Lenalidomide Versus Placebo in Myelodysplastic Syndromes With a Deletion 5q[31] Abnormality

• Sponsor: Celgene Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00179621
• Collaborator: ICON Clinical Research (Industry)
• Enrollment: 205
• Locations: 38
• Arms: 3
• Duration (Months): 59
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to compare 2 doses (10 mg and 5 mg) of lenalidomide to that of placebo in subjects with red blood cell (RBC) transfusion-dependent low- or intermediate-1-risk IPSS MDS associated with a deletion (del) 5q[31] cytogenetic abnormality. Study participants were randomized to one of the two treatment groups or to placebo and took the study drug for 16 weeks. At this timepoint, participants were evaluated for erythroid response. If participants did not achieve at least a minor erythroid response, they were discontinued from the Double-Blind phase and entered into the Open-Label phase. All erythroid responders at Week 16 were to continue in the Double-Blind phase for up to 52 weeks. For participants that were still responding at the end of Double-Blind phase, they could then rollover into the Open-Label phase for an additional two years. Participants could remain on study for up to a total of 3 years. All participants who discontinued from the study were followed every 4 months for overall survival and progression to acute myeloid leukemia (AML).

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Drug: Lenalidomide 5 mg; Drug: Lenalidomide 10 mg; Drug: Placebo	Phase 3

Detailed Description

MDS-004 was a multicenter, randomized, double-blind, placebo-controlled, 3-arm study of 2 doses of lenalidomide versus placebo administered to RBC transfusion-dependent adults with low- or intermediate-1 risk MDS associated with a del 5q[31] cytogentetic abnormality. Potential participants that had a del 5q[31] cytogenetic abnormality plus other additional cytogenetic abnormalities were also eligible for enrollment. Transfusion-dependent anemia was defined as documentation that a participant with anemia due to MDS did not have any consecutive 56 days (8 weeks) that were RBC transfusion free during at least the 112 days (16 weeks) prior to Day 1 of the Pre-Randomization Phase.

This study was conducted in three phases:

1. a Pre-Randomization Phase

2. a Double-Blind Treatment Phase

3. an Open-Label Extension Phase

Potentially protocol-eligible participants entered the Pre-Randomization Phase and were evaluated for the inclusion and exclusion criteria for the Double-Blind Treatment Phase. The Pre-Randomization Phase was not to last for more than 56 days (8 weeks). When the participant's baseline RBC transfusion requirement was calculated, and it had been determined that all eligibility criteria had been met, the participant could be randomized for treatment in the Double-Blind Treatment Phase at the time of their next RBC transfusion. This RBC transfusion had to occur within 56 days of the participant's last previous RBC transfusion.

Participants meeting eligibility criteria were randomized (1:1:1 ratio) to receive either lenalidomide 10 mg/day on days 1-21, lenalidomide 5 mg/day on days 1-28, or placebo on days 1-28; all on a 28-day cycle. Randomization was performed using a validated interactive voice response system. Participants were stratified according to karyotype (IPSS karyotype score: 0 vs > 0; i.e., isolated del 5q[31] vs del 5q[31] plus ≥ 1 additional cytogenetic abnormality). A complete blood count (CBC), serum or plasma ferritin, and EPO levels were measured to determine baseline levels.

Participants who achieved at least a minor erythroid response (i.e. 50% decrease in transfusion requirements) by week 16 could continue treatment in the Double-Blind phase for up to 52 weeks, unless there was evidence of erythroid relapse, disease progression, or unacceptable toxicity. Those who did not achieve at least a minor erythroid response by week 16 were discontinued from the Double-Blind phase for lack of therapeutic efficacy, and unblinded and were potentially eligible for Open-Label treatment. All participants who completed the double-blind treatment phase (the first 52 weeks of the trial) without disease progression or erythroid relapse were unblinded and entered the Open-Label extension phase at their current lenalidomide dose. Participants in the placebo or lenalidomide 5 mg arms who failed to achieve at least a minor erythroid response by week 16 or who had an erythroid relapse could cross over to lenalidomide 5 mg or 10 mg, respectively, in the Open-Label Extension phase.

Lenalidomide treatment could be continued in the Open-label Extension phase for up to 3 years (156 weeks) of total study participation. Participants with disease progression at any time and participants in the lenalidomide 10 mg group who did not achieve at least a minor erythroid response by week 16 were withdrawn from the study and were ineligible for Open-Label treatment.

Serial measurements for efficacy and safety were performed every 28 days. In addition, CBCs were monitored weekly for the first 8 weeks, every 2 weeks for the next 8 weeks, and every 4 weeks thereafter. Bone marrow aspirate (BMA) and standard cytogenetic studies were performed at baseline, weeks 12, week 24, and every 24 weeks thereafter and when clinically indicated for assessment of disease progression. BMAs were submitted for central pathology review and sent to a central cytogenetics laboratory for processing and review. All participants were followed for overall survival (OS) and progression to acute myeloid leukemia (AML).

Lenalidomide or placebo dosing was reduced for dose-limiting toxicities according to the following dose reduction schedule:

• Lenalidomide 5 mg (starting dose)

• dose level -1 (5 mg every other day)

• dose level -2 (5 mg twice a week)

• dose level -3 (5 mg weekly)

• Lenalidomide 10 mg (starting dose)

• dose level -1 (5 mg daily)

• dose level -2 (5 mg every other day)

• dose level -3 (5 mg twice a week)

Participants who could not tolerate dose level -3 discontinued treatment. For grade 4 neutropenia, lenalidomide was required per protocol to be interrupted and resumed at a decreased dose level when the absolute neutrophil count (ANC) recovered to ≥ 500/μL. For grade 4 thrombocytopenia, lenalidomide was interrupted and then resumed at a decreased dose level when the platelet count recovered to: between ≥ 25,000/μL and < 50,000/μL on at least 2 occasions for ≥ 7 days; or ≥ 50,000 at any time, respectively. Prophylactic and therapeutic use of granulocyte colony-stimulating factors (G-CSF) or granulocyte macrophage colony-stimulating factors (GM-CSF) was allowed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 205 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study of the Efficacy and Safety of 2 Doses of Lenalidomide Versus Placebo in Red Blood Cell (RBC) Transfusion-Dependent Subjects With Low- or Intermediate-1-Risk Myelodysplastic Syndromes Associated With a Deletion (Del) 5q[31] Cytogenetic Abnormality
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo matching to active study arms.	Drug: Placebo; Placebo, matching to active study drug arms
Experimental: Lenalidomide 5 mg Lenalidomide 5 mg daily 28/28 days	Drug: Lenalidomide 5 mg; Lenalidomide 5 mg daily 28/28 days; Other Names: Revlimid
Experimental: Lenalidomide 10 mg Lenalidomide 10 mg daily 21/28 days	Drug: Lenalidomide 10 mg; Lenalidomide 10 mg daily 21/28 days; Other Names: Revlimid

Outcome Measures

Primary Outcome Measures

1. Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for >= 26 Weeks (182 Days) [Up to 52 weeks]

   The count of study participants who had no RBC transfusions for 26 consecutive weeks or more during the double-blind period.

Secondary Outcome Measures

1. Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for 56 Days [Up to 52 weeks]

   Count of study participants who had no RBC transfusions during any 56 or more consecutive study days during the double-blind period.

2. Duration of Red Blood Cell (RBC) Transfusion Independence for Participants Who Became RBC Transfusion Independent for at Least 182 Days [up to 3 years]

   Mean number of weeks that participants who achieved RBC transfusion independence for at least 182 days were able to maintain RBC transfusion independence. Both double-blind and open-label periods are included.

3. Maximum Change From Baseline in Hemoglobin During the Double-blind Period for Participants Who Became Red Blood Cell (RBC) Transfusion Independent for at Least 182 Days [Baseline, up to 52 weeks]

   For participants who became RBC transfusion independent for at least 182 days during the double-blind study period, the mean maximum change from baseline in hemoglobin is summarized.

4. Participants' Response in Platelet Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period [up to 52 weeks]

   The International MDS Working Group (IWG) defines a major platelet response for participants with a pre-treatment platelet count of <100,000/mm^3 as an absolute increase of ≥30,000/mm^3 whereas a minor response is defined as a ≥50% increase in platelet count with a net increase greater than 10,000/mm^3 but less than 30,000/mm^3.

5. Participants' Response in Absolute Neutrophil Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period [up to week 52]

   A major neutrophil response is defined by the International MDS Working Group (IWG) criteria as at least a 100% increase, or an absolute increase of ≥500/mm^3 for participants with absolute neutrophil counts (ANC) of less than 1,500/mm^3 before therapy, whichever is greater. A minor response for such participants is defined as an ANC increase of at least 100%, but absolute increase <500/mm^3.

6. Participants' Response Based on Bone Marrow Samples by the International MDS Working Group (IWG 2000) During Double-blind Period [up to 52 weeks]

   The IWG criteria for bone marrow improvement: a complete remission is bone marrow sampling showing less than 5% myeloblasts with normal maturation of all cell lines, with no evidence for dysplasia. A partial remission is ≥ 50% decrease in blasts over pre-treatment. Bone marrow progression is a ≥ 50% increase in blasts that exceed the top range of the pretreatment percentile range: a) <5% blasts b) 5-10% blasts c) 10-20% blasts d) 20-30% blasts. For example, a participant with <5% blasts pretreatment with an on study blast increase of 50% which is now >5% showed bone marrow progression.

7. Participants Showing Cytogenetic Response by the International MDS Working Group (IWG 2000) During Double-blind Period as Evaluated by Central Review [up to 52 weeks]

   The IWG criteria for evaluating cytogenetic response require a minimum of 20 baseline and post-baseline analyzable metaphases using conventional cytogenetic techniques. A major cytogenetic response is defined as no detectable cytogenetic abnormality if preexisting abnormality was present whereas a minor response requires ≥50% reduction in abnormal metaphases. Progression could be concluded based on as few as 3 metaphases if there were additional abnormalities. The best response is represented.

8. Participants Who Progressed to Acute Myeloid Leukemia (AML) During the Study [up to 3 years]

   Number of participants who progressed to acute myeloid leukemia during the study, summarized at three different timepoints: first 16 weeks of the double-blind study, week 52 of the double-blind study, and up to 36 months which includes the double-blind and open-label periods of the study. The counts are cumulative by timeframe.

9. Kaplan Meier Estimates of Overall Survival by Randomized Group [up to 3 years]

   Kaplan Meier estimate for median length of survival for study participants as they were randomized at the start of the study.

10. Participant Count of Deaths During Double-blind and Open-label by Randomized Group [up to 3 years]

    Count of participant deaths throughout the entire study and reported by the original treatment assignment.

11. Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Week 12 [Baseline, Week 12]

    The Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire (Yellen, 1997) was used to assess health-related quality of life (HRQoL). In addition to general HRQoL, the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning. The overall score range for the FACT-An is 0-188. Higher scores indicate better HRQoL.

12. Change From Baseline in the Trial Outcome Index-Anemia (TOI-An) Endpoints at Week 12 [Baseline, Week 12]

    The Trial Outcome Index-Anemia (TOI-An) composed of the physical and functional subscales of the FACT-G along with the Anemia subscale was used to assess health-related quality of life (HRQoL). The overall score range for the TOI-An is 0-136. Higher scores indicate better HRQoL.

13. Change From Baseline in the Trial Outcome Index-Fatigue (TOI-F) Endpoints at Week 12 [Baseline, Week 12]

    The Trial Outcome Index-Fatigue(TOI-F) composed of the physical and functional subscales of the FACT-G along with the fatigue items from the Anemia subscale was used to assess health-related quality of life (HRQoL). The overall score range for the TOI-F is 0-108. Higher scores indicate better HRQoL.

14. Summary of Participants Who Had Adverse Events (AE) During the Double-blind Period [up to week 52]

    Counts of study participants who had adverse events (AEs) during the double-blind period by MedDRA System Organ Class (SOC) and preferred term. A participant with multiple occurrences of an adverse event within a category is counted only once in that category. Adverse events were evaluated by the investigator. The National Cancer Institute (NCI)'s Common Terminology Criteria for AEs (CTCAE) was used to grade AE severity. Severity grade 3= severe and undesirable AE. Severity grade 4= life-threatening or disabling AE.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Must understand and voluntarily sign an informed consent form

• Age 18 years at the time of signing the informed consent form

• Documented diagnosis of myelodysplastic syndromes (MDS) that meets International Prognostic Scoring System (IPSS) criteria for low to intermediate-1-risk disease and has an associated del 5q(31) cytogenetic abnormality

• Red blood cell (RBC) transfusion dependent anaemia defined as not having any 56 days without a RBC transfusion within at least the immediate 112 days

• Must be able to adhere to the study visit schedule and other protocol requirements

• Women of childbearing potential must have a negative pregnancy test prior to inclusion

Exclusion Criteria:

• Pregnant or lactating females

• Prior therapy with lenalidomide

• Proliferative (white blood cell (WBC)= 12,000/mL) chronic myelomonocytic leukemia (CMML)

• Prior >= grade-2 (using the National Cancer Institute (NCI)'s Common Terminology Criteria for AEs (CTCAE) (v 3.0)) allergic reaction to thalidomide

• Prior desquamating (blistering) rash while taking thalidomide

• Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for >3 years

• Use of cytotoxic chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS within 28 days

• Less than 6 months since prior allogeneic bone marrow transplantation

• Less than 3 months since prior autologous bone marrow or stem cell transplantation

• Less than 28 days since prior myelosuppressive anticancer biologic therapy

• Recombinant human erythropoietin (rHuEPO) therapy received within 28 days

• Known human immunodeficiency virus (HIV-1) positivity

• Any serious medical condition or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he or she participates in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	AZ St-Jan Brugge AV	Brugge		Belgium	8000
2	UZ Gent	Gent		Belgium	900
3	UZ Gasthuisberg	Leuven		Belgium	3000
4	CHU Mont Godine	Yvoir		Belgium	5530
5	Institut Paoli-Calmettes	Marseille	Cedex 9	France	B.P.156 - 13272
6	CHU d'Angers Service des Maladies du Sang	Angers		France	49933
7	Hopital Avicenne	Bobigny Cedex		France
8	CHRU Lille Service des Maladies du Sang	Lille		France	59037
9	CHU Nantes Hematologie et Medicine interne	Nantes		France	44093
10	CHU Archet 1Hematologie Clinique	Nice		France	06202
11	Hôpital Cochin Hematologie Clinique	Paris		France	75014
12	Centre Jean Bernhard Service Onco-Hematologie	Poitiers		France	86021
13	Centre Henri Becquerel Service d'Hematologie Clinique	Rouen		France	76038
14	CHU Purpan, Place du Dr Baylac, Pavillon des Médecines	Toulouse		France	31059
15	CHU Purpan, Place du Dr. Baylac, Pavillion des Medecines	Toulouse		France	31059
16	CHU Nancy Hematologie et Medecine interne	Vandoeuvre		France	54511
17	Universitaetsklinikum Carl Gustav Carus	Dresden		Germany	01307
18	St Johannes Hospital	Duisburg		Germany	47166
19	Universitaetsklinikum Freiburg	Freiburg		Germany	79106
20	Hannover Medical School	Hannover		Germany	D-30625
21	Tel Aviv Sourasky Medical Center	Tel Aviv		Israel	64239
22	Ospedale Niguarda Ca Granda	Milano		Italy	20162
23	University of Pavia Division of Hematology	Pavia		Italy	27100
24	University of Medical Centre	Nijmegen		Netherlands	6526 GA
25	Hematologie Erasmus MC	Rotterdam		Netherlands	3000CA
26	Hospital Universitario de Salamanca	Salamanca		Spain	37007
27	Hospital Universitario La Fe	Valencia		Spain	46009
28	SU/Sahlgrenska Section of Hematology & Coagulation	Goteborg		Sweden	SE 413 45
29	Department of Medicine University Hospital	Lund		Sweden	S-221 85
30	Korolinska Institutet Department of Hematology	Stockholm		Sweden	14186
31	University Hospital of Wales, Dept of Haematology	Cardiff	Wales	United Kingdom	CF14 4XW
32	Leed General Infirmary	Leeds	West Yorkshire	United Kingdom	LS1 3 EX
33	The Royal Bournemouth Hospital	Bournemouth		United Kingdom	BH7 7DW
34	Ninewells Hospital and Medical School	Dundee		United Kingdom	DD1 9SY
35	Kings College Hospital, Denmark Hill	London		United Kingdom	SE 5 9RS
36	Central Manchester and Manchester Children's University Hospitals NHS Trust	Manchester		United Kingdom	M13 9WL
37	Nottingham City Hospital	Nottingham		United Kingdom	NG5 1PB
38	John Radcliffe Hospital and the Weatherall Institute of Molecular Medicine	Oxford		United Kingdom	OX3 9DS

Sponsors and Collaborators

• Celgene Corporation
• ICON Clinical Research

Investigators

• Study Director: Jay Backstrom, MD, Celgene Corporation

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00179621
• Other Study ID Numbers: CC-5013-MDS-004; 2005-000454-73
• First Posted: Sep 16, 2005
• Last Update Posted: Apr 14, 2011
• Last Verified: Apr 1, 2011

• Keywords provided by , ,: MDS; transfusion dependent; anaemia; cytogenetic abnormality 5q-; erythroid response; leukaemia; CC-5013; Celgene; revlimid; lenalidomide
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Congenital Abnormalities; Syndrome; Lenalidomide

Study Results

Participant Flow

Pre-assignment Detail	A total of 263 potential participants were screened. Potentially protocol-eligible participants were then entered into the Pre-Randomization Phase (up to 56 days) to ensure eligibility criteria were met prior to entering the Double-Blind Phase. A total of 205 participants were randomized into the study.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg	Placebo Crossover to 5 mg Open-label Period
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days	Participants receiving placebo in the Double-Blind phase and Lenalidomide in the Open-Label phase.
Period Title: Double-Blind Period
STARTED	67	69	69	0
COMPLETED	3	23	39	0
NOT COMPLETED	64	46	30	0
Period Title: Double-Blind Period
STARTED	0	42	47	56
COMPLETED	0	14	19	13
NOT COMPLETED	0	28	28	43

Baseline Characteristics

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg	Total
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days	Total of all reporting groups
Overall Participants	67	69	69	205
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69.9	66.0	68.0	68.0
Sex: Female, Male (Count of Participants)
Female	54 80.6%	53 76.8%	49 71%	156 76.1%
Male	13 19.4%	16 23.2%	20 29%	49 23.9%
Race/Ethnicity, Customized (participants) [Number]
White	66 98.5%	67 97.1%	69 100%	202 98.5%
Other	1 1.5%	2 2.9%	0 0%	3 1.5%
5q- (31-33) Chromosomal Abnormality (Number) [Number]
Yes	63 94%	64 92.8%	64 92.8%	191 93.2%
No	1 1.5%	2 2.9%	1 1.4%	4 2%
Missing	3 4.5%	3 4.3%	4 5.8%	10 4.9%
International Prognostic Scoring System (IPSS) (participants) [Number]
Low risk (0)	30 44.8%	20 29%	20 29%	70 34.1%
Intermediate-1 (0.5 - 1.0)	22 32.8%	29 42%	23 33.3%	74 36.1%
Intermediate-2 (1.5 - 2.0)	2 3%	5 7.2%	3 4.3%	10 4.9%
High Risk (≥ 2.5)	0 0%	0 0%	1 1.4%	1 0.5%
Missing data	13 19.4%	15 21.7%	22 31.9%	50 24.4%
French-American-British (FAB) Classification (participants) [Number]
Refractory anemia (RA)	37 55.2%	38 55.1%	32 46.4%	107 52.2%
Refractory anemia with ringed sideroblasts (RARS)	8 11.9%	7 10.1%	9 13%	24 11.7%
Refractory anemia with excess blasts (RAEB)	4 6%	9 13%	9 13%	22 10.7%
Chronic myelomonocytic leukemia (CMML)	1 1.5%	2 2.9%	0 0%	3 1.5%
RAEB in transformation	1 1.5%	0 0%	0 0%	1 0.5%
Chronic myelogenous leukemia (CML)	0 0%	0 0%	1 1.4%	1 0.5%
Specimen not adequate from diagnosis	12 17.9%	11 15.9%	17 24.6%	40 19.5%
Other or missing	4 6%	2 2.9%	1 1.4%	7 3.4%

Outcome Measures

1. Primary Outcome

Title	Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for >= 26 Weeks (182 Days)
Description	The count of study participants who had no RBC transfusions for 26 consecutive weeks or more during the double-blind period.
Time Frame	Up to 52 weeks

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) population included all participants with centrally-confirmed Low- or Int-1-risk MDS with del 5q[31] and documented RBC transfusion dependence who had received ≥ 1 dose of study drug.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	51	47	41
Number [Participants]	3 4.5%	20 29%	23 33.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lenalidomide 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	To compare the response rates of Lenalidomide 5 mg QD vs. placebo, the Hochberg procedure was used to control the familywise error rate of 0.05.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by International Prognostic Scoring System (IPSS) score (IPSS combined score =0 versus >0) to compare lenalidomide treatment with placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lenalidomide 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	To compare the response rates of Lenalidomide 10 mg QD vs. placebo, the Hochberg procedure was used to control the familywise error rate of 0.05.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by International Prognostic Scoring System (IPSS) score (IPSS combined score =0 versus >0) to compare lenalidomide treatment with placebo.

2. Secondary Outcome

Title	Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for 56 Days
Description	Count of study participants who had no RBC transfusions during any 56 or more consecutive study days during the double-blind period.
Time Frame	Up to 52 weeks

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) population included all participants with centrally-confirmed Low- or Int-1-risk MDS with del 5q[31] and documented RBC transfusion dependence who had received ≥ 1 dose of study drug.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	51	47	41
Number [Participants]	4 6%	24 34.8%	25 36.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lenalidomide 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by International Prognostic Scoring System (IPSS) score (IPSS combined score =0 versus >0) to compare lenalidomide treatment with placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lenalidomide 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by International Prognostic Scoring System (IPSS) score (IPSS combined score =0 versus >0) to compare lenalidomide treatment with placebo.

3. Secondary Outcome

Title	Duration of Red Blood Cell (RBC) Transfusion Independence for Participants Who Became RBC Transfusion Independent for at Least 182 Days
Description	Mean number of weeks that participants who achieved RBC transfusion independence for at least 182 days were able to maintain RBC transfusion independence. Both double-blind and open-label periods are included.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) population included all participants who achieved RBC transfusion independence for at least 182 days.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	3	20	23
Mean (Standard Deviation) [Weeks]	61.4 (10.93)	107.7 (52.35)	108.6 (40.63)

4. Secondary Outcome

Title	Maximum Change From Baseline in Hemoglobin During the Double-blind Period for Participants Who Became Red Blood Cell (RBC) Transfusion Independent for at Least 182 Days
Description	For participants who became RBC transfusion independent for at least 182 days during the double-blind study period, the mean maximum change from baseline in hemoglobin is summarized.
Time Frame	Baseline, up to 52 weeks

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) population included all participants with centrally-confirmed Low- or Int-1-risk MDS with del 5q[31] and documented RBC transfusion dependence who had received ≥ 1 dose of study drug. MITT participants who were transfusion independent for >= 182 study days are included.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	3	20	23
Mean (Standard Deviation) [g/dL]	2.0 (0.61)	5.5 (1.79)	6.0 (1.97)

5. Secondary Outcome

Title	Participants' Response in Platelet Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period
Description	The International MDS Working Group (IWG) defines a major platelet response for participants with a pre-treatment platelet count of <100,000/mm^3 as an absolute increase of ≥30,000/mm^3 whereas a minor response is defined as a ≥50% increase in platelet count with a net increase greater than 10,000/mm^3 but less than 30,000/mm^3.
Time Frame	up to 52 weeks

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) population included all participants with centrally-confirmed Low- or Int-1-risk MDS with del 5q[31] and documented RBC transfusion dependence who had received ≥ 1 dose of study drug. Additionally, the participant must have had a baseline platelet count of <100,000/mm^3 to be included in the analysis.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	3	6	4
Major	0 0%	1 1.4%	1 1.4%
Minor	0 0%	0 0%	0 0%
None	3 4.5%	5 7.2%	3 4.3%

6. Secondary Outcome

Title	Participants' Response in Absolute Neutrophil Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period
Description	A major neutrophil response is defined by the International MDS Working Group (IWG) criteria as at least a 100% increase, or an absolute increase of ≥500/mm^3 for participants with absolute neutrophil counts (ANC) of less than 1,500/mm^3 before therapy, whichever is greater. A minor response for such participants is defined as an ANC increase of at least 100%, but absolute increase <500/mm^3.
Time Frame	up to week 52

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) population included all participants with centrally-confirmed Low- or Int-1-risk MDS with del 5q[31] and documented RBC transfusion dependence who had received ≥ 1 dose of study drug. Additionally, the participant must have had a baseline absolute neutrophil counts (ANC) < 1,000/mm^3.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	10	18	17
Major	1 1.5%	3 4.3%	2 2.9%
Minor	0 0%	0 0%	1 1.4%
None	9 13.4%	15 21.7%	14 20.3%

7. Secondary Outcome

Title	Participants' Response Based on Bone Marrow Samples by the International MDS Working Group (IWG 2000) During Double-blind Period
Description	The IWG criteria for bone marrow improvement: a complete remission is bone marrow sampling showing less than 5% myeloblasts with normal maturation of all cell lines, with no evidence for dysplasia. A partial remission is ≥ 50% decrease in blasts over pre-treatment. Bone marrow progression is a ≥ 50% increase in blasts that exceed the top range of the pretreatment percentile range: a) <5% blasts b) 5-10% blasts c) 10-20% blasts d) 20-30% blasts. For example, a participant with <5% blasts pretreatment with an on study blast increase of 50% which is now >5% showed bone marrow progression.
Time Frame	up to 52 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat population. Participants represented in the treatment groups to which they were randomized. Placebo response is limited to the double-blind phase. There were 10 responders in the placebo group who achieved their response under lenalidomide treatment after crossover to open-label.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	67	69	69
Complete remission	0 0%	7 10.1%	12 17.4%
Partial remission	0 0%	5 7.2%	1 1.4%
Stable Disease	37 55.2%	35 50.7%	33 47.8%
Progression	3 4.5%	4 5.8%	3 4.3%

8. Secondary Outcome

Title	Participants Showing Cytogenetic Response by the International MDS Working Group (IWG 2000) During Double-blind Period as Evaluated by Central Review
Description	The IWG criteria for evaluating cytogenetic response require a minimum of 20 baseline and post-baseline analyzable metaphases using conventional cytogenetic techniques. A major cytogenetic response is defined as no detectable cytogenetic abnormality if preexisting abnormality was present whereas a minor response requires ≥50% reduction in abnormal metaphases. Progression could be concluded based on as few as 3 metaphases if there were additional abnormalities. The best response is represented.
Time Frame	up to 52 weeks

Outcome Measure Data

Analysis Population Description

Modified intent to treat population, which is defined as participants with centrally-confirmed Low- or Int-1-risk MDS with del 5q[31] and documented RBC transfusion dependence who had received ≥ 1 dose of study drug. Participants had to have had more than 1 post-baseline assessment in order to be evaluable for cytogenetic response.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	41	37	40
Major response	0 0%	5 7.2%	10 14.5%
Minor response	0 0%	3 4.3%	7 10.1%
Cytogenetic progression	5 7.5%	10 14.5%	8 11.6%
Not evaluable/data not available	10 14.9%	10 14.5%	1 1.4%

9. Secondary Outcome

Title	Participants Who Progressed to Acute Myeloid Leukemia (AML) During the Study
Description	Number of participants who progressed to acute myeloid leukemia during the study, summarized at three different timepoints: first 16 weeks of the double-blind study, week 52 of the double-blind study, and up to 36 months which includes the double-blind and open-label periods of the study. The counts are cumulative by timeframe.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

Intent to treat population. Participants represented in the treatment groups to which they were randomized.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	67	69	69
Double-Blind (first 16 weeks)	2 3%	2 2.9%	0 0%
Double-Blind (52 weeks)	4 6%	7 10.1%	2 2.9%
Double-Blind + Open-Label	21 31.3%	16 23.2%	15 21.7%

10. Secondary Outcome

Title	Kaplan Meier Estimates of Overall Survival by Randomized Group
Description	Kaplan Meier estimate for median length of survival for study participants as they were randomized at the start of the study.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

Safety population: All randomized participants who received any Lenalidomide or placebo.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	67	69	69
Median (95% Confidence Interval) [Months]	42.4	NA	44.5

11. Secondary Outcome

Title	Participant Count of Deaths During Double-blind and Open-label by Randomized Group
Description	Count of participant deaths throughout the entire study and reported by the original treatment assignment.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	67	69	69
Number [Participants]	35 52.2%	32 46.4%	34 49.3%

12. Secondary Outcome

Title	Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Week 12
Description	The Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire (Yellen, 1997) was used to assess health-related quality of life (HRQoL). In addition to general HRQoL, the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning. The overall score range for the FACT-An is 0-188. Higher scores indicate better HRQoL.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Participants who had both Baseline and Week 12 FACT-An data.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	52	45	48
Mean (Standard Deviation) [units on a scale]	-2.5 (18.50)	5.9 (18.26)	5.8 (23.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lenalidomide 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lenalidomide 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments

13. Secondary Outcome

Title	Change From Baseline in the Trial Outcome Index-Anemia (TOI-An) Endpoints at Week 12
Description	The Trial Outcome Index-Anemia (TOI-An) composed of the physical and functional subscales of the FACT-G along with the Anemia subscale was used to assess health-related quality of life (HRQoL). The overall score range for the TOI-An is 0-136. Higher scores indicate better HRQoL.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Participants who had both Baseline and Week 12 TOI-An data.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	52	46	49
Mean (Standard Deviation) [units on a scale]	-1.1 (17.13)	5.6 (15.56)	4.9 (18.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lenalidomide 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.054
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lenalidomide 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.080
	Comments
	Method	ANOVA
	Comments

14. Secondary Outcome

Title	Change From Baseline in the Trial Outcome Index-Fatigue (TOI-F) Endpoints at Week 12
Description	The Trial Outcome Index-Fatigue(TOI-F) composed of the physical and functional subscales of the FACT-G along with the fatigue items from the Anemia subscale was used to assess health-related quality of life (HRQoL). The overall score range for the TOI-F is 0-108. Higher scores indicate better HRQoL.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Participants who had both Baseline and Week 12 TOI-F data.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	53	46	49
Mean (Standard Deviation) [units on a scale]	-0.8 (14.76)	4.8 (14.21)	3.9 (15.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lenalidomide 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.062
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lenalidomide 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.113
	Comments
	Method	ANOVA
	Comments

15. Secondary Outcome

Title	Summary of Participants Who Had Adverse Events (AE) During the Double-blind Period
Description	Counts of study participants who had adverse events (AEs) during the double-blind period by MedDRA System Organ Class (SOC) and preferred term. A participant with multiple occurrences of an adverse event within a category is counted only once in that category. Adverse events were evaluated by the investigator. The National Cancer Institute (NCI)'s Common Terminology Criteria for AEs (CTCAE) was used to grade AE severity. Severity grade 3= severe and undesirable AE. Severity grade 4= life-threatening or disabling AE.
Time Frame	up to week 52

Outcome Measure Data

Analysis Population Description

Safety population.

Arm/Group Title	Placebo	Lenalidomide 5 mg	Lenalidomide 10 mg
Arm/Group Description	Placebo matching to active study arms.	Lenalidomide 5 mg daily for 28 days	Lenalidomide 10 mg daily for 21 of 28 days
Measure Participants	67	69	69
At least one AE	64 95.5%	69 100%	69 100%
At least one AE related to study drug	34 50.7%	68 98.6%	66 95.7%
At least one NCI CTCAE grade 3-4 AE	29 43.3%	62 89.9%	65 94.2%
At least one related NCI CTCAE grade 3-4 AE	13 19.4%	61 88.4%	61 88.4%
At least one serious AE	14 20.9%	31 44.9%	32 46.4%
At least one serious AE related to study drug	1 1.5%	17 24.6%	13 18.8%
An AE leading to discontinuation of study drug	3 4.5%	12 17.4%	6 8.7%
An AE leading to dose reduction or interruption	5 7.5%	44 63.8%	51 73.9%
Deaths within 30 days of last dose of study drug	4 6%	2 2.9%	4 5.8%

Adverse Events

Time Frame	Placebo arm is limited to the double-blind period. Lenalidomide 5 mg and 10 mg treatment arms cover both double-blind and open-label periods. The Placebo Crossover to 5 mg Open-label Period arm is limited to the open-label period.
Arm/Group Title	Placebo		Lenalidomide 5 mg		Lenalidomide 10 mg		Placebo Crossover to 5 mg Open-label Period
Arm/Group Description	Placebo matching to active study arms.		Lenalidomide 5 mg daily for 28 days		Lenalidomide 10 mg daily for 21 of 28 days		Participants receiving placebo in the Double-Blind phase and Lenalidomide in the Open-Label phase.
All Cause Mortality
	Placebo		Lenalidomide 5 mg		Lenalidomide 10 mg		Placebo Crossover to 5 mg Open-label Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Lenalidomide 5 mg		Lenalidomide 10 mg		Placebo Crossover to 5 mg Open-label Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/67 (20.9%)		42/69 (60.9%)		42/69 (60.9%)		33/56 (58.9%)
Blood and lymphatic system disorders
Anaemia	0/67 (0%)		4/69 (5.8%)		1/69 (1.4%)		1/56 (1.8%)
Amaemia Haemolytic Autoimmune	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Autoimmune Thrombocytopenia	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Bone Marrow Failure	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Coagulopathy	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Febrile Neutropenia	0/67 (0%)		2/69 (2.9%)		2/69 (2.9%)		3/56 (5.4%)
Haemolysis	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Neutropenia	0/67 (0%)		5/69 (7.2%)		5/69 (7.2%)		5/56 (8.9%)
Pancytopenia	0/67 (0%)		1/69 (1.4%)		1/69 (1.4%)		0/56 (0%)
Splenomegaly	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Thrombocytopenia	0/67 (0%)		6/69 (8.7%)		3/69 (4.3%)		3/56 (5.4%)
Cardiac disorders
Atrial Flutter	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		0/56 (0%)
Acute Myocardial Infarction	0/67 (0%)		0/69 (0%)		2/69 (2.9%)		1/56 (1.8%)
Angina unstable	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Atrial Fibrillation	0/67 (0%)		2/69 (2.9%)		0/69 (0%)		2/56 (3.6%)
Cardiac Arrest	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Cardiac Failure	0/67 (0%)		2/69 (2.9%)		1/69 (1.4%)		3/56 (5.4%)
Myocardial Infarction	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Sinus Bradycardia	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Tachyarrhythmia	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Congenital, familial and genetic disorders
Cytogenetic Abnormality	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Ear and labyrinth disorders
Vertigo	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Eye disorders
Cataract	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		0/56 (0%)
Gastrointestinal disorders
Gastrointestinal Haemorrhage	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Abdominal Pain	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Abdominal Pain Upper	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Colitis	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		1/56 (1.8%)
Constipation	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Diarrhoea	0/67 (0%)		1/69 (1.4%)		3/69 (4.3%)		1/56 (1.8%)
Food Poisoning	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Haemorrhoidal Haemorrhage	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Intestinal Obstruction	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Intestinal Perforation	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Intussusception	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Tooth Disorder	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Vomiting	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
General disorders
Pyrexia	2/67 (3%)		5/69 (7.2%)		2/69 (2.9%)		3/56 (5.4%)
Asthenia	1/67 (1.5%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Chest Pain	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Fatigue	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
General Physical Health Deterioration	0/67 (0%)		0/69 (0%)		2/69 (2.9%)		0/56 (0%)
Generalised Oedema	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Mucosal Inflammation	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Multi-Organ Failure	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Non-cardiac Chest Pain	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Infections and infestations
Arthritis Bacterial	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		0/56 (0%)
Bronchopneumonia	1/67 (1.5%)		0/69 (0%)		1/69 (1.4%)		1/56 (1.8%)
Pneumonia	1/67 (1.5%)		5/69 (7.2%)		3/69 (4.3%)		1/56 (1.8%)
Anal Abscess	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Bacteraemia	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Bronchitis	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Cellulitis	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Erysipelas	0/67 (0%)		1/69 (1.4%)		1/69 (1.4%)		0/56 (0%)
Febrile Infection	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Gastroenteritis	0/67 (0%)		1/69 (1.4%)		1/69 (1.4%)		0/56 (0%)
Infection	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Lower Respiratory Tract Infection	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Neutropenic Sepsis	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Pneumonia Legionella	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Pyelonephritis	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Respiratory Tract Infection	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Septic Shock	0/67 (0%)		0/69 (0%)		2/69 (2.9%)		0/56 (0%)
Sinusitis	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Staphylococcal Sepsis	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Urinary Tract Infection	0/67 (0%)		3/69 (4.3%)		1/69 (1.4%)		0/56 (0%)
Urosepsis	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Injury, poisoning and procedural complications
Spinal Fracture	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		0/56 (0%)
Fall	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Femoral Neck Fracture	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Humerus Fracture	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Injury	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Meniscus Lesion	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Spinal Compression Fracture	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Subdural Haematoma	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Synovial Rupture	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Transfusion Reaction	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Investigations
International normalised Ratio Increased	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Urine Human Chorionic Gonadotropin Abnormal	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Metabolism and nutrition disorders
Malnutrition	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		0/56 (0%)
Diabetes Mellitus Inadequate Control	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Hyperglycaemia	0/67 (0%)		1/69 (1.4%)		1/69 (1.4%)		0/56 (0%)
Hypoglycaemia	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		1/56 (1.8%)
Back Pain	0/67 (0%)		0/69 (0%)		2/69 (2.9%)		0/56 (0%)
Chondropathy	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Fibromyalgia	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Gouty Arthritis	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Joint Range of Motion Decreased	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Muscle Spasms	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Musculoskeletal Pain	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Myalgia	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Osteoarthritis	0/67 (0%)		0/69 (0%)		0/69 (0%)		2/56 (3.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Myeloid Leukaemia	2/67 (3%)		8/69 (11.6%)		8/69 (11.6%)		5/56 (8.9%)
Acute Leukaemia	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Bladder Cancer	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Breast Cancer	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Colon Cancer	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Colorectal Cancer	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Histiocytosis Haematophagic	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Leukaemia	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		2/56 (3.6%)
Lung Cancer Metastatic	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Myelodysplastic syndrome	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Refractory Anaemia with an excess of blasts	0/67 (0%)		1/69 (1.4%)		2/69 (2.9%)		1/56 (1.8%)
Nervous system disorders
Sciatica	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		0/56 (0%)
Cerebral Haemorrhage	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Cerebrovascular Accident	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Coma	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Dizziness	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Headache	0/67 (0%)		1/69 (1.4%)		1/69 (1.4%)		0/56 (0%)
Psychiatric disorders
Cotard's Syndrome	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		0/56 (0%)
Suicide Attempt	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		0/56 (0%)
Anxiety Disorder	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Confusional State	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		1/56 (1.8%)
Delirium	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Depression	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Mood Altered	0/67 (0%)		1/69 (1.4%)		1/69 (1.4%)		0/56 (0%)
Renal and urinary disorders
Urethral caruncle	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		0/56 (0%)
Renal Colic	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Renal Failure	0/67 (0%)		1/69 (1.4%)		1/69 (1.4%)		0/56 (0%)
Stress Urinary Incontinence	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Urinary Incontinence	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Reproductive system and breast disorders
Acute Respiratory Distress Syndrome	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/67 (1.5%)		1/69 (1.4%)		1/69 (1.4%)		1/56 (1.8%)
Pleural Effusion	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		0/56 (0%)
Pulmonary Fibrosis	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		0/56 (0%)
Chronic Obstructive Pulmonary Disease	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Epistaxis	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		1/56 (1.8%)
Haemoptysis	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Hypoxia	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		1/56 (1.8%)
Interstitial Lung Disease	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Lung Disorder	0/67 (0%)		1/69 (1.4%)		1/69 (1.4%)		0/56 (0%)
Pneumonia Aspiration	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Pulmonary Embolism	0/67 (0%)		3/69 (4.3%)		2/69 (2.9%)		0/56 (0%)
Pulmonary Haemorrhage	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Respiratory Failure	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Skin and subcutaneous tissue disorders
Pyoderma Gangrenosum	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Skin Ulcer	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Urticaria	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Vascular disorders
Deep Vein Thrombosis	1/67 (1.5%)		1/69 (1.4%)		4/69 (5.8%)		3/56 (5.4%)
Arterial Occlusive Disease	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Hypotension	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Orthostatic Hypotension	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		0/56 (0%)
Phlebitis	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Thrombophlebitis Superficial	0/67 (0%)		0/69 (0%)		0/69 (0%)		1/56 (1.8%)
Venous Thrombosis	0/67 (0%)		1/69 (1.4%)		0/69 (0%)		0/56 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Lenalidomide 5 mg		Lenalidomide 10 mg		Placebo Crossover to 5 mg Open-label Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/67 (95.5%)		69/69 (100%)		69/69 (100%)		56/56 (100%)
Blood and lymphatic system disorders
Neutropenia	12/67 (17.9%)		55/69 (79.7%)		57/69 (82.6%)		45/56 (80.4%)
Anaemia	6/67 (9%)		10/69 (14.5%)		6/69 (8.7%)		13/56 (23.2%)
Leukopenia	3/67 (4.5%)		12/69 (17.4%)		8/69 (11.6%)		5/56 (8.9%)
Thrombocytopenia	2/67 (3%)		38/69 (55.1%)		36/69 (52.2%)		26/56 (46.4%)
Cardiac disorders
Atrial Fibrillation	2/67 (3%)		0/69 (0%)		1/69 (1.4%)		4/56 (7.1%)
Tachycardia	1/67 (1.5%)		0/69 (0%)		0/69 (0%)		4/56 (7.1%)
Ear and labyrinth disorders
Vertigo	1/67 (1.5%)		8/69 (11.6%)		3/69 (4.3%)		2/56 (3.6%)
Eye disorders
Cataract	0/67 (0%)		1/69 (1.4%)		5/69 (7.2%)		2/56 (3.6%)
Conjunctivitis	0/67 (0%)		0/69 (0%)		5/69 (7.2%)		2/56 (3.6%)
Gastrointestinal disorders
Diarrhoea	12/67 (17.9%)		32/69 (46.4%)		37/69 (53.6%)		26/56 (46.4%)
Nausea	6/67 (9%)		16/69 (23.2%)		21/69 (30.4%)		11/56 (19.6%)
Constipation	5/67 (7.5%)		18/69 (26.1%)		19/69 (27.5%)		17/56 (30.4%)
Abdominal Pain	4/67 (6%)		7/69 (10.1%)		14/69 (20.3%)		10/56 (17.9%)
Vomiting	4/67 (6%)		8/69 (11.6%)		9/69 (13%)		3/56 (5.4%)
Dry Mouth	2/67 (3%)		4/69 (5.8%)		5/69 (7.2%)		5/56 (8.9%)
Abdominal Pain Upper	1/67 (1.5%)		8/69 (11.6%)		8/69 (11.6%)		2/56 (3.6%)
Dyspepsia	1/67 (1.5%)		4/69 (5.8%)		5/69 (7.2%)		4/56 (7.1%)
Flatulence	0/67 (0%)		2/69 (2.9%)		1/69 (1.4%)		4/56 (7.1%)
General disorders
Asthenia	10/67 (14.9%)		10/69 (14.5%)		10/69 (14.5%)		9/56 (16.1%)
Fatigue	5/67 (7.5%)		17/69 (24.6%)		17/69 (24.6%)		11/56 (19.6%)
Oedema Peripheral	5/67 (7.5%)		15/69 (21.7%)		13/69 (18.8%)		10/56 (17.9%)
Chest Pain	4/67 (6%)		1/69 (1.4%)		0/69 (0%)		1/56 (1.8%)
Pyrexia	3/67 (4.5%)		11/69 (15.9%)		16/69 (23.2%)		9/56 (16.1%)
Non-Cardiac Chest Pain	1/67 (1.5%)		5/69 (7.2%)		1/69 (1.4%)		2/56 (3.6%)
Influenza Like Illness	0/67 (0%)		5/69 (7.2%)		5/69 (7.2%)		1/56 (1.8%)
Oedema	0/67 (0%)		3/69 (4.3%)		4/69 (5.8%)		1/56 (1.8%)
Pain	0/67 (0%)		1/69 (1.4%)		4/69 (5.8%)		0/56 (0%)
Infections and infestations
Nasopharyngitis	5/67 (7.5%)		15/69 (21.7%)		16/69 (23.2%)		8/56 (14.3%)
Upper Respiratory Tract Infection	4/67 (6%)		11/69 (15.9%)		12/69 (17.4%)		8/56 (14.3%)
Urinary Tract Infection	4/67 (6%)		6/69 (8.7%)		12/69 (17.4%)		8/56 (14.3%)
Bronchitis	3/67 (4.5%)		7/69 (10.1%)		14/69 (20.3%)		8/56 (14.3%)
Cystitis	1/67 (1.5%)		2/69 (2.9%)		4/69 (5.8%)		4/56 (7.1%)
Lower Respiratory Tract Infection	1/67 (1.5%)		2/69 (2.9%)		5/69 (7.2%)		2/56 (3.6%)
Respiratory Tract Infection	1/67 (1.5%)		9/69 (13%)		3/69 (4.3%)		6/56 (10.7%)
Sinusitis	1/67 (1.5%)		1/69 (1.4%)		6/69 (8.7%)		4/56 (7.1%)
Gastroenteritis	0/67 (0%)		7/69 (10.1%)		6/69 (8.7%)		2/56 (3.6%)
Gastroenteritis Viral	0/67 (0%)		4/69 (5.8%)		0/69 (0%)		0/56 (0%)
Influenza	0/67 (0%)		5/69 (7.2%)		5/69 (7.2%)		3/56 (5.4%)
Oral Herpes	0/67 (0%)		6/69 (8.7%)		0/69 (0%)		2/56 (3.6%)
Pharyngitis	0/67 (0%)		3/69 (4.3%)		4/69 (5.8%)		0/56 (0%)
Rhinitis	0/67 (0%)		4/69 (5.8%)		3/69 (4.3%)		4/56 (7.1%)
Pneumonia	2/67 (3%)		2/69 (2.9%)		2/69 (2.9%)		5/56 (8.9%)
Injury, poisoning and procedural complications
Contusion	1/67 (1.5%)		3/69 (4.3%)		4/69 (5.8%)		1/56 (1.8%)
Fall	0/67 (0%)		2/69 (2.9%)		4/69 (5.8%)		2/56 (3.6%)
Joint Sprain	0/67 (0%)		0/69 (0%)		1/69 (1.4%)		3/56 (5.4%)
Wound	0/67 (0%)		2/69 (2.9%)		4/69 (5.8%)		1/56 (1.8%)
Investigations
Alanine Aminotransferase Increased	2/67 (3%)		7/69 (10.1%)		5/69 (7.2%)		4/56 (7.1%)
Weight Decreased	1/67 (1.5%)		6/69 (8.7%)		5/69 (7.2%)		12/56 (21.4%)
Metabolism and nutrition disorders
Decreased Appetite	2/67 (3%)		8/69 (11.6%)		8/69 (11.6%)		8/56 (14.3%)
Iron Overload	2/67 (3%)		4/69 (5.8%)		5/69 (7.2%)		2/56 (3.6%)
Hypoalbuminaemia	0/67 (0%)		4/69 (5.8%)		1/69 (1.4%)		0/56 (0%)
Hypokalaemia	0/67 (0%)		7/69 (10.1%)		3/69 (4.3%)		1/56 (1.8%)
Hypomagnesaemia	0/67 (0%)		3/69 (4.3%)		3/69 (4.3%)		4/56 (7.1%)
Musculoskeletal and connective tissue disorders
Muscle Spasms	6/67 (9%)		12/69 (17.4%)		15/69 (21.7%)		13/56 (23.2%)
Back Pain	4/67 (6%)		12/69 (17.4%)		8/69 (11.6%)		10/56 (17.9%)
Myalgia	2/67 (3%)		4/69 (5.8%)		6/69 (8.7%)		3/56 (5.4%)
Arthralgia	1/67 (1.5%)		6/69 (8.7%)		5/69 (7.2%)		5/56 (8.9%)
Pain in Extremity	1/67 (1.5%)		5/69 (7.2%)		10/69 (14.5%)		9/56 (16.1%)
Musculoskeletal Chest Pain	0/67 (0%)		1/69 (1.4%)		5/69 (7.2%)		1/56 (1.8%)
Neck Pain	0/67 (0%)		3/69 (4.3%)		3/69 (4.3%)		3/56 (5.4%)
Musculoskeletal Pain	3/67 (4.5%)		5/69 (7.2%)		11/69 (15.9%)		9/56 (16.1%)
Nervous system disorders
Headache	6/67 (9%)		12/69 (17.4%)		14/69 (20.3%)		5/56 (8.9%)
Dizziness	3/67 (4.5%)		8/69 (11.6%)		10/69 (14.5%)		8/56 (14.3%)
Paraesthesia	3/67 (4.5%)		8/69 (11.6%)		3/69 (4.3%)		6/56 (10.7%)
Sciatica	2/67 (3%)		2/69 (2.9%)		4/69 (5.8%)		0/56 (0%)
Balance Disorder	0/67 (0%)		0/69 (0%)		4/69 (5.8%)		0/56 (0%)
Peripheral Sensory Neuropathy	0/67 (0%)		4/69 (5.8%)		1/69 (1.4%)		2/56 (3.6%)
Psychiatric disorders
Insomnia	5/67 (7.5%)		6/69 (8.7%)		9/69 (13%)		6/56 (10.7%)
Depression	3/67 (4.5%)		4/69 (5.8%)		2/69 (2.9%)		2/56 (3.6%)
Anxiety	2/67 (3%)		3/69 (4.3%)		5/69 (7.2%)		4/56 (7.1%)
Renal and urinary disorders
Dysuria	2/67 (3%)		1/69 (1.4%)		3/69 (4.3%)		3/56 (5.4%)
Respiratory, thoracic and mediastinal disorders
Cough	4/67 (6%)		12/69 (17.4%)		10/69 (14.5%)		9/56 (16.1%)
Dyspnoea	4/67 (6%)		12/69 (17.4%)		9/69 (13%)		5/56 (8.9%)
Epistaxis	2/67 (3%)		3/69 (4.3%)		4/69 (5.8%)		3/56 (5.4%)
Dyspnoea Exertional	1/67 (1.5%)		4/69 (5.8%)		3/69 (4.3%)		1/56 (1.8%)
Oropharyngeal Pain	1/67 (1.5%)		7/69 (10.1%)		6/69 (8.7%)		3/56 (5.4%)
Skin and subcutaneous tissue disorders
Pruritus	3/67 (4.5%)		16/69 (23.2%)		20/69 (29%)		7/56 (12.5%)
Dry Skin	1/67 (1.5%)		10/69 (14.5%)		10/69 (14.5%)		6/56 (10.7%)
Rash	1/67 (1.5%)		18/69 (26.1%)		12/69 (17.4%)		8/56 (14.3%)
Alopecia	0/67 (0%)		0/69 (0%)		4/69 (5.8%)		1/56 (1.8%)
Hyperhidrosis	0/67 (0%)		2/69 (2.9%)		4/69 (5.8%)		1/56 (1.8%)
Petechiae	0/67 (0%)		3/69 (4.3%)		4/69 (5.8%)		3/56 (5.4%)
Vascular disorders
Haematoma	2/67 (3%)		6/69 (8.7%)		6/69 (8.7%)		5/56 (8.9%)
Phlebitis	1/67 (1.5%)		1/69 (1.4%)		4/69 (5.8%)		2/56 (3.6%)
Hypertension	0/67 (0%)		7/69 (10.1%)		9/69 (13%)		5/56 (8.9%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Multicenter publication must include input from investigators and Celgene, agreement to be established before publication. It has priority over subset (single center) publication, for duration of 1 year after study completion. Individual investigators have publication right after multicenter publication is complete (or 1 year after study completion), whichever is first. In this case, Celgene has the right to comment and right to ask delay of publication for 90 days.