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Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study To Compare The Efficacy And Safety Of Lenalidomide (Revlimid) Versus Placebo In Subjects With Transfusion-Dependent Anemia Due To Ipss Low Or Intermediate- 1 Risk Myelodysplastic Syndromes Without Deletion 5q [31] And Unresponsive Or Refractory To Erythropoiesis-Stimulating Agents

Summary
EudraCT number	2009-011513-24
Trial protocol	BE ES DE FR CZ AT IT PT GB PL
Global end of trial date	09 May 2018

Results information
Results version number	v1(current)
This version publication date	24 May 2019
First version publication date	24 May 2019
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-MDS-005

ISRCTN number

US NCT number

NCT01029262

WHO universal trial number (UTN)

Sponsor organisation name

Celgene Corporation

Sponsor organisation address

86 Morris Avenue, Summit, United States, 07901

Public contact

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

Scientific contact

CL Beach, PharmD, Celgene Corporation, 01 913-266-0302, CLBeach@celgene.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

18 Jun 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 May 2018

Was the trial ended prematurely?

Main objective of the trial

To compare the efficacy of lenalidomide versus placebo in subjects with red blood cell (RBC) transfusion-dependent low or Int-1 risk Myelodysplastic Syndrome (MDS) associated with any karyotype except deletion 5q[31] and unresponsive or refractory to erythropoiesis- stimulating agents in the intent to treat ITT population and in the pre-specified subgroup of subjects with an erythroid differentiation signature predictive of lenalidomide response

Protection of trial subjects

Patient Confidentiality, Personal Data Protection; Archiving Essential Documents

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Feb 2010

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy, Regulatory reason

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 15

Country: Number of subjects enrolled

Turkey: 1

Country: Number of subjects enrolled

United Kingdom: 21

Country: Number of subjects enrolled

United States: 7

Country: Number of subjects enrolled

Australia: 1

Country: Number of subjects enrolled

Austria: 9

Country: Number of subjects enrolled

Belgium: 11

Country: Number of subjects enrolled

Canada: 17

Country: Number of subjects enrolled

Czech Republic: 14

Country: Number of subjects enrolled

France: 19

Country: Number of subjects enrolled

Germany: 30

Country: Number of subjects enrolled

Israel: 16

Country: Number of subjects enrolled

Italy: 44

Country: Number of subjects enrolled

Japan: 12

Country: Number of subjects enrolled

Poland: 2

Country: Number of subjects enrolled

Portugal: 20

Worldwide total number of subjects

239

EEA total number of subjects

185

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

170

85 years and over

Subject disposition

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Recruitment details

Participants were randomized at 239 total sites including: Europe (185), North America (24), Asia/Pacific (13) and the Middle East (17).

Screening details

Participants must have had transfusion-dependent anemia defined as having an average transfusion need of at least 2 units of packed red blood cells (pRBCs) per 28 days during the 112 days preceding randomization; No consecutive 56-day period that was RBC-transfusion-free during the 112 days preceding randomization; hemoglobin levels ≤ 9.5 g/dL.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Data analyst, Subject

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants received 3 placebo capsules by mouth (PO) daily (QD) for at least 168 days until disease progression occurred, intolerable side effects or withdrawal of consent.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

3 placebo capsules by PO daily for at least 168 days until disease progression occurred, intolerable side effects or withdrawal of consent

Lenalidomide

Arm description

Participants received lenalidomide 10 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 60 mL/min for at least 168 days until disease progression, intolerable side effects or withdrawal of consent. Lenalidomide 5 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 40 and < 60 mL/min.

Arm type

Experimental

Investigational medicinal product name

CC-5013

Investigational medicinal product code

Other name

Revlimid

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Lenalidomide 10 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 60 mL/min for at least 168 days until disease progression, intolerable side effects or withdrawal of consent. Lenalidomide 5 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 40 and < 60 mL/min.

Number of subjects in period 1	Placebo	Lenalidomide
Started	79	160
Completed	0	0
Not completed	79	160
Adverse event, serious fatal	-	3
Consent withdrawn by subject	10	17
Adverse event, non-fatal	9	52
Miscellaneous	1	9
Lack of therapeutic effect	57	76
Protocol deviation	2	3

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Participants received 3 placebo capsules by mouth (PO) daily (QD) for at least 168 days until disease progression occurred, intolerable side effects or withdrawal of consent.

Reporting group title

Lenalidomide

Reporting group description

Reporting group values	Placebo	Lenalidomide	Total
Number of subjects	79	160	239
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	27	36	63
From 65-84 years	50	120	170
85 years and over	2	4	6
Age Continuous
Units: years
arithmetic mean (standard deviation)	68.9 ( 8.26 )	70.0 ( 8.19 )	-
Sex: Female, Male
Units: Subjects
Female	25	52	77
Male	54	108	162
Race/Ethnicity, Customized
Units: Subjects
Asian	1	1	2
Black or African American	0	2	2
White	69	133	202
Japanese	4	8	12
Other: Race Not disclosed	4	15	19
Other	1	1	2
International Prognostic Scoring System (IPSS) Investigator Determined
The Myelodysplastic Syndrome (MDS) IPSS score assesses the severity of MDS based on 3 prognostic factors each assigned a score: the percentage of bone marrow blasts, chromosome changes in the marrow cells (karyotype) and the presence of one or more low blood cell counts (cytopenias). The IPSS score is the sum of the bone marrow blast + karyotype + cytopenia score and ranges from 0 (low risk) to 3.5 (high risk). Prognosis is categorized as Low risk (score = 0), Intermediate-1 (score 0.5 to 1.0), Intermediate-2 (score 1.5 to 2.0) or High risk (score ≥ 2.5).
Units: Subjects
Low	30	85	115
Intermediate 1	49	75	124
World Health Organization Classification 2008 of MDS by Central Review
The World Health Organization (WHO) 2008 classification recognizes eight subtypes of MDS that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts (i.e., erythroid precursors with iron deposits surrounding the nucleus), presence of a monocytosis or a deletion 5q.
Units: Subjects
Refractory anemia (RA)	1	1	2
Refractory cytopenia unilineage dysplasia (RCUD)	0	5	5
RA with ringed sideroblasts (RARS)	7	12	19
Refractory cytopenia multilineage dysplasia (RCMD)	59	115	174
Refractory anemia with excess blasts-1 (RAEB-1)	12	27	39
Prior Erythropoiesis-stimulating Agent (ESA) Treatment
Erythropoiesis-stimulating agents (ESA) are similar to the cytokine (erythropoietin) that stimulates red blood cell production (erythropoieisis). ESAs, structurally and biologically, are similar to naturally occurring protein erythropoietin. ESAs are used to maintain hemoglobin at the lowest level that both minimizes transfusions and best meets a person's needs
Units: Subjects
Participants with Prior ESA Treatment	63	125	188
Participants with no Prior ESA Treatment	16	35	51
Gene Expression Signature
A prespecified subgroup of participants with an erythroid differentiation gene expression signature predictive of lenalidomide response
Units: Subjects
Gene Expression Signature	3	14	17
No Gene Expression Signature	76	146	222
Packed RBC (pRBC) Transfusion Burden
The baseline transfusion burden is the average number of RBC units/28 days during the 112 days prior to randomization.
Units: pRBC units
arithmetic mean (standard deviation)	3.4 ( 1.37 )	3.4 ( 1.23 )	-
Hemoglobin
Units: g/dL
arithmetic mean (standard deviation)	8.7 ( 1.37 )	8.7 ( 1.23 )	-

End points

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Reporting group title

Placebo

Reporting group description

Participants received 3 placebo capsules by mouth (PO) daily (QD) for at least 168 days until disease progression occurred, intolerable side effects or withdrawal of consent.

Reporting group title

Lenalidomide

Reporting group description

Primary: Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 days as Determined by an Independent Review Committee (IRC)

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End point title

Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 days as Determined by an Independent Review Committee (IRC)

End point description

The percentage of participants who achieved the 56-day RBC transfusion independent (TI) response was defined as the absence of any RBC transfusions during any consecutive “rolling” 56-day interval within the double-blind treatment phase (ie, Days 2 (Day 1 is the first study drug day) to 57, Days 3 to 58, etcetera). The double-blind treatment phase was defined as the period between the 1st dosing up until 28 days after the last study drug dose. The ITT population includes all participants who were randomized to either lenalidomide or placebo.

End point type

Primary

End point timeframe

From first dose of study drug until 28 days after the last dose, as of the data cut-off date of 17 March 2014; median (minimum, maximum) duration of treatment was 168 (14, 449) and 164 (7, 1158) days in each treatment group respectively

End point values	Placebo	Lenalidomide
Number of subjects analysed	79	160
Units: percentage of participants
number (not applicable)	2.5	26.9

Statistical Analysis 1

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

239

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[1]

Method

Fisher exact

Parameter type

Risk ratio (RR)

Point estimate

10.616

Confidence interval

level

95%

sides

2-sided

lower limit

2.639

upper limit

42.702

Notes
[1] - p-value is from Fisher's exact test to compare lenalidomide treatment group to placebo group

Primary: Percentage of Participants with a Erythroid Gene Signature Who Achieved RBC Transfusion Independence for ≥ 56 Days as Determined by an Independent Review Committee (IRC)

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End point title

Percentage of Participants with a Erythroid Gene Signature Who Achieved RBC Transfusion Independence for ≥ 56 Days as Determined by an Independent Review Committee (IRC)

End point description

The percentage of participants who achieved the 56-day RBC TI response was defined as the absence of any RBC transfusions during any consecutive "rolling" 56-day interval within the double-blind treatment phase (ie, Days 2 (Day 1 is the first study drug day) to 57, Days 3 to 58, etcetera). A participant who achieved at least a 56-day RBC-transfusion-independent response was considered a 56-day RBC-TI responder. Analysis population includes ITT participants with an erythroid gene expression signature.

End point type

Primary

End point timeframe

End point values	Placebo	Lenalidomide
Number of subjects analysed	3	14
Units: percentage of participants
number (not applicable)	0.0	7.1

Statistical Analysis 1

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants who Achieved RBC Transfusion Independence (TI) with a Duration of ≥ 24 Weeks (168 days) as Determined by the Sponsor

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End point title

Percentage of Participants who Achieved RBC Transfusion Independence (TI) with a Duration of ≥ 24 Weeks (168 days) as Determined by the Sponsor

End point description

The 168-day RBC-transfusion-independent response was defined as the absence of any RBC transfusion during any consecutive “rolling” 168 days during the treatment period, for example Days 2 (Day 1 is the first study drug day) to 169, Days 3 to 170, Days 4 to 171, etcetera. A responder was defined as a participant who had a ≥ 168 consecutive days of RBC-transfusion-free period after the first dose of study drug in the treatment phase. The ITT population included all participants who were randomized to either lenalidomide or placebo.

End point type

Secondary

End point timeframe

End point values	Placebo	Lenalidomide
Number of subjects analysed	79	160
Units: percentage of participants
number (not applicable)	0.0	17.5

Statistical Analysis 1

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

239

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

< 0.001 ^[3]

Method

Fisher exact

Parameter type

Risk ratio (RR)

Point estimate

99999

Confidence interval

level

95%

sides

2-sided

lower limit

-99999

upper limit

99999

Notes
[2] - 99999 = Not estimable
[3] - P-value is from Fisher's exact test to compare the lenalidomide arm to the placebo arm.

Secondary: Kaplan Meier Estimates of Duration of 56-day RBC TI response as Determined by the Sponsor

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End point title

Kaplan Meier Estimates of Duration of 56-day RBC TI response as Determined by the Sponsor

End point description

The duration of the first 56-day RBC TI response was calculated for those who achieved a response and was dependent on whether a subsequent RBC transfusion was given after the transfusion-free period (response) started: • For those who received a subsequent RBC transfusion after the response starts, the duration of response was not censored, and was calculated as response duration = last day of response – first day of response +1 where the last day of response was defined as 1 day before the first RBC transfusion which was given at 56 days or more after the response starts. • For those who did not receive a subsequent RBC transfusion after the response started, the end day of the response was censored and duration of response was calculated as response duration = date of last RBC transfusion assessment – first day of response + 1. Analysis included all responders who had a ≥ 56 consecutive days of RBC-transfusion-free period after the first study drug started.

End point type

Secondary

End point timeframe

End point values	Placebo	Lenalidomide
Number of subjects analysed	1 ^[4]	41
Units: weeks
median (confidence interval 95%)	99999 (-99999 to 99999)	30.9 (20.7 to 59.1)

Notes
[4] - 99999 = Median not estimable for 1 subject

Statistical Analysis 1

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.639 ^[5]

Method

Logrank

Confidence interval

Notes
[5] - p-value from log-rank test to compare lenalidomide and placebo.

Secondary: Time to 56-Day RBC-Transfusion-independent Response as Determined by the Sponsor

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End point title

Time to 56-Day RBC-Transfusion-independent Response as Determined by the Sponsor

End point description

The time to the first 56-day RBC-transfusion-independent response was calculated for participants who achieved a response. The day from the first dose of study drug to the date at which RBC-transfusion-independence starts was achieved and calculated using: Start date of the first response period – the date of the first study drug +1. A responder was defined as a participant who had a ≥ 56 consecutive days of RBC-transfusion-free period after the first dose of study drug in the treatment phase. The analysis was conducted only for those participants who achieved a 56-day TI response according to the sponsor's assessment. Responders in the intent to treat population.

End point type

Secondary

End point timeframe

End point values	Placebo	Lenalidomide
Number of subjects analysed	1	41
Units: weeks
median (full range (min-max))	0.3 (0.3 to 0.3)	10.1 (0.3 to 23.6)

No statistical analyses for this end point

Secondary: Kaplan Meier Estimates for Progression to Acute Myeloid Leukemia (AML)

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End point title

Kaplan Meier Estimates for Progression to Acute Myeloid Leukemia (AML)

End point description

Progression to AML is part of the natural course of MDS and is a manifestation of disease progression. The time to progress to AML was calculated from the day of randomization to the first day when AML was diagnosed. Participants who died without AML were censored at the date of death. The participants who were lost to follow-up were censored at the last known day when participants did not have AML. Participants who did not progress to AML at the last follow-up contact were censored at the day of the last follow-up contact. The ITT population included all participants who were randomized and received either lenalidomide or placebo. 99999 indicates data could not be estimated.

End point type

Secondary

End point timeframe

From randomization to the last subject last visit date of 09 May 2018; median follow-up time for progression to AML was 2.3 years for placebo and 2.6 years for lenalidomide arm.

End point values	Placebo	Lenalidomide
Number of subjects analysed	78 ^[6]	160 ^[7]
Units: years
median (confidence interval 95%)	99999 (-99999 to 99999)	99999 (5.2 to 99999)

Notes
[6] - 99999 = only a few subjects progressed to AML; median time to progression was not reached
[7] - 99999 = only a few subjects progressed to AML; median time to progression was not reached

Statistical Analysis 1

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.864 ^[8]

Method

Logrank

Confidence interval

Notes
[8] - p-value from log-rank test to compare lenalidomide and placebo.

Secondary: Kaplan Meier Estimate for Overall Survival (OS)

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End point title

Kaplan Meier Estimate for Overall Survival (OS)

End point description

Overall survival was assessed using the time between randomization and the date of death or date of censoring. Participants who were alive at a data cutoff date and participants who were lost to follow-up were censored at the last date when participants were known to be alive. ITT population was all participants who were randomized. 99999 = OS could not be reached for the upper limit.

End point type

Secondary

End point timeframe

From randomization to last subject last visit date of 09 May 2018; maximum survival follow up was 6.4 years.

End point values	Placebo	Lenalidomide
Number of subjects analysed	79 ^[9]	160
Units: years
median (confidence interval 95%)	3.0 (2.3 to 99999)	3.8 (2.9 to 4.8)

Notes
[9] - 99999 = Placebo upper limit not estimable.

Statistical Analysis 1

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

239

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.98 ^[10]

Method

Logrank

Confidence interval

Notes
[10] - p-value from log-rank test to compare lenalidomide and placebo.

Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAE)

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End point title

Number of Participants with Treatment Emergent Adverse Events (TEAE)

End point description

A TEAE = an AE that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug. A serious AE (SAE) is any: • Death • Life-threatening event • Any inpatient hospitalization or prolongation of hospitalization • Persistent or significant disability or incapacity • Congenital anomaly or birth defect • Any other important medical event the investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug given and whether or not other drugs, therapeutic interventions, or underlying conditions could provide an explanation for the event. The severity of an AE was evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 3.0) where Grade (GR) 1 = Mild, GR 2 = Moderate, GR 3 = Severe, GR 4 = Life-threatening and GR 5 = Death. Safety population = all patients who received ≥1 dose of lenalidomide or placebo.

End point type

Secondary

End point timeframe

From the first dose of study drug through 28 days after discontinuation from the study treatment; up to the final data cut-off date of 03 July 2018; maximum exposure was 2100 days in the lenalidomide arm and 529 days in the placebo arm.

End point values	Placebo	Lenalidomide
Number of subjects analysed	79	160
Units: participants
At least 1 TEAE	74	160
≥ 1 Treatment Related AE (TEAE)	42	144
≥ 1 Treatment Related TEAE Causing Discontinuation	3	40
≥ 1 TEAE Leading to Dose Reduction	1	10
≥ 1 TEAE Leading to Dose Interruption	11	89
≥ 1 TEAE Leading to Dose Interruption & Reduction	5	68
≥ 1 TEAE Leading to Discontinuation of Study Drug	9	51
≥ 1 Serious TEAE	16	62
≥1 Treatment-Related Serious TEAE	3	25
≥1 Serious TEAE Leading to Dose Reduction	0	1
≥1 serious TEAE Leading to Dose Interruption	4	21
≥1 SAE Causing Dose Interruption & Reduction	1	3
≥1 Serious TEAE Leading to Stopping of Study Drug	4	24
≥1 Grade (GR) 3-4 TEAE	35	139
≥ 1 GR 3-4 Related TEAE	16	127
≥ 1 GR 3-4 Leading to Dose Reduction	1	8
≥ 1 GR 3-4 TEAE Leading to Dose Interruption	9	80
≥ 1 GR 3-4 TEAE Dose Interrupt/Reduction	4	64
≥ 1 GR 3-4 TEAE Leading to Stopping of Study Med	6	41
≥ 1 GR 5 TEAE	2	6
≥1 GR Treatment Related 5 TEAE	1	3

No statistical analyses for this end point

Secondary: Compliance Rates using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) from Baseline to Week 48

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End point title

Compliance Rates using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) from Baseline to Week 48

End point description

The EORTC QOL Questionnaire for Patients with Cancer was a 30-item oncology-specific questionnaire and was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher score on symptom scales indicating worse symptoms. A participant was considered compliant at a visit if at least 15 out of the QLQ-C30 items in the questionnaire were checked. Analyses were performed based on the Health Related Quality of Life (HRQoL) evaluable population.

End point type

Secondary

End point timeframe

Baseline, Week 12, (±3 days), Week 24, (±3 days), Week 36, (±3 days), and Week 48 (±3 days); up to data cut-off of 17 Mar 2014

End point values	Placebo	Lenalidomide
Number of subjects analysed	79	160
Units: percentage of participants
number (not applicable)
Baseline	88.6	90.0
Week 12	78.5	83.8
Week 24	80.6	85.8
Week 36	100.0	80.5
Week 48	50.0	71.9

Statistical Analysis 1

Statistical analysis description

Baseline

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

239

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.823 ^[11]

Method

Fisher exact

Confidence interval

Notes
[11] - The p-values are calculated based on the Fisher exact test.

Statistical Analysis 2

Statistical analysis description

Week 12 (±3 days)

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

239

Analysis specification

Pre-specified

Analysis type

P-value

= 0.371 ^[12]

Method

Fisher exact

Confidence interval

Notes
[12] - The p-values are calculated based on the Fisher exact test.

Statistical Analysis 3

Statistical analysis description

Week 24 (±3 days)

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

239

Analysis specification

Pre-specified

Analysis type

P-value

= 0.391

Method

Fisher exact

Confidence interval

Statistical Analysis 4

Statistical analysis description

Week 36 (±3 days)

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

239

Analysis specification

Pre-specified

Analysis type

P-value

= 1

Method

Fisher exact

Confidence interval

Statistical Analysis 5

Statistical analysis description

Week 48 (±3 days)

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

239

Analysis specification

Pre-specified

Analysis type

P-value

= 0.508

Method

Fisher exact

Confidence interval

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Fatigue Domain at Week 12 and 24

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End point title

Mean Change From Baseline in the EORTC QLQ-C30 Fatigue Domain at Week 12 and 24

End point description

The EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from baseline values indicate reduction in fatigue (i.e. improvement in symptom) and positive values indicate increases in fatigue (i.e. worsening of symptom). Analyses were performed on the HRQoL evaluable population = defined as all randomized subjects who completed the baseline assessment and at least one post-baseline assessment from the ITT population. Only subjects with available data at baseline and each time point (indicated by "n") are included.

End point type

Secondary

End point timeframe

Baseline and Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: units on a scale
arithmetic mean (standard deviation)
Week 12, N = 56,122	0.6 ( 17.53 )	2.4 ( 28.26 )
Week 24, N= 47, 83	7.6 ( 20.74 )	-1.5 ( 26.42 )

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.323

Method

ANOVA

Confidence interval

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.071 ^[13]

Method

ANOVA

Confidence interval

Notes
[13] - P-value from ANOVA comparison for change from baseline between Lenalidomide and placebo adjusted with baseline score.

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain at Week 12 and 24

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End point title

Mean Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain at Week 12 and 24

End point description

The EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom). Analyses were performed on the HRQoL evaluable population, defined as all randomized subjects who completed the baseline assessment and at least one post-baseline assessment from the ITT population. Only subjects with available data at baseline and each time point (indicated by "N") are included.

End point type

Secondary

End point timeframe

Baseline and Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: units on a scale
arithmetic mean (standard deviation)
Week 12, N= 56, 122	0.6 ( 28.06 )	2.2 ( 29.92 )
Week 24, N = 47, 83	4.3 ( 26.57 )	1.2 ( 26.26 )

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.76 ^[14]

Method

ANOVA

Confidence interval

Notes
[14] - P-value from ANOVA comparison for change from baseline between Lenalidomide and placebo adjusted with baseline score

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.251 ^[15]

Method

ANOVA

Confidence interval

Notes
[15] - P-value from ANOVA comparison for change from baseline between Lenalidomide and placebo adjusted with baseline score.

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain at Week 12 and 24

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End point title

Mean Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain at Week 12 and 24

End point description

The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale was scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Analyses were performed on the HRQoL evaluable population, defined as all randomized subjects who completed the baseline assessment and at least one post-baseline assessment from the ITT population. Only subjects with available data at baseline and each time point (indicated by "N") are included.

End point type

Secondary

End point timeframe

Baseline and Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: units on a scale
arithmetic mean (standard deviation)
Week 12, N = 56,122	-1.4 ( 15.76 )	-2.1 ( 18.09 )
Week 24, N= 47, 83	-5.7 ( 14.84 )	-0.4 ( 18.19 )

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.424 ^[16]

Method

ANOVA

Confidence interval

Notes
[16] - P-value from ANOVA comparison for change from baseline between Lenalidomide and placebo adjusted with baseline score.

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.116 ^[17]

Method

ANOVA

Confidence interval

Notes
[17] - P-value from ANOVA comparison for change from baseline between Lenalidomide and placebo adjusted with baseline score.

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life (QOL) Domain at Week 12 and 24

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End point title

Mean Change From Baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life (QOL) Domain at Week 12 and 24

End point description

The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale was scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement. Analyses were performed on the HRQoL evaluable population, defined as all randomized subjects who completed the baseline assessment and at least one post-baseline assessment from the ITT population. Only subjects with available data at baseline and each time point (indicated by "N") are included.

End point type

Secondary

End point timeframe

Baseline and Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: units on a scale
arithmetic mean (standard deviation)
Week 12, N = 56,122	-2.1 ( 20.18 )	-1.4 ( 24.35 )
Week 24, N= 47, 83	-4.1 ( 20.25 )	-2.4 ( 27.87 )

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.746 ^[18]

Method

ANOVA

Confidence interval

Notes
[18] - P-value from ANOVA comparison for change from baseline between lenalidomide and placebo adjusted with baseline score.

Week 24 Analysis-Statistical Analysis 2

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.46 ^[19]

Method

ANOVA

Confidence interval

Notes
[19] - P-value from ANOVA comparison for change from baseline between Lenalidomide and placebo adjusted with baseline score.

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain at Week 12 and 24

Top of page

End point title

Mean Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain at Week 12 and 24

End point description

The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Domain was scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Analyses were performed on the HRQoL evaluable population, defined as all randomized subjects who completed the baseline assessment and at least one post-baseline assessment from the ITT population. Only subjects with available data at baseline and each time point (indicated by "N") are included.

End point type

Secondary

End point timeframe

Baseline and Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: units on a scale
arithmetic mean (standard deviation)
Week 12, N = 56,122	1.2 ( 18.70 )	-1.4 ( 22.39 )
Week 24, N= 47, 83	-7.1 ( 20.78 )	0.8 ( 20.06 )

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.265 ^[20]

Method

ANOVA

Confidence interval

Notes
[20] - P-value from ANOVA comparison for change from baseline between lenalidomide and placebo adjusted with baseline score.

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.047 ^[21]

Method

ANOVA

Confidence interval

Notes
[21] - 3]: P-value from ANOVA comparison for change from baseline between lenalidomide and placebo adjusted with baseline score.

Secondary: Mean Change from Baseline in Fatigue Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Top of page

End point title

Mean Change from Baseline in Fatigue Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

End point description

The EORTC QLQ-C30 was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate reduction in fatigue (i.e. improvement in symptom) and positive values indicate increases in fatigue (i.e. worsening of symptom). Analyses were performed on the HRQoL evaluable population.

End point type

Secondary

End point timeframe

Baseline, Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: units on a scale
least squares mean (confidence interval 95%)
Week 12, N = 56,122	-0.464 (-6.562 to 5.635)	3.497 (-0.631 to 7.624)
Week 24, N= 47, 83	7.376 (0.990 to 13.762)	0.196 (-4.505 to 4.897)

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2909 ^[22]

Method

t-test, 2-sided

Confidence interval

Notes
[22] - P-value is based on a two-sample t-test comparing the difference between treatments.

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0759 ^[23]

Method

t-test, 2-sided

Confidence interval

Notes
[23] - P-value is based on a two-sample t-test comparing the difference between treatments.

Secondary: Percentage of Participants who Achieved an Erythroid Response Based on Modified International Working Group (IWG) 2006 Criteria

Top of page

End point title

Percentage of Participants who Achieved an Erythroid Response Based on Modified International Working Group (IWG) 2006 Criteria

End point description

A participant was considered as having achieved an erythroid response if they either: - Had a hemoglobin (Hgb) increase ≥1.5 g/dL compared to baseline and confirmed by another central laboratory hemoglobin value at 4 to 8 weeks after the first Hgb measurement that also increased ≥1.5 g/dL. All Hgb values during this time interval must have had a ≥ 1.5 g/dL increase (ie, no central laboratory Hgb increase during this timeframe could be less <1.5 g/dL). OR - Had a 50% reduction in the number of the RBC transfusion units over any consecutive 56 days period compared to the baseline transfusion burden. The baseline transfusion burden is the number of units over 112 days prior to randomization divided by 2. Only transfusions given for a pre-transfusion Hgb value of 9 g/dL or less were used in this response assessment. Analyses = ITT population.

End point type

Secondary

End point timeframe

End point values	Placebo	Lenalidomide
Number of subjects analysed	79	160
Units: percentage of participants
number (not applicable)	30.4	38.8

Statistical Analysis 1

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

239

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.252 ^[24]

Method

Fisher exact

Parameter type

Risk ratio (RR)

Point estimate

1.276

Confidence interval

level

95%

sides

2-sided

lower limit

0.867

upper limit

1.877

Notes
[24] - p-value is from Fisher's exact test to compare the lenalidomide arm to the placebo arm.

Secondary: Mean Change From Baseline in the Dyspnea Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Top of page

End point title

Mean Change From Baseline in the Dyspnea Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24

End point description

The EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom). Analyses were performed on the HRQoL evaluable population, defined as all randomized subjects who completed the baseline assessment and at least one post-baseline assessment from the ITT population. Only subjects with available data at baseline and each time point (indicated by "N") are included.

End point type

Secondary

End point timeframe

Baseline, Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: units on a scale
least squares mean (confidence interval 95%)
Week 12, N= 56, 122	1.696 (-5.313 to 8.706)	3.374 (-1.369 to 8.117)
Week 24, N = 47, 83	5.998 (-1.174 to 13.171)	-0.206 (-5.557 to 5.146)

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6957 ^[25]

Method

t-test, 2-sided

Confidence interval

Notes
[25] - P-value is based on a two-sample t-test comparing the difference between treatments

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1729 ^[26]

Method

t-test, 2-sided

Confidence interval

Notes
[26] - P-value is based on a two-sample t-test comparing the difference between treatments

Secondary: Mean Change from Baseline in the Physical Functioning Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Top of page

End point title

Mean Change from Baseline in the Physical Functioning Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

End point description

TThe EORTC QLQ-C30 was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). The EORTC QLQ-C30 Physical Functioning was scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement. Analyses were performed on the HRQoL evaluable population. Only subjects with available data at baseline and each time point are included.

End point type

Secondary

End point timeframe

Baseline, Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: units on a scale
least squares mean (confidence interval 95%)
Week 12, N = 56,122	0.732 (-4.939 to 3.475)	-2.919 (-5.768 to -0.071)
Week 24, N= 47, 83	-5.451 (-10.046 to -0.85)	-1.484 (-4.861 to 1.892)

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3975

Method

t-test, 2-sided

Confidence interval

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1714 ^[27]

Method

t-test, 2-sided

Confidence interval

Notes
[27] - P-value is based on a two-sample t-test comparing the difference between treatments.

Secondary: Mean Change from Baseline in the Global Health Status/QoL Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Top of page

End point title

Mean Change from Baseline in the Global Health Status/QoL Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

End point description

The EORTC QLQ-C30 was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). The EORTC QLQ-C30 Global Health Status/QOL scale was scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement. Analyses were performed on the HRQoL evaluable population. Only subjects with available data at baseline and each time point are included.

End point type

Secondary

End point timeframe

Baseline, Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: units on a scale
least squares mean (confidence interval 95%)
Week 12, N = 56,122	-1.201 (-6.401 to 3.999)	-2.690 (-6.211 to 0.831)
Week 24, N= 47, 83	-4.502 (-10.330 to 1.326)	-2.441 (-6.761 to 1.880)

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6408 ^[28]

Method

t-test, 2-sided

Confidence interval

Notes
[28] - P-value is based on a two-sample t-test comparing the difference between treatments.

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.575 ^[29]

Method

t-test, 2-sided

Confidence interval

Notes
[29] - P-value is based on a two-sample t-test comparing the difference between treatments.

Secondary: Mean Change From Baseline in the Emotional Functioning Domain associated with the EORTC QLQ-C30 Scale at Weeks 12 and 24

Top of page

End point title

Mean Change From Baseline in the Emotional Functioning Domain associated with the EORTC QLQ-C30 Scale at Weeks 12 and 24

End point description

The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Scale is scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Analyses were performed on the HRQoL evaluable population, defined as all randomized subjects who completed the baseline assessment and at least one post-baseline assessment from the ITT population. Only subjects with available data at baseline and each time point (indicated by "N") are included.

End point type

Secondary

End point timeframe

Baseline, Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: units on a scale
least squares mean (confidence interval 95%)
Week 12, N = 56,122	1.458 (-3.621 to 6.536)	-1.876 (-5.307 to 1.556)
Week 24, N= 47, 83	-6.746 (-12.228 to -1.26)	-1.129 (-5.174 to 2.917)

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2848

Method

t-test, 2-sided

Confidence interval

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1053 ^[30]

Method

t-test, 1-sided

Confidence interval

Notes
[30] - P-value is based on a two-sample t-test comparing the difference between treatments

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in QOL (EORTC QLQ-C-30 scale) from Baseline in Fatigue Domain at Weeks 12 and 24

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvement in QOL (EORTC QLQ-C-30 scale) from Baseline in Fatigue Domain at Weeks 12 and 24

End point description

The EORTC QLQ-C30 was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher score on symptom scales indicating worse symptoms. Improvement means at least 10 points better compared to baseline. Analyses were performed on the HRQoL evaluable population. Only subjects with available data at baseline and each time point are included.

End point type

Secondary

End point timeframe

Baseline, Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: percentage of participants
number (not applicable)
Week 12, N = 56,122	30.4	39.3
Week 24, N= 47, 83	29.8	38.6

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.042 ^[31]

Method

Fisher exact

Confidence interval

Notes
[31] - The P-values are calculated based on Fisher exact test.

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.448 ^[32]

Method

Fisher exact

Confidence interval

Notes
[32] - The P-values are calculated based on Fisher exact test.

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Dyspnea Domain at Weeks 12 and 24

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Dyspnea Domain at Weeks 12 and 24

End point description

The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom). Improvement means at least 10 points better compared to baseline. Analyses were performed based on the HRQoL evaluable population = all participants who completed the baseline assessment and at least one post-baseline assessment for the ITT population.

End point type

Secondary

End point timeframe

Baseline, Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: percentage of participants
number (not applicable)
Week 12, N= 56, 122	19.6	21.3
Week 24, N = 47, 83	12.8	20.5

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.825 ^[33]

Method

Fisher exact

Confidence interval

Notes
[33] - The P-values are calculated based on Fisher exact test.

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.568 ^[34]

Method

Fisher exact

Confidence interval

Notes
[34] - The P-values are calculated based on Fisher exact test.

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline within the Physical Functioning Domain at Weeks 12 and 24

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline within the Physical Functioning Domain at Weeks 12 and 24

End point description

The EORTC QLQ-C30 was a 30-item oncology-specific questionnaire and was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher score on symptom scales indicating worse symptoms. A change of at least 10 points on the standardized domain scores was required for it to be considered clinically meaningful. Analyses were performed on the HRQoL evaluable population. Only subjects with available data at baseline and each time point are included.

End point type

Secondary

End point timeframe

Baseline, Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: percentage of participants
number (not applicable)
Week 12, N = 56,122	26.8	16.4
Week 24, N= 47, 83	12.8	24.1

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.119 ^[35]

Method

Fisher exact

Confidence interval

Notes
[35] - The P-values are calculated based on Fisher exact test.

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.172 ^[36]

Method

Fisher exact

Confidence interval

Notes
[36] - The P-values are calculated based on Fisher exact test.

Secondary: Percentage of participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Global Health Status/QOL Domain at Weeks 12 and 24

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End point title

Percentage of participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Global Health Status/QOL Domain at Weeks 12 and 24

End point description

e EORTC QLQ-C30 was a 30-item oncology-specific questionnaire and was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher score on symptom scales indicating worse symptoms. A change of at least 10 points on the standardized domain scores was required for it to be considered clinically meaningful. Analyses were performed on the HRQoL evaluable population. Only subjects with available data at baseline and each time point are included.

End point type

Secondary

End point timeframe

Baseline, Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: percentage of participants
number (not applicable)
Week 12, N = 56,122	19.6	22.1
Week 24, N= 47, 83	14.9	26.5

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.279 ^[37]

Method

Fisher exact

Confidence interval

Notes
[37] - The P-values are calculated based on Fisher exact test.

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.792 ^[38]

Method

Fisher exact

Confidence interval

Notes
[38] - The P-values were calculated based on Fisher exact test.

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Emotional Functioning Domain at Weeks 12 and 24

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End point title

Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Emotional Functioning Domain at Weeks 12 and 24

End point description

The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Domain was scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Analyses were performed on the HRQoL evaluable population, defined as all randomized subjects who completed the baseline assessment and at least one post-baseline assessment from the ITT population. Only subjects with available data at baseline and each time point (indicated by "N") are included.

End point type

Secondary

End point timeframe

Baseline, Week 12, ±3 days and Week 24, ±3 days

End point values	Placebo	Lenalidomide
Number of subjects analysed	58	131
Units: percentage of participants
number (not applicable)
Week 12, N = 56,122	25.0	20.5
Week 24, N= 47, 83	17.0	21.7

Week 12 Analysis-Statistical Analysis 1

Statistical analysis description

Week 12

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.476 ^[39]

Method

Fisher exact

Confidence interval

Notes
[39] - The P-values are calculated based on Fisher exact test.

Week 24 Analysis-Statistical Analysis 2

Statistical analysis description

Week 24

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

189

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.052 ^[40]

Method

Fisher exact

Confidence interval

Notes
[40] - The P-values are calculated based on Fisher exact test.

Secondary: Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Related to Adverse Events Per Person Years

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End point title

Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Related to Adverse Events Per Person Years

End point description

Hospitalizations due to adverse events exclude those for transfusions, elective procedures or protocol-driven procedures. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. Safety population includes all participants who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

End point values	Placebo	Lenalidomide
Number of subjects analysed	79	160
Units: Hospitilzations-person-years
number (confidence interval 95%)	0.47 (0.3 to 0.75)	0.77 (0.62 to 0.96)

No statistical analyses for this end point

Secondary: Healthcare Resource Utilization (HRU): Duration of Hospitalizations due to Adverse Events

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End point title

Healthcare Resource Utilization (HRU): Duration of Hospitalizations due to Adverse Events

End point description

Hospitalizations due to adverse events exclude those for transfusions, elective procedures or protocol-driven procedures. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. Includes subjects with at least one hospitalization.

End point type

Secondary

End point timeframe

End point values	Placebo	Lenalidomide
Number of subjects analysed	14	57
Units: Days
median (full range (min-max))	9.0 (1.0 to 66.0)	11.0 (1.0 to 76.0)

No statistical analyses for this end point

Secondary: Healthcare Resource Utilization (HRU): Number of Days of Hospitalization Due to Adverse Events Per Person

Top of page

End point title

Healthcare Resource Utilization (HRU): Number of Days of Hospitalization Due to Adverse Events Per Person

End point description

End point type

Secondary

End point timeframe

End point values	Placebo	Lenalidomide
Number of subjects analysed	79	160
Units: Days Per Person
number (confidence interval 95%)	6.37 (4.64 to 8.74)	8.92 (7.35 to 10.82)

No statistical analyses for this end point

Post-hoc: Percentage of Participants who Achieved an Erythroid Response Based on Original IWG 2006 Criteria

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End point title

Percentage of Participants who Achieved an Erythroid Response Based on Original IWG 2006 Criteria

End point description

A participant was considered as having achieved an erythroid response when: - A Hgb increase ≥1.5 g/dL compared to baseline and confirmed by another central laboratory hemoglobin value at 4 to 8 weeks after the first Hgb measurement that had also increased ≥1.5 g/dL for at least 8 weeks. All Hgb values during this time interval must have had a ≥ 1.5 g/dL increase (ie, no central laboratory Hgb increase during this timeframe can be less than a 1.5 g/dL) OR - had an absolute reduction of 4 RBC transfusion units over any consecutive 56 days period compared to the baseline transfusion burden. The baseline transfusion burden is the number of units over the 112 days prior to randomization divided by 2. Only transfusions given for a pre-transfusion Hgb value of 9.5 g/dL or less may be used in this response assessment.

End point type

Post-hoc

End point timeframe

End point values	Placebo	Lenalidomide
Number of subjects analysed	79	160
Units: Percentage of Participants
number (not applicable)	20.3	35.6

Statistical Analysis 1

Comparison groups

Placebo v Lenalidomide

Number of subjects included in analysis

239

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.017 ^[41]

Method

Fisher exact

Parameter type

Risk ratio (RR)

Point estimate

1.759

Confidence interval

level

95%

sides

2-sided

lower limit

1.083

upper limit

2.856

Notes
[41] - p-value is from Fisher's exact test to compare lenalidomide treatment group to placebo group.

Adverse events

Top of page

Timeframe for reporting adverse events

From the first dose of study drug through 28 days after last dose; up to the final data cut-off date of 03 July 2018; maximum exposure was 2100 days in the lenalidomide treatment group and 529 days in the placebo group.

Adverse event reporting additional description

Second primary malignancies were considered special areas of interest and were documented as a serious adverse event (considered to be at least “medically important” even if no other seriousness criteria apply) throughout the duration of this study (including the post treatment follow-up period).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Lenalidomide

Reporting group description

Participants received lenalidomide 10 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 60 mL/min for at least 168 days until disease progression, intolerable side effects or withdrawal of consent. Participants received lenalidomide 5 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 40 and < 60 mL/min.

Reporting group title

Placebo

Reporting group description

Participants received 3 placebo capsules by mouth daily for at least 168 days until disease progression occurred, intolerable side effects or withdrawal of consent.

Serious adverse events	Lenalidomide	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	62 / 160 (38.75%)	16 / 79 (20.25%)
number of deaths (all causes)	6	2
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MYELODYSPLASTIC SYNDROME
subjects affected / exposed	2 / 160 (1.25%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
ADENOCARCINOMA OF COLON
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INVASIVE DUCTAL BREAST CARCINOMA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LUNG SQUAMOUS CELL CARCINOMA STAGE IV
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA OF THE TONGUE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ACUTE MYELOID LEUKAEMIA
subjects affected / exposed	0 / 160 (0.00%)	2 / 79 (2.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
CHRONIC MYELOMONOCYTIC LEUKAEMIA
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PROSTATE CANCER
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA OF LUNG
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
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	3 / 160 (1.88%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CIRCULATORY COLLAPSE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	2 / 160 (1.25%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DISUSE SYNDROME
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MALAISE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MULTI-ORGAN FAILURE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
PYREXIA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SUDDEN DEATH
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
PLEURAL EFFUSION
subjects affected / exposed	3 / 160 (1.88%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ACUTE RESPIRATORY DISTRESS SYNDROME
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ACUTE RESPIRATORY FAILURE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ASTHMA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LUNG DISORDER
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONITIS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PULMONARY OEDEMA
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Psychiatric disorders
MENTAL STATUS CHANGES
subjects affected / exposed	2 / 160 (1.25%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
FEMUR FRACTURE
subjects affected / exposed	2 / 160 (1.25%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
FEMORAL NECK FRACTURE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HIP FRACTURE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (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 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SPINAL FRACTURE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
THORACIC VERTEBRAL FRACTURE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
TRAUMATIC INTRACRANIAL HAEMORRHAGE
subjects affected / exposed	2 / 160 (1.25%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
CARDIAC FAILURE
subjects affected / exposed	3 / 160 (1.88%)	2 / 79 (2.53%)
occurrences causally related to treatment / all	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
MYOCARDIAL INFARCTION
subjects affected / exposed	2 / 160 (1.25%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
ATRIAL FIBRILLATION
subjects affected / exposed	1 / 160 (0.63%)	2 / 79 (2.53%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC FAILURE CONGESTIVE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
TACHYARRHYTHMIA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
ATRIAL FLUTTER
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
TRANSIENT ISCHAEMIC ATTACK
subjects affected / exposed	2 / 160 (1.25%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DIZZINESS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DYSKINESIA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	5 / 160 (3.13%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	3 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	3 / 160 (1.88%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	6 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMOLYSIS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PANCYTOPENIA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (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	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
CATARACT
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ULCERATIVE KERATITIS
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
ASCITES
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTRITIS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL NECROSIS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMATEMESIS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INGUINAL HERNIA, OBSTRUCTIVE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
UPPER GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ABDOMINAL PAIN
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PANCREATITIS
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PANCREATITIS NECROTISING
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
HEPATIC CIRRHOSIS
subjects affected / exposed	1 / 160 (0.63%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC FAILURE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
SKIN ULCER
subjects affected / exposed	2 / 160 (1.25%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
NEURODERMATITIS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
NEPHROLITHIASIS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RENAL COLIC
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RENAL FAILURE ACUTE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
INTERVERTEBRAL DISC PROTRUSION
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MYALGIA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
OSTEOARTHRITIS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RHABDOMYOLYSIS
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
PNEUMONIA
subjects affected / exposed	10 / 160 (6.25%)	2 / 79 (2.53%)
occurrences causally related to treatment / all	4 / 11	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1
NEUTROPENIC SEPSIS
subjects affected / exposed	3 / 160 (1.88%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	2 / 160 (1.25%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ATYPICAL PNEUMONIA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BRONCHOPNEUMONIA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BRONCHOPULMONARY ASPERGILLOSIS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
CELLULITIS
subjects affected / exposed	2 / 160 (1.25%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ESCHERICHIA SEPSIS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LOBAR PNEUMONIA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA VIRAL
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
TOOTH ABSCESS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	0 / 160 (0.00%)	2 / 79 (2.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
INFLUENZA
subjects affected / exposed	0 / 160 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PSEUDOMONAL SEPSIS
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (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
DECREASED APPETITE
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOKALAEMIA
subjects affected / exposed	1 / 160 (0.63%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	1 / 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	Lenalidomide	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	154 / 160 (96.25%)	70 / 79 (88.61%)
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	38 / 160 (23.75%)	13 / 79 (16.46%)
occurrences all number	62	16
FATIGUE
subjects affected / exposed	36 / 160 (22.50%)	9 / 79 (11.39%)
occurrences all number	49	10
OEDEMA PERIPHERAL
subjects affected / exposed	35 / 160 (21.88%)	14 / 79 (17.72%)
occurrences all number	53	16
PYREXIA
subjects affected / exposed	20 / 160 (12.50%)	6 / 79 (7.59%)
occurrences all number	25	7
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	17 / 160 (10.63%)	6 / 79 (7.59%)
occurrences all number	21	7
DYSPNOEA
subjects affected / exposed	15 / 160 (9.38%)	9 / 79 (11.39%)
occurrences all number	19	16
EPISTAXIS
subjects affected / exposed	10 / 160 (6.25%)	2 / 79 (2.53%)
occurrences all number	12	4
Psychiatric disorders
INSOMNIA
subjects affected / exposed	9 / 160 (5.63%)	7 / 79 (8.86%)
occurrences all number	9	7
Investigations
WEIGHT DECREASED
subjects affected / exposed	17 / 160 (10.63%)	2 / 79 (2.53%)
occurrences all number	17	2
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	13 / 160 (8.13%)	2 / 79 (2.53%)
occurrences all number	21	3
SERUM FERRITIN INCREASED
subjects affected / exposed	1 / 160 (0.63%)	4 / 79 (5.06%)
occurrences all number	1	4
Injury, poisoning and procedural complications
OVERDOSE
subjects affected / exposed	15 / 160 (9.38%)	0 / 79 (0.00%)
occurrences all number	23	0
Nervous system disorders
DIZZINESS
subjects affected / exposed	13 / 160 (8.13%)	9 / 79 (11.39%)
occurrences all number	19	11
HEADACHE
subjects affected / exposed	9 / 160 (5.63%)	8 / 79 (10.13%)
occurrences all number	15	15
Blood and lymphatic system disorders
NEUTROPENIA
subjects affected / exposed	102 / 160 (63.75%)	9 / 79 (11.39%)
occurrences all number	323	16
THROMBOCYTOPENIA
subjects affected / exposed	66 / 160 (41.25%)	6 / 79 (7.59%)
occurrences all number	161	8
LEUKOPENIA
subjects affected / exposed	22 / 160 (13.75%)	2 / 79 (2.53%)
occurrences all number	75	2
ANAEMIA
subjects affected / exposed	8 / 160 (5.00%)	4 / 79 (5.06%)
occurrences all number	11	15
Eye disorders
CONJUNCTIVITIS
subjects affected / exposed	8 / 160 (5.00%)	0 / 79 (0.00%)
occurrences all number	8	0
Gastrointestinal disorders
DIARRHOEA
subjects affected / exposed	69 / 160 (43.13%)	18 / 79 (22.78%)
occurrences all number	115	27
CONSTIPATION
subjects affected / exposed	36 / 160 (22.50%)	9 / 79 (11.39%)
occurrences all number	46	9
NAUSEA
subjects affected / exposed	19 / 160 (11.88%)	12 / 79 (15.19%)
occurrences all number	29	14
VOMITING
subjects affected / exposed	13 / 160 (8.13%)	5 / 79 (6.33%)
occurrences all number	17	5
ABDOMINAL PAIN UPPER
subjects affected / exposed	12 / 160 (7.50%)	5 / 79 (6.33%)
occurrences all number	12	6
ABDOMINAL PAIN
subjects affected / exposed	10 / 160 (6.25%)	5 / 79 (6.33%)
occurrences all number	15	6
DYSPEPSIA
subjects affected / exposed	8 / 160 (5.00%)	2 / 79 (2.53%)
occurrences all number	11	2
Skin and subcutaneous tissue disorders
RASH
subjects affected / exposed	35 / 160 (21.88%)	4 / 79 (5.06%)
occurrences all number	61	6
PRURITUS
subjects affected / exposed	30 / 160 (18.75%)	9 / 79 (11.39%)
occurrences all number	47	13
DRY SKIN
subjects affected / exposed	12 / 160 (7.50%)	2 / 79 (2.53%)
occurrences all number	14	2
NIGHT SWEATS
subjects affected / exposed	8 / 160 (5.00%)	3 / 79 (3.80%)
occurrences all number	8	3
Musculoskeletal and connective tissue disorders
MUSCLE SPASMS
subjects affected / exposed	19 / 160 (11.88%)	2 / 79 (2.53%)
occurrences all number	28	3
PAIN IN EXTREMITY
subjects affected / exposed	18 / 160 (11.25%)	3 / 79 (3.80%)
occurrences all number	20	3
BACK PAIN
subjects affected / exposed	16 / 160 (10.00%)	9 / 79 (11.39%)
occurrences all number	17	9
ARTHRALGIA
subjects affected / exposed	14 / 160 (8.75%)	5 / 79 (6.33%)
occurrences all number	16	6
MYALGIA
subjects affected / exposed	8 / 160 (5.00%)	1 / 79 (1.27%)
occurrences all number	10	1
Infections and infestations
NASOPHARYNGITIS
subjects affected / exposed	19 / 160 (11.88%)	9 / 79 (11.39%)
occurrences all number	26	11
INFLUENZA
subjects affected / exposed	10 / 160 (6.25%)	2 / 79 (2.53%)
occurrences all number	10	2
URINARY TRACT INFECTION
subjects affected / exposed	9 / 160 (5.63%)	6 / 79 (7.59%)
occurrences all number	18	6
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	4 / 160 (2.50%)	5 / 79 (6.33%)
occurrences all number	6	6
PNEUMONIA
subjects affected / exposed	4 / 160 (2.50%)	4 / 79 (5.06%)
occurrences all number	5	5
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	19 / 160 (11.88%)	3 / 79 (3.80%)
occurrences all number	22	3
HYPOKALAEMIA
subjects affected / exposed	10 / 160 (6.25%)	0 / 79 (0.00%)
occurrences all number	19	0
IRON OVERLOAD
subjects affected / exposed	4 / 160 (2.50%)	4 / 79 (5.06%)
occurrences all number	4	4

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Were there any global substantial amendments to the protocol? Yes

16 Jul 2010

1. Change the CrCl exclusion criteria from < 60 mL/min to < 40 mL/min; 2. Modification of the criteria necessary to remain on treatment beyond Day 168: - The original protocol followed the IWG 2006 erythroid response criteria and required subjects to demonstrate a reduction of ≥ 4 units in 56 days prior to Day 168 in addition to a ≥ 1.5 g/dL increase in Hgb. A 50% reduction in the transfusion requirements from baseline was deemed a clinical relevant decrease with respect to the Day 168 decision point; therefore, the transfusion portion of the erythroid response requirement was modified to instead require a 50% reduction in transfusion requirement

27 Apr 2011

• Require that SPMs be monitored as SAEs and reported throughout the study duration including the follow-up period (at least 4 years from randomization); • Revise Dose Modification Guidelines for febrile neutropenia, Grade 4 neutropenia, Grade 3 or 4 thrombocytopenia; • Change to one Global Pregnancy Prevention Program (PPP) for all regions except Japan.

12 Apr 2012

• Expand exclusion criteria surrounding history of prior malignancies from 3 years to 5 years; • Revise subject eligibility criteria to exclude subjects who previously received immunomodulating or immunosuppressive agents; or epigenetic or DNA modulating agents or investigational agents; • Allow the use of anticoagulants; • Revise criteria for remaining on study drug past Day 168. Subjects need meet only one erythroid response criteria – either ≥ 1.5 g/dL Hgb increase or at least a 50% reduction in transfusion burden; rather than requiring both criteria. • Change in second primary malignancy follow-up period from at least 4 years to at least 5 years from randomization to allow for additional time to collect information.

17 Sep 2012

• Expand duration of enrollment period from 2 years to 3 years; • Clarify the assessments carried out by the IRC; • Clarify: the “overall population” is the “ITT population”; • Determine a new sample size (228 instead of 375); • New statistical analyses “strategy” (see Section 9.7.2).

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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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 days as Determined by an Independent Review Committee (IRC)

Primary: Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 days as Determined by an Independent Review Committee (IRC)

Primary: Percentage of Participants with a Erythroid Gene Signature Who Achieved RBC Transfusion Independence for ≥ 56 Days as Determined by an Independent Review Committee (IRC)

Primary: Percentage of Participants with a Erythroid Gene Signature Who Achieved RBC Transfusion Independence for ≥ 56 Days as Determined by an Independent Review Committee (IRC)

Secondary: Percentage of Participants who Achieved RBC Transfusion Independence (TI) with a Duration of ≥ 24 Weeks (168 days) as Determined by the Sponsor

Secondary: Percentage of Participants who Achieved RBC Transfusion Independence (TI) with a Duration of ≥ 24 Weeks (168 days) as Determined by the Sponsor

Secondary: Kaplan Meier Estimates of Duration of 56-day RBC TI response as Determined by the Sponsor

Secondary: Kaplan Meier Estimates of Duration of 56-day RBC TI response as Determined by the Sponsor

Secondary: Time to 56-Day RBC-Transfusion-independent Response as Determined by the Sponsor

Secondary: Time to 56-Day RBC-Transfusion-independent Response as Determined by the Sponsor

Secondary: Kaplan Meier Estimates for Progression to Acute Myeloid Leukemia (AML)

Secondary: Kaplan Meier Estimates for Progression to Acute Myeloid Leukemia (AML)

Secondary: Kaplan Meier Estimate for Overall Survival (OS)

Secondary: Kaplan Meier Estimate for Overall Survival (OS)

Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAE)

Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAE)

Secondary: Compliance Rates using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) from Baseline to Week 48

Secondary: Compliance Rates using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) from Baseline to Week 48

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Fatigue Domain at Week 12 and 24

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Fatigue Domain at Week 12 and 24

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain at Week 12 and 24

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain at Week 12 and 24

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain at Week 12 and 24

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain at Week 12 and 24

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life (QOL) Domain at Week 12 and 24

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life (QOL) Domain at Week 12 and 24

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain at Week 12 and 24

Secondary: Mean Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain at Week 12 and 24

Secondary: Mean Change from Baseline in Fatigue Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Secondary: Mean Change from Baseline in Fatigue Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Secondary: Percentage of Participants who Achieved an Erythroid Response Based on Modified International Working Group (IWG) 2006 Criteria

Secondary: Percentage of Participants who Achieved an Erythroid Response Based on Modified International Working Group (IWG) 2006 Criteria

Secondary: Mean Change From Baseline in the Dyspnea Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Secondary: Mean Change From Baseline in the Dyspnea Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Secondary: Mean Change from Baseline in the Physical Functioning Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Secondary: Mean Change from Baseline in the Physical Functioning Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Secondary: Mean Change from Baseline in the Global Health Status/QoL Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Secondary: Mean Change from Baseline in the Global Health Status/QoL Domain associated with the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Secondary: Mean Change From Baseline in the Emotional Functioning Domain associated with the EORTC QLQ-C30 Scale at Weeks 12 and 24

Secondary: Mean Change From Baseline in the Emotional Functioning Domain associated with the EORTC QLQ-C30 Scale at Weeks 12 and 24

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in QOL (EORTC QLQ-C-30 scale) from Baseline in Fatigue Domain at Weeks 12 and 24

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in QOL (EORTC QLQ-C-30 scale) from Baseline in Fatigue Domain at Weeks 12 and 24

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Dyspnea Domain at Weeks 12 and 24

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Dyspnea Domain at Weeks 12 and 24

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline within the Physical Functioning Domain at Weeks 12 and 24

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline within the Physical Functioning Domain at Weeks 12 and 24

Secondary: Percentage of participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Global Health Status/QOL Domain at Weeks 12 and 24

Secondary: Percentage of participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Global Health Status/QOL Domain at Weeks 12 and 24

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Emotional Functioning Domain at Weeks 12 and 24

Secondary: Percentage of Participants with a Clinically Meaningful Improvement in HRQOL Associated with the EORTC QLQ-C-30 Scale from Baseline in the Emotional Functioning Domain at Weeks 12 and 24

Secondary: Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Related to Adverse Events Per Person Years

Secondary: Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Related to Adverse Events Per Person Years

Secondary: Healthcare Resource Utilization (HRU): Duration of Hospitalizations due to Adverse Events

Secondary: Healthcare Resource Utilization (HRU): Duration of Hospitalizations due to Adverse Events

Secondary: Healthcare Resource Utilization (HRU): Number of Days of Hospitalization Due to Adverse Events Per Person

Secondary: Healthcare Resource Utilization (HRU): Number of Days of Hospitalization Due to Adverse Events Per Person

Post-hoc: Percentage of Participants who Achieved an Erythroid Response Based on Original IWG 2006 Criteria

Post-hoc: Percentage of Participants who Achieved an Erythroid Response Based on Original IWG 2006 Criteria

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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