECTION
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROENTERITIS
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROENTERITIS SALMONELLA
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HERPES ZOSTER
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFECTIOUS MONONUCLEOSIS
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LUNG INFECTION
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPENIC INFECTION
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OESOPHAGEAL CANDIDIASIS
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ORAL CANDIDIASIS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMOCYSTIS JIROVECII PNEUMONIA
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	5 / 34 (14.71%)	4 / 34 (11.76%)	10 / 35 (28.57%)
occurrences causally related to treatment / all	2 / 6	1 / 4	4 / 12
deaths causally related to treatment / all	1 / 1	1 / 1	0 / 1
PNEUMONIA INFLUENZAL
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
POST PROCEDURAL CELLULITIS
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SALMONELLOSIS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
SEPTIC SHOCK
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SOFT TISSUE INFECTION
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SYSTEMIC MYCOSIS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TUBERCULOSIS OF PERIPHERAL LYMPH NODES
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
WOUND INFECTION
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
DEHYDRATION
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERCALCAEMIA
subjects affected / exposed	3 / 34 (8.82%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	1 / 4	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERKALAEMIA
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TUMOUR LYSIS SYNDROME
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Lenalidomide 5 mg	Lenalidomide 10 mg	Lenalidomide 15 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	34 / 34 (100.00%)	34 / 34 (100.00%)	35 / 35 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
TUMOUR FLARE
subjects affected / exposed	17 / 34 (50.00%)	21 / 34 (61.76%)	23 / 35 (65.71%)
occurrences all number	35	41	39
Vascular disorders
HYPOTENSION
subjects affected / exposed	4 / 34 (11.76%)	4 / 34 (11.76%)	5 / 35 (14.29%)
occurrences all number	4	4	10
ORTHOSTATIC HYPOTENSION
subjects affected / exposed	3 / 34 (8.82%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	3	0	2
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	4 / 34 (11.76%)	4 / 34 (11.76%)	4 / 35 (11.43%)
occurrences all number	10	4	7
CHEST DISCOMFORT
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	2	0	0
CHILLS
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	6 / 35 (17.14%)
occurrences all number	0	4	6
FATIGUE
subjects affected / exposed	18 / 34 (52.94%)	17 / 34 (50.00%)	23 / 35 (65.71%)
occurrences all number	37	35	49
INFLUENZA LIKE ILLNESS
subjects affected / exposed	1 / 34 (2.94%)	3 / 34 (8.82%)	0 / 35 (0.00%)
occurrences all number	3	4	0
LOCAL SWELLING
subjects affected / exposed	1 / 34 (2.94%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	1	2	0
MALAISE
subjects affected / exposed	2 / 34 (5.88%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences all number	3	1	1
NON-CARDIAC CHEST PAIN
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	2	1
OEDEMA PERIPHERAL
subjects affected / exposed	6 / 34 (17.65%)	8 / 34 (23.53%)	5 / 35 (14.29%)
occurrences all number	8	9	7
PYREXIA
subjects affected / exposed	12 / 34 (35.29%)	15 / 34 (44.12%)	16 / 35 (45.71%)
occurrences all number	18	30	35
Immune system disorders
HYPOGAMMAGLOBULINAEMIA
subjects affected / exposed	5 / 34 (14.71%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	5	0	0
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	10 / 34 (29.41%)	15 / 34 (44.12%)	12 / 35 (34.29%)
occurrences all number	11	27	25
DYSPHONIA
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	3 / 35 (8.57%)
occurrences all number	2	0	4
DYSPNOEA
subjects affected / exposed	7 / 34 (20.59%)	6 / 34 (17.65%)	9 / 35 (25.71%)
occurrences all number	8	13	18
DYSPNOEA EXERTIONAL
subjects affected / exposed	1 / 34 (2.94%)	4 / 34 (11.76%)	3 / 35 (8.57%)
occurrences all number	1	5	4
EPISTAXIS
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	3 / 35 (8.57%)
occurrences all number	2	0	3
HYPOXIA
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	3 / 35 (8.57%)
occurrences all number	2	1	4
NASAL CONGESTION
subjects affected / exposed	4 / 34 (11.76%)	2 / 34 (5.88%)	3 / 35 (8.57%)
occurrences all number	4	2	3
NASAL DRYNESS
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	3
OROPHARYNGEAL PAIN
subjects affected / exposed	6 / 34 (17.65%)	1 / 34 (2.94%)	9 / 35 (25.71%)
occurrences all number	9	2	9
PLEURAL EFFUSION
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	3	2
PRODUCTIVE COUGH
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	3	0	5
RHINORRHOEA
subjects affected / exposed	5 / 34 (14.71%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	5	0	0
SINUS CONGESTION
subjects affected / exposed	2 / 34 (5.88%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	2	1	2
Psychiatric disorders
ANXIETY
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	4 / 35 (11.43%)
occurrences all number	0	2	4
DEPRESSION
subjects affected / exposed	1 / 34 (2.94%)	3 / 34 (8.82%)	2 / 35 (5.71%)
occurrences all number	1	3	2
INSOMNIA
subjects affected / exposed	3 / 34 (8.82%)	4 / 34 (11.76%)	8 / 35 (22.86%)
occurrences all number	3	4	8
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	6 / 34 (17.65%)	7 / 34 (20.59%)	5 / 35 (14.29%)
occurrences all number	9	28	17
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	3 / 34 (8.82%)	4 / 34 (11.76%)	5 / 35 (14.29%)
occurrences all number	5	24	10
BLOOD ALKALINE PHOSPHATASE INCREASED
subjects affected / exposed	2 / 34 (5.88%)	3 / 34 (8.82%)	1 / 35 (2.86%)
occurrences all number	3	6	1
BLOOD CREATININE INCREASED
subjects affected / exposed	2 / 34 (5.88%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	2	2	5
BLOOD IMMUNOGLOBULIN G DECREASED
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	2
BLOOD PHOSPHORUS DECREASED
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	2	0
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed	2 / 34 (5.88%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	5	7	0
WEIGHT DECREASED
subjects affected / exposed	7 / 34 (20.59%)	13 / 34 (38.24%)	10 / 35 (28.57%)
occurrences all number	18	22	16
Injury, poisoning and procedural complications
CONTUSION
subjects affected / exposed	3 / 34 (8.82%)	2 / 34 (5.88%)	2 / 35 (5.71%)
occurrences all number	3	2	3
LACERATION
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	2	0	0
PROCEDURAL PAIN
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	3	0
Cardiac disorders
ANGINA PECTORIS
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	0	1	2
TACHYCARDIA
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	2	0
Nervous system disorders
DIZZINESS
subjects affected / exposed	6 / 34 (17.65%)	1 / 34 (2.94%)	4 / 35 (11.43%)
occurrences all number	10	3	4
DYSGEUSIA
subjects affected / exposed	3 / 34 (8.82%)	0 / 34 (0.00%)	3 / 35 (8.57%)
occurrences all number	4	0	8
HEADACHE
subjects affected / exposed	5 / 34 (14.71%)	4 / 34 (11.76%)	4 / 35 (11.43%)
occurrences all number	9	4	4
HYPOAESTHESIA
subjects affected / exposed	2 / 34 (5.88%)	2 / 34 (5.88%)	2 / 35 (5.71%)
occurrences all number	3	3	2
LETHARGY
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	2	0	1
NEUROPATHY PERIPHERAL
subjects affected / exposed	3 / 34 (8.82%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	4	2	7
PARAESTHESIA
subjects affected / exposed	2 / 34 (5.88%)	2 / 34 (5.88%)	3 / 35 (8.57%)
occurrences all number	2	4	3
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	1	0	2
SOMNOLENCE
subjects affected / exposed	1 / 34 (2.94%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	1	2	0
TREMOR
subjects affected / exposed	2 / 34 (5.88%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	2	6	0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	11 / 34 (32.35%)	18 / 34 (52.94%)	15 / 35 (42.86%)
occurrences all number	40	52	48
AUTOIMMUNE HAEMOLYTIC ANAEMIA
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	6	0	0
FEBRILE NEUTROPENIA
subjects affected / exposed	2 / 34 (5.88%)	2 / 34 (5.88%)	2 / 35 (5.71%)
occurrences all number	2	2	2
LEUKOPENIA
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	1	0	6
LYMPH NODE PAIN
subjects affected / exposed	1 / 34 (2.94%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	1	4	0
NEUTROPENIA
subjects affected / exposed	25 / 34 (73.53%)	30 / 34 (88.24%)	26 / 35 (74.29%)
occurrences all number	197	220	140
THROMBOCYTOPENIA
subjects affected / exposed	17 / 34 (50.00%)	25 / 34 (73.53%)	21 / 35 (60.00%)
occurrences all number	73	104	95
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	3
Eye disorders
DRY EYE
subjects affected / exposed	3 / 34 (8.82%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	3	0	0
LACRIMATION INCREASED
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Gastrointestinal disorders
ABDOMINAL DISTENSION
subjects affected / exposed	1 / 34 (2.94%)	3 / 34 (8.82%)	1 / 35 (2.86%)
occurrences all number	1	3	2
ABDOMINAL PAIN
subjects affected / exposed	3 / 34 (8.82%)	10 / 34 (29.41%)	6 / 35 (17.14%)
occurrences all number	5	18	8
ABDOMINAL PAIN UPPER
subjects affected / exposed	1 / 34 (2.94%)	3 / 34 (8.82%)	3 / 35 (8.57%)
occurrences all number	1	4	7
CONSTIPATION
subjects affected / exposed	11 / 34 (32.35%)	13 / 34 (38.24%)	13 / 35 (37.14%)
occurrences all number	11	15	22
DIARRHOEA
subjects affected / exposed	14 / 34 (41.18%)	18 / 34 (52.94%)	16 / 35 (45.71%)
occurrences all number	24	29	37
DRY MOUTH
subjects affected / exposed	1 / 34 (2.94%)	2 / 34 (5.88%)	6 / 35 (17.14%)
occurrences all number	1	3	9
DYSPEPSIA
subjects affected / exposed	1 / 34 (2.94%)	3 / 34 (8.82%)	0 / 35 (0.00%)
occurrences all number	1	3	0
DYSPHAGIA
subjects affected / exposed	3 / 34 (8.82%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	5	0	1
GASTRITIS
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	2	0
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	2	0
NAUSEA
subjects affected / exposed	10 / 34 (29.41%)	15 / 34 (44.12%)	11 / 35 (31.43%)
occurrences all number	13	27	17
ORAL PAIN
subjects affected / exposed	2 / 34 (5.88%)	1 / 34 (2.94%)	0 / 35 (0.00%)
occurrences all number	2	1	0
STOMATITIS
subjects affected / exposed	3 / 34 (8.82%)	1 / 34 (2.94%)	4 / 35 (11.43%)
occurrences all number	7	1	10
VOMITING
subjects affected / exposed	8 / 34 (23.53%)	5 / 34 (14.71%)	8 / 35 (22.86%)
occurrences all number	8	6	12
Hepatobiliary disorders
CHOLELITHIASIS
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	1	0	2
HYPERBILIRUBINAEMIA
subjects affected / exposed	4 / 34 (11.76%)	2 / 34 (5.88%)	3 / 35 (8.57%)
occurrences all number	38	2	7
Skin and subcutaneous tissue disorders
ERYTHEMA
subjects affected / exposed	1 / 34 (2.94%)	5 / 34 (14.71%)	1 / 35 (2.86%)
occurrences all number	1	6	1
EXFOLIATIVE RASH
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	0	3	6
HYPERHIDROSIS
subjects affected / exposed	1 / 34 (2.94%)	2 / 34 (5.88%)	7 / 35 (20.00%)
occurrences all number	1	2	7
NIGHT SWEATS
subjects affected / exposed	6 / 34 (17.65%)	10 / 34 (29.41%)	11 / 35 (31.43%)
occurrences all number	10	13	16
PRURITUS
subjects affected / exposed	3 / 34 (8.82%)	4 / 34 (11.76%)	3 / 35 (8.57%)
occurrences all number	3	7	5
RASH
subjects affected / exposed	9 / 34 (26.47%)	8 / 34 (23.53%)	16 / 35 (45.71%)
occurrences all number	12	13	31
RASH ERYTHEMATOUS
subjects affected / exposed	1 / 34 (2.94%)	2 / 34 (5.88%)	1 / 35 (2.86%)
occurrences all number	2	2	1
RASH GENERALISED
subjects affected / exposed	2 / 34 (5.88%)	2 / 34 (5.88%)	1 / 35 (2.86%)
occurrences all number	4	2	1
RASH MACULAR
subjects affected / exposed	3 / 34 (8.82%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	3	0	1
RASH MACULO-PAPULAR
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	3 / 35 (8.57%)
occurrences all number	1	0	8
RASH PRURITIC
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	2
SKIN EXFOLIATION
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	2
SWELLING FACE
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	1	0	2
URTICARIA PAPULAR
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	4	0
Renal and urinary disorders
DYSURIA
subjects affected / exposed	2 / 34 (5.88%)	4 / 34 (11.76%)	1 / 35 (2.86%)
occurrences all number	2	6	2
HAEMATURIA
subjects affected / exposed	1 / 34 (2.94%)	2 / 34 (5.88%)	1 / 35 (2.86%)
occurrences all number	1	2	1
POLLAKIURIA
subjects affected / exposed	2 / 34 (5.88%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	3	1	2
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	6 / 34 (17.65%)	4 / 34 (11.76%)	2 / 35 (5.71%)
occurrences all number	8	7	2
BACK PAIN
subjects affected / exposed	4 / 34 (11.76%)	2 / 34 (5.88%)	10 / 35 (28.57%)
occurrences all number	4	4	14
BONE PAIN
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	2 / 35 (5.71%)
occurrences all number	0	2	3
MUSCLE SPASMS
subjects affected / exposed	6 / 34 (17.65%)	7 / 34 (20.59%)	11 / 35 (31.43%)
occurrences all number	9	10	13
MUSCULAR WEAKNESS
subjects affected / exposed	1 / 34 (2.94%)	2 / 34 (5.88%)	1 / 35 (2.86%)
occurrences all number	1	2	1
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	1	1	2
MUSCULOSKELETAL PAIN
subjects affected / exposed	2 / 34 (5.88%)	1 / 34 (2.94%)	4 / 35 (11.43%)
occurrences all number	2	2	5
NECK PAIN
subjects affected / exposed	2 / 34 (5.88%)	2 / 34 (5.88%)	3 / 35 (8.57%)
occurrences all number	2	2	5
PAIN IN EXTREMITY
subjects affected / exposed	8 / 34 (23.53%)	5 / 34 (14.71%)	5 / 35 (14.29%)
occurrences all number	8	5	5
Infections and infestations
BRONCHITIS
subjects affected / exposed	5 / 34 (14.71%)	2 / 34 (5.88%)	3 / 35 (8.57%)
occurrences all number	8	5	5
CELLULITIS
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	2 / 35 (5.71%)
occurrences all number	0	4	2
CYTOMEGALOVIRUS INFECTION
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	2	0	0
HERPES SIMPLEX
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	4 / 35 (11.43%)
occurrences all number	0	0	5
LABYRINTHITIS
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	2
LOCALISED INFECTION
subjects affected / exposed	0 / 34 (0.00%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	0	1	2
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	3	0	1
NASOPHARYNGITIS
subjects affected / exposed	3 / 34 (8.82%)	0 / 34 (0.00%)	1 / 35 (2.86%)
occurrences all number	7	0	2
ORAL CANDIDIASIS
subjects affected / exposed	0 / 34 (0.00%)	3 / 34 (8.82%)	3 / 35 (8.57%)
occurrences all number	0	6	4
ORAL HERPES
subjects affected / exposed	2 / 34 (5.88%)	3 / 34 (8.82%)	4 / 35 (11.43%)
occurrences all number	2	3	5
OTITIS MEDIA
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	3	0
PHARYNGITIS
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	3 / 35 (8.57%)
occurrences all number	1	1	4
PNEUMONIA
subjects affected / exposed	2 / 34 (5.88%)	4 / 34 (11.76%)	5 / 35 (14.29%)
occurrences all number	2	5	5
RESPIRATORY TRACT INFECTION
subjects affected / exposed	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 35 (0.00%)
occurrences all number	3	0	0
RHINITIS
subjects affected / exposed	1 / 34 (2.94%)	3 / 34 (8.82%)	2 / 35 (5.71%)
occurrences all number	1	9	5
SALMONELLOSIS
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	2	0
SINUSITIS
subjects affected / exposed	4 / 34 (11.76%)	1 / 34 (2.94%)	3 / 35 (8.57%)
occurrences all number	6	2	4
SKIN INFECTION
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	3 / 35 (8.57%)
occurrences all number	1	0	4
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	0 / 34 (0.00%)	2 / 34 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	3	1
TOOTH INFECTION
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	1	0	2
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	8 / 34 (23.53%)	5 / 34 (14.71%)	3 / 35 (8.57%)
occurrences all number	10	13	7
URINARY TRACT INFECTION
subjects affected / exposed	4 / 34 (11.76%)	5 / 34 (14.71%)	2 / 35 (5.71%)
occurrences all number	10	8	2
VIRAL UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	2 / 34 (5.88%)	1 / 34 (2.94%)	7 / 35 (20.00%)
occurrences all number	4	1	16
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	5 / 34 (14.71%)	11 / 34 (32.35%)	9 / 35 (25.71%)
occurrences all number	5	21	12
DEHYDRATION
subjects affected / exposed	1 / 34 (2.94%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	1	0	2
HYPERCALCAEMIA
subjects affected / exposed	2 / 34 (5.88%)	2 / 34 (5.88%)	2 / 35 (5.71%)
occurrences all number	6	2	2
HYPERGLYCAEMIA
subjects affected / exposed	2 / 34 (5.88%)	2 / 34 (5.88%)	2 / 35 (5.71%)
occurrences all number	5	2	2
HYPERKALAEMIA
subjects affected / exposed	2 / 34 (5.88%)	1 / 34 (2.94%)	1 / 35 (2.86%)
occurrences all number	6	1	1
HYPOCALCAEMIA
subjects affected / exposed	3 / 34 (8.82%)	2 / 34 (5.88%)	2 / 35 (5.71%)
occurrences all number	10	2	2
HYPOKALAEMIA
subjects affected / exposed	5 / 34 (14.71%)	5 / 34 (14.71%)	5 / 35 (14.29%)
occurrences all number	6	9	7
HYPOMAGNESAEMIA
subjects affected / exposed	1 / 34 (2.94%)	4 / 34 (11.76%)	1 / 35 (2.86%)
occurrences all number	1	5	1
HYPONATRAEMIA
subjects affected / exposed	1 / 34 (2.94%)	1 / 34 (2.94%)	2 / 35 (5.71%)
occurrences all number	1	1	3
HYPOPHOSPHATAEMIA
subjects affected / exposed	1 / 34 (2.94%)	3 / 34 (8.82%)	2 / 35 (5.71%)
occurrences all number	2	3	3
TUMOUR LYSIS SYNDROME
subjects affected / exposed	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	2

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Were there any global substantial amendments to the protocol? Yes

09 Jun 2009

Amendment 1 included the following changes: - Added back-up North American and 24-hour European emergency medical contacts. - Clarified which assessments could be performed for subjects who discontinued the study but continued to be assessed for response until disease progression. - Updated to allow greater investigator discretion in determining thromboembolic prophylaxis regimen based on individual subject status. - Corrections to the Schedule of Assessments: - Clarified that 28-day visit could be the 1st day of each new cycle, and to reflect that 84 days equaled to 12 weeks (not 16 weeks). - The “for Central Pathology Reviewer” was deleted from the procedure name (“Bone marrow aspirate, biopsy, peripheral blood slides”) to avoid confusion. In addition to submission of samples for central pathology review, local pathology review of the bone marrow aspirate and biopsy samples was also required. - Although specified in the respective footnote, “CR/CRi only” was added to clarify that the assessments MRD evaluation and bone marrow biopsy slides and/or aspirate for biomarker analyses, were only required for a CR/CRi confirmation visit, not a PR confirmation visit. - Corrected interval for follow-up ECG assessment to reflect 84 days equals 12 weeks (not 16 weeks). - Added details to clarify required central versus local clinical laboratory assessments (hematology, chemistry, and urinalysis). - Corrected interval for follow-up TSH assessment to reflect 84 days equals 12 weeks (not 16 weeks). - Updated footnote to specify time points for exploratory assessments and that those were to be analyzed centrally. - Updated to specify a maximum number of lymph node biopsies that could be performed for any one subject enrolled into the lymph node biopsy substudy. - Added statement to clarify that PK and exploratory biomarker assessments were to be analyzed centrally. - Added the average dose of radiation exposure per CT scan as required by IECs/IBs.

11 Feb 2010

Amendment 2 included the following key changes: - For select exploratory assessments: - Sampling time points for select exploratory assessments were revised to better support the exploratory objectives of the study. These assessments included the cytokines/soluble protein analysis, immune and B-CLL cells analysis by flow cytometry and immune cell and B-CLL cell activation, protein expression, and functional studies and micro-ribonucleic acid (miRNA) and gene expression profiling. - Tumor Protein 53 mutation analysis was added to the protocol based on recent publications and presentation at major international hematology meetings; it was to be performed at screening on the same sample as those collected for the VH mutational status analysis and was not to require additional blood sampling. - Added to the protocol that for subjects enrolled in Europe, SNP/mutational status analysis could also be performed from CD19 isolated cells if sufficient sample was available from the ZAP-70, VH mutational status/TP53 mutation analysis, and FISH studies. The sampling for gene copy number/SNP analysis that was part of the optional testing was deleted from the study. - Added to the protocol that for subjects enrolled in the US/Canada, an additional exploratory MRD marker analysis could be performed on the same sample as that collected for disease diagnosis confirmation and MRD evaluation. - The maximum number of prior treatment regimen for B-CLL was increased from 3 to 4. - Additional guidance was added to emphasize the importance of monitoring subjects’ platelet counts during the study. - The 24-hour emergency call center information was added to the protocol as this was implemented for all Celgene-sponsored studies to ensure subject safety. - Added further details on when study drug had to be permanently discontinued in case of renal insufficiency. - Added details on AE reporting timeframes required for the study.

09 Dec 2010

Amendment 3 included the following changes: - Based on delayed enrollment, the number of planned subjects was decreased from up to 120 to up to 90. - The frequency of visits during Cycles 2, 3 and 4 were decreased. - Changes to eligibility criteria: - Removed cap on the number of prior treatment regimens for B-CLL. - Allowed inclusion of subjects with prior treatment with either a purine-analog or bendamustine based regimen. - Stratification factor was updated to include relapsed versus refractory to a purine-analog or bendamustine based regimen (if subject had received both, status post most recent regimen was to be used). - The 120-day washout period for prior alemtuzumab treatment was decreased to 60 days. - Inclusion criteria were changed to allow screening of subjects with prior history of carcinoma in situ of the bladder if the subject was disease free for < 2 years prior to enrollment. - Since this was a Phase 2 study, the following administrative decisions were made: - Study was to be closed once 80% of randomized subjects had progressed or died. All subjects on study drug at the time the study was closed were to be transferred to commercial drug on a free basis. Survival follow-up was to cease at study closure. - CT scans for lymph nodes, liver, and spleen were not to be reviewed centrally. - To simplify laboratory sampling, the following exploratory assessments were removed: - Immune and B-CLL cells analysis by flow cytometry, cell activation, protein expression, and functional studies - Micro-ribonucleic acid and gene expression profiling - Bone marrow biopsy slides and/or aspirate for biomarker analyses - Sampling for prognostic factors and confirmation of disease diagnosis were to be performed at baseline instead of screening. - An exploratory substudy involving FNA of lymph nodes was added. - sampling time points for the cytokine and soluble protein biomarker assay and sparse PK were updated.

11 May 2011

Amendment 4 included the following key changes: - Required that SPMs were collected and monitored as SAEs and reported throughout the study duration, from the time of signing the informed consent up to and including the survival follow up phase. Subjects were followed until 80% of the subjects had progressed or died or up to 5 years after the last subject was randomized, whichever came later. - Incorporated current Celgene Pregnancy Prevention Plan language regarding the risks of lenalidomide and other text regarding source data verification.

09 Nov 2011

Amendment 5 included the following key changes: - Increased the sample size and required that following the enrollment of 90 subjects, participation in the PK substudy was mandatory. - Clarified that the second primary malignancy assessment had to be completed during the PFS follow-up phase and the survival phase. - Clarified the schedule for the baseline bone marrow biopsy and aspirate, which could be completed either during the screening phase or could be completed once the subject had been confirmed as eligible and entered into the study. - Expanded exclusion criteria surrounding history of prior malignancies from 2 years to 5 years. - Updated study contact information (clinical research physician and study manager).

14 Apr 2015

Amendment 6 included the following key changes: - The study drug packaging was changed from blister cards to bottles. - Subjects on study drug at the time of study closure could transition to non-study lenalidomide. - IVRS was discontinued. Sites ordered study drug when needed through the Celgene investigational drug dispensing program. This permitted sites to order study drug only when needed rather than maintain a stock of study drug for the IVRS to allocate. The change was possible at that time since few subjects remained on study drug and the study drug was no longer blinded. - Removed the 1.25-mg dose level and applied corresponding changes in the Dose Reduction Steps for Lenalidomide as no subjects utilized this dose level. - As all subjects were beyond the risk for TLS, Celgene no longer provided allopurinol supply for sites outside of North America. - Removed lymph node biopsy and fine needle aspirate assessments as no subjects consented for these additional tests. - Removed additional PK sample collection. PK samples were drawn at Study Day 1 and at dose escalation. Since the last subject was randomized in 2012, further dose escalations were not anticipated and hence no further PK samples were collected. - Removed the requirement to submit blood samples (hematology, chemistry, thyroid hormone, quantitative immunoglobulins and MRD), urine (urinalysis) and bone marrow (biopsy and aspirate) samples to the central laboratory for analysis. Local laboratories continued to be collected. The purpose of this change was to simplify the protocol procedures to reduce the workload for site personnel. - Removed the blood drawn for cytokines at the start and end of tumor flare. Tumor flare events were anticipated at the start of study drug administration. Since the last subject was randomized in 2012, additional events of tumor flare were not anticipated. - Removed the text for blinding and emergency unblinding activities as the study was unblinded.

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

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