A Study of CC-5013 Plus Dexamethasone Versus Dexamethasone Alone in Previously Treated Subjects With Multiple Myeloma

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00424047
• Collaborator: (none)
• Enrollment: 351
• Locations: 69
• Arms: 2
• Actual Duration (Months): 130.4
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

To compare the efficacy of oral CC-5013 in combination with oral pulse high-dose dexamethasone to that of placebo and oral high-dose pulse dexamethasone as treatment for subjects with relapsed or refractory multiple myeloma."

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: CC-5013 plus dexamethasone; Drug: Dexamethasone plus Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 351 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Official Title is A Multi-center, Randomized, Parallel-group, Double-blind, Placebo Controlled Study of CC-5013 Plus Dexamethasone Versus Dexamethasone Alone in Previously Treated Subjects With Multiple Myeloma.
• Actual Study Start Date: Jan 1, 2003
• Actual Primary Completion Date: Nov 1, 2005
• Actual Study Completion Date: Nov 12, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CC-5013 plus dexamethasone Arm A: Oral CC-5013 is initiated on Day 1 of Cycle 1 at a dose of 25 mg daily for 21 days every 28 days. Therefore, the subject will take a placebo identical in appearance to the CC-5013 capsule for week 4 of every 28 days. Oral pulse dexamethasone is administered at a dose of 40mg daily on Days 1-4, 9-12, and 17-20 of each 28 day cycle for Cycles 1 through 4. Beginning with Cycle 5, the oral dexamethasone dosing schedule will be reduced to 40mg daily for Days 1-4 every 28 days. In addition, oral CC-5013 placebo capsules will be administered for 28 days of every cycle.	Drug: CC-5013 plus dexamethasone; 25 mg daily for 21 days every 28 days.; Other Names: Revlimid lenalidomide
Experimental: Dexamethasone plus placebo Arm B: Oral pulse dexamethasone is administered at a dose of 40mg daily on Days 1-4, 9-12, and 17-20 of each 28 day cycle for Cycles 1 through 4. Beginning with Cycle 5, the oral dexamethasone dosing schedule will be reduced to 40mg daily for Days 1-4 every 28 days. In addition, oral placebo capsules will be administered for 28 days of every cycle.	Drug: Dexamethasone plus Placebo; Oral pulse dexamethasone is administered at a dose of 40mg daily on Days 1-4, 9-12, and 17-20 of each 28 day cycle for Cycles 1 through 4. Beginning with Cycle 5, the oral dexamethasone dosing schedule will be reduced to 40mg daily for Days 1-4 every 28 days. In addition, oral placebo capsules will be administered for 28 days of every cycle.; Other Names: Dexamethasone Placebo

Outcome Measures

Primary Outcome Measures

1. Kaplan-Meier Estimate of Time to Tumor Progression (TTP) [From randomization up to cut-off date of 03 August 2005; up to 24 months]

   Time to progression was calculated as the time from randomization to the first occurrence of disease progression, as determined by a detailed review of all the myeloma response assessment data using the Bladé criteria (Bladé, 1998). Disease progression was also based on bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia.

2. Kaplan-Meier Estimate of Time to Tumor Progression (TTP) (Later Cut-off Date of 02 Mar 2008) [From randomization up to cut-off date of 02 March 2008; up to 51 months]

   Time to progression was calculated as the time from randomization to the first occurrence of disease progression, as determined by a detailed review of all the myeloma response assessment data using the Bladé criteria (Bladé, 1998). Disease progression was also based on bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia.

Secondary Outcome Measures

1. Kaplan-Meier Estimate of Overall Survival (OS) [Randomization to data cut off of 03 August 2005; up to 24 months]

   OS was calculated as the time from randomization to death from any cause. OS was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented.

2. Kaplan-Meier Estimate of Overall Survival (OS) (Later Cut-off Date of 02 March 2008) [Randomization to data cut off of 02 March 2008; up to 51 months]

   OS was calculated as the time from randomization to death from any cause. OS was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented.

3. Summary of Myeloma Response Rates Based on Best Response Assessment [Randomization to 03 August 2005; up to 24 months]

   Complete Response (CR): Disappearance of monoclonal paraprotein and maintained for ≥ 6 weeks . Remission Response (RR):75-99% reduction in the level of the serum monoclonal paraprotein compared to baseline; 90-99% reduction in 24-hr urinary light chain excretion. Partial Response (PR): 50-74% reduction in the level of monoclonal paraprotein compared to baseline; 50-89% reduction in 24-hr urinary light chain excretion. Stable Disease (SD): Criteria for PR or PD have not been met. Plateau Phase: If PR, stable monoclonal paraprotein values (within 25% above or below nadir)/stable soft tissue plasmacytomas maintained for at least 3 months. Progressive Disease (PD): Reappearance of serum or urinary monoclonal paraprotein on immunofixation or electrophoresis on two consecutive occasions at least one week apart. Increase of percentage of plasma cells in bone marrow aspirate or biopsy to ≥ 5%. Development of at least one new lytic bone lesion or soft tissue plasmacytoma.

4. Myeloma Response Rates Based on the Reviewers Best Response Assessment (Later Cut-off Date of 02 March 2008) [Randomization to data cut-off of 02 Mar 2008; up to 51 months]

   Complete Response (CR): Disappearance of monoclonal paraprotein and maintained for ≥ 6 weeks . Remission Response (RR):75-99% reduction in the level of the serum monoclonal paraprotein compared to baseline; 90-99% reduction in 24-hr urinary light chain excretion. Partial Response (PR): 50-74% reduction in the level of monoclonal paraprotein compared to baseline; 50-89% reduction in 24-hr urinary light chain excretion. Stable Disease (SD): Criteria for PR or PD have not been met. Plateau Phase: If PR, stable monoclonal paraprotein values (within 25% above or below nadir)/stable soft tissue plasmacytomas maintained for at least 3 months. Progressive Disease (PD): Reappearance of serum or urinary monoclonal paraprotein on immunofixation or electrophoresis on two consecutive occasions at least one week apart. Increase of percentage of plasma cells in bone marrow aspirate or biopsy to ≥ 5%. Development of at least one new lytic bone lesion or soft tissue plasmacytoma.

5. Number of Participants With Adverse Events (AE) [From first dose of study drug through to 30 days after the last dose, until the data cut-off date of 25 June 2013; up to 90 months]

   An AE is any sign, symptom, illness, or diagnosis that appears or worsens during the course of the study. Treatment-emergent AEs (TEAEs) are any AE occurring or worsening on or after the first treatment of the study drug and within 30 days after the last cycle end date of study drug. A serious AE = any AE which results in death; is life-threatening; requires or prolongs existing inpatient hospitalization; results in persistent or significant disability is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE, Version 2.0): Grade 1 = Mild (no limitation in activity or intervention required); Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention required); Grade 3 = Severe (marked limitation in activity; medical intervention required, hospitalization possible); Grade 4 = Life-threatening; Grade 5 = Death.

6. Time to First Symptomatic Skeletal-related Event (SRE) (Clinical Need for Radiation or Surgery to Bone) [Up to unblinding data cut off of 03 August 2005; up to 24 months]

   Time from randomization to the date of the first occurrence of a symptomatic SRE (clinical need for radiotherapy or surgery to bone).

7. Time to First Worsening on the Eastern Cooperative Oncology Group (ECOG) Performance Scale [Randomization to cut off date of 03 August 2005; up to 24 months]

   The time to first worsening of the ECOG performance status was calculated as the time from randomization to the date of the first worsening compared with the last ECOG evaluation obtained prior to randomization. Data were censored at the last date that the participant was known to be unchanged or improved from before randomization for the participants who had not had worsened at the time of the analysis and for the patients who were lost to follow-up before worsening in the ECOG performance status was documented.

8. Time to First Worsening on the Eastern Cooperative Oncology Group (ECOG) Performance Scale (Later Cut-off Date of 02 March 2008) [Randomization to cut off date of 02 March 2008; up to 51 months]

   The time to first worsening of the ECOG performance status was calculated as the time from randomization to the date of the first worsening compared with the last ECOG evaluation obtained prior to randomization. Data were censored at the last date that the participant was known to be unchanged or improved from before randomization for the participants who had not had worsened at the time of the analysis and for the patients who were lost to follow-up before worsening in the ECOG performance status was documented.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Prior or current diagnosis Durie-Salmon stage II or III multiple myeloma.

• Measurable levels of myeloma paraprotein in serum or urine (24-hour collection sample).

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0,1, or 2

• Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days of starting study drug

Exclusion Criteria:

• Prior development of disease progression during high-dose dexamethasone containing therapy

• Pregnant or lactating females

• The development of a desquamating rash while taking thalidomide

• Use of any standard/experimental anti-myeloma therapy within 28 days of randomization or use of any experimental non-drug therapy within 56 days of initiation of drug treatment

• Laboratory abnormalities: Absolute neutrophil count less than 1,000 cells/mm3

• Laboratory abnormalities: Platelet count < 75,000/mm3

• Laboratory abnormalities: Serum creatinine > 2.5 mg/dL

• Laboratory abnormalities: Serum Serum glutamic oxaloacetic transaminase (SGOT)/Aspartate aminotransferase (AST) or Serum glutamic pyruvic transaminase (SGPT)/Alanine aminotransferase (ALT) > 3.0 x upper limit of normal

• Laboratory abnormalities: Serum total bilirubin > 2.0 mg/dL

• Prior history of malignancies other than multiple myeloma unless the subject has been free of the disease for ≥ 3 years.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia	2050
2	Peter MacCallum Cancer Centre Divsion of Haematology/Medical Oncology	East Melbourne	Victoria	Australia	3006
3	The Alfred Hospital	Prahran	Victoria	Australia	3121
4	Border Medical Oncology	Wodonga	Victoria	Australia	3690
5	Box Hill Hospital	Box Hill		Australia	VIC 3128
6	Frankston Hospital Oncology Research	Frankston		Australia	VIC 3199
7	Royal Brisbane Hospital	Herston		Australia	QLD4029
8	The Royal Melbourne Hospital	Parkville		Australia	3050
9	Mater Public Hospital	South Brisbane		Australia	QLD 4101
10	University Hospital of Salzburg St Johanns Spital	Salzburg		Austria	A -5020
11	Wilhelminenspital	Vienna		Austria	1160
12	CHU Saint-Luc	Brussel		Belgium	1200
13	UZ Gasthuisberg	Leuven		Belgium	3000
14	Centre Hospitalier Lyon Sud	Chemin Grand Revoyet		France	69495 Pierre Benite cedex
15	Hopital Claude Huriez	Lille		France	59037
16	Centre Hospitalier Hotel-Dieu	Nantes		France
17	Hopital Saint-Loius	Paris		France	75010
18	Chu de Bordeaux Groupe Hospitalier Sud	Pessac		France	33640
19	CHU Purpan	Toulouse cedex 9		France	TSA 40031-31059
20	CHU Nancy - Hopital Brabois	Vandoeuvre		France	54511
21	Universitaetsklinikum Charite	Berlin		Germany	13125
22	Universitatsklinik ChariteMedizinische Fakultaet der HumboldtUniversitaet zu Berlin	Berlin		Germany	13353
23	Universitaetsklinikum Dusseldorf Klinik fuer Haematologie	Dusseldorf		Germany	40225
24	Universitaetsklinkum Erlangen	Erlangen		Germany	91054
25	Klininkum der Johann-Wolfgang-Goethe-Universtat	Frankfurt am Main		Germany	60590
26	Universitaetsklinikum Heidelberg Medizinische Klinik und Poliklinik V	Heidelberg		Germany	69120
27	Universitatsklinik Muenster Medizinische Klinik A	Muenster		Germany	48129
28	Klinikum der Univeristact Muenchen	Munchen		Germany	80336
29	Universitaetsklinikum Tuebingen	Tubingen		Germany	72076
30	"Alexandras" General Hospital of Athens	Athens		Greece	11538
31	University Hospital GalwayHaematology Department	Galway	Co. Galway	Ireland
32	Belfast City HospitalHaematology Department	Belfast		Ireland	BT9 7AB
33	Hope Directorate Haematology Oncology Service St. James Hospital	Dublin 8		Ireland
34	MidWestern Regional Hospital	Limerick		Ireland
35	Rambam Medical Center	Haifa		Israel	31096
36	Hadassah University Hospital	Jerusalem		Israel
37	Tel Aviv Sourasky Medical Center Department of Hematology	Tel Aviv		Israel	64239
38	The Chaim Sheba Medical Center	Tel Hashomer		Israel	52621
39	Policlinico Sant'Orsola-Malpighi	Bologna		Italy	40138
40	Azienda Ospedaliera San Martino	Genova		Italy	16132
41	Ospedale Niguarda Ca Granda	Milano		Italy	20162
42	Policlinico San Matteo	Pavia		Italy	27100
43	Univerita La Sapien	Roma		Italy	00161
44	Azienda Sanitaria Ospedaliera Molinette S. Giovanni Battista	Torio		Italy	10126
45	Policlinico Universitario a Gesttione diretta di Udine	Udine		Italy	33100
46	Institute of Internal Diseases University of Medicine	Gdansk		Poland	80-211
47	University School of Medicine	Lublin		Poland	20-290
48	Institute of Haematology and Blood Transfusion	Warsaw		Poland	00-957
49	Hospital Clinic	Barcelona		Spain	08036
50	Hospital Universitario de la Princessa	Madrid		Spain	28006
51	Hospital Doce de Octubre	Madrid		Spain	28041
52	Clinica Universitaria de Navarra	Pamplona		Spain	31080
53	Hospital Universitario de Salamanca	Salamanca		Spain	37007
54	Hospital Universtario Marques de Valdecilla	Santander		Spain	39008
55	Sahlgrenska University Hospital Department of Hematology and Coagulation	Goteborg		Sweden	S-413 45
56	Centre Hospitalier Universitaire Vaudois (CHUV)	Lausanne		Switzerland	1011
57	Kantonsspital St. Gallen	St. Gallen		Switzerland
58	Universitätsspital Zürich	Zürich		Switzerland	8091
59	Cherkassy Regional Oncology Center	Cherkassy		Ukraine	18009
60	Dnepropetrovsk City Clinical Hospital #4	Dnepropetrovsk		Ukraine	49044
61	Kiev Bone Marrow Transplantation Center Bone Marrow Department	Kiev		Ukraine	03115
62	Institute of Hematology and Transfusiology of the UAMS Department of blood diseases	Kiev		Ukraine	04060
63	Institute of Blood Pathology and Transfusion Medicine of the UAMS	Lviv		Ukraine	79044
64	Institute of Blood Pathology and Transfusion Medicine of the UAMS Hematology Department	Lvov		Ukraine	79044
65	Odess Regional Clinical Hospital	Odessa		Ukraine	65025
66	Zhitomir Regional Clinical Hospital	Zhitomir		Ukraine	10003
67	University College Hospital Trust	London	Bloomsbury	United Kingdom	WC1E 6AU
68	Bristol Haematology and Oncology Centre	Bristol		United Kingdom	BS2 8ED
69	Haematology Dept, 4th Floor Thomas Guy House	London		United Kingdom	SE1 9RT

Sponsors and Collaborators

• Celgene

Investigators

• Study Director: Robert Knight, MD, Celgene Corporation

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Link to CSR synopsis

Publications

None provided.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT00424047
• Other Study ID Numbers: CC-5013-MM-010
• First Posted: Jan 18, 2007
• Last Update Posted: Oct 19, 2017
• Last Verified: Sep 1, 2017

• Keywords provided by Celgene: Multiple Myeloma; Celgene; Revlimid; CC-5013
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Dexamethasone acetate; Lenalidomide; BB 1101

Study Results

Participant Flow

Recruitment Details	The study was conducted at 55 sites in Australia, Europe, and Israel. Eligible participants were randomized in a 1:1 ratio to: lenalidomide plus oral pulse high-dose dexamethasone or Placebo plus oral pulse high-dose dexamethasone.
Pre-assignment Detail	A pre-specified interim analysis revealed a highly significant benefit favoring the lenalidomide/dexamethasone regimen, crossing the pre-specified O'Brien-Fleming superiority boundary. A decision was made to unblind the study allowing those receiving Placebo/dexamethasone to receive the lenalidomide/dexamethasone regimen.

Arm/Group Title	Lenalidomide Plus Dexamethasone (Len/Dex)	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days. Participants with documented progressive disease were permitted to crossover to receive lenalidomide at the same doses mentioned. After the study was unblinded in August 2005 participants were given the option to add lenalidomide to their dexamethasone treatment regimen immediately or to add lenalidomide to their dexamethasone therapy at the time of disease progression.
Period Title: Blinded Treatment (Up to 03 Aug 2005)
STARTED	176	175
Safety Population	176	175
Evaluable Population	175	171
COMPLETED	54	19
NOT COMPLETED	122	156
Period Title: Blinded Treatment (Up to 03 Aug 2005)
STARTED	176	175
COMPLETED	21	8
NOT COMPLETED	155	167
Period Title: Blinded Treatment (Up to 03 Aug 2005)
STARTED	21	8
COMPLETED	0	0
NOT COMPLETED	21	8

Baseline Characteristics

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone	Total
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days.	Total of all reporting groups
Overall Participants	176	175	351
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.2 (10.12)	62.9 (8.80)	62.6 (9.47)
Sex: Female, Male (Count of Participants)
Female	72 40.9%	72 41.1%	144 41%
Male	104 59.1%	103 58.9%	207 59%
Eastern Cooperative Oncology Group Performance Status (participants) [Number]
0 = (Fully Active)	78 44.3%	65 37.1%	143 40.7%
1 = (Restrictive but Ambulatory)	72 40.9%	79 45.1%	151 43%
2 = Ambulatory unable to Work)	23 13.1%	27 15.4%	50 14.2%
3 = (Limited Self-Care)	0 0%	1 0.6%	1 0.3%
4 = (Completely Disabled)	0 0%	0 0%	0 0%
Missing	3 1.7%	3 1.7%	6 1.7%
Number of Prior Anti-Myeloma Therapies (participants) [Number]
1 Prior anti-myeloma therapy	56 31.8%	57 32.6%	113 32.2%
2 or more prior anti-myeloma therapies	120 68.2%	118 67.4%	238 67.8%
Time from First Pathological Diagnosis (years) [Median (Full Range) ]
Median (Full Range) [years]	3.4	4.0	3.7
Baseline multiple myeloma stage (participants) [Number]
Stage I	11 6.3%	8 4.6%	19 5.4%
Stage II	50 28.4%	57 32.6%	107 30.5%
Stage III	115 65.3%	110 62.9%	225 64.1%

Outcome Measures

1. Primary Outcome

Title	Kaplan-Meier Estimate of Time to Tumor Progression (TTP)
Description	Time to progression was calculated as the time from randomization to the first occurrence of disease progression, as determined by a detailed review of all the myeloma response assessment data using the Bladé criteria (Bladé, 1998). Disease progression was also based on bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia.
Time Frame	From randomization up to cut-off date of 03 August 2005; up to 24 months

Outcome Measure Data

Analysis Population Description

Intent to treat included all participants who were randomized.

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days.
Measure Participants	176	175
Median (95% Confidence Interval) [weeks]	52.1	20.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus Dexamethasone, Placebo Plus Dexamethasone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Log Rank
	Comments	The p-value is based on an unstratified log rank test of survival curve differences between the treatment groups
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.324
	Confidence Interval	(2-Sided) 95%; 0.240 to 0.438
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a proportional hazards model comparing the hazard functions associated with the treatment groups (Lenalidomide/Dex:Placebo/Dexamethasone)

2. Secondary Outcome

Title	Kaplan-Meier Estimate of Overall Survival (OS)
Description	OS was calculated as the time from randomization to death from any cause. OS was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented.
Time Frame	Randomization to data cut off of 03 August 2005; up to 24 months

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all participants who were randomized.

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days.
Measure Participants	176	175
Median (95% Confidence Interval) [weeks]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus Dexamethasone, Placebo Plus Dexamethasone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.105
	Comments
	Method	Log Rank
	Comments	The p-value is based on an unstratified log rank test of survival curve differences between the treatment groups.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.730
	Confidence Interval	(2-Sided) 95%; 0.498 to 1.070
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a proportional hazards model comparing the hazard functions associated with the treatment groups (Lenalidomide/Dexamethasone:Placebo/Dexamethasone)

3. Secondary Outcome

Title	Kaplan-Meier Estimate of Overall Survival (OS) (Later Cut-off Date of 02 March 2008)
Description	OS was calculated as the time from randomization to death from any cause. OS was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented.
Time Frame	Randomization to data cut off of 02 March 2008; up to 51 months

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all participants who were randomized.

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40 mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40 mg PO QD for Days 1-4 every 28 days. Participants with documented progressive disease were permitted to crossover to receive lenalidomide at the same doses mentioned. After the study was unblinded in August 2005 participants were given the option to add lenalidomide to their dexamethasone treatment regimen immediately or to add lenalidomide to their dexamethasone therapy at the time of disease progression.
Measure Participants	176	175
Median (95% Confidence Interval) [weeks]	161.9	133.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus Dexamethasone, Placebo Plus Dexamethasone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.302
	Comments
	Method	Log Rank
	Comments	The p-value is based on an unstratified log rank test of survival curve differences between the treatment groups
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.863
	Confidence Interval	(2-Sided) 95%; 0.651 to 1.143
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a proportional hazards model comparing the hazard functions associated with the treatment groups (CC-5013/Dex:Placebo/Dex)

4. Secondary Outcome

Title	Summary of Myeloma Response Rates Based on Best Response Assessment
Description	Complete Response (CR): Disappearance of monoclonal paraprotein and maintained for ≥ 6 weeks . Remission Response (RR):75-99% reduction in the level of the serum monoclonal paraprotein compared to baseline; 90-99% reduction in 24-hr urinary light chain excretion. Partial Response (PR): 50-74% reduction in the level of monoclonal paraprotein compared to baseline; 50-89% reduction in 24-hr urinary light chain excretion. Stable Disease (SD): Criteria for PR or PD have not been met. Plateau Phase: If PR, stable monoclonal paraprotein values (within 25% above or below nadir)/stable soft tissue plasmacytomas maintained for at least 3 months. Progressive Disease (PD): Reappearance of serum or urinary monoclonal paraprotein on immunofixation or electrophoresis on two consecutive occasions at least one week apart. Increase of percentage of plasma cells in bone marrow aspirate or biopsy to ≥ 5%. Development of at least one new lytic bone lesion or soft tissue plasmacytoma.
Time Frame	Randomization to 03 August 2005; up to 24 months

Outcome Measure Data

Analysis Population Description

Intent to Treat Population includes all participants who were randomized

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days.
Measure Participants	176	175
Complete Response (CR)	15.3 8.7%	4.0 2.3%
Partial Response (PR)	43.8 24.9%	19.4 11.1%
Stable Disease (SD)	29.0 16.5%	56.6 32.3%
Progressive Disease (PD)	2.8 1.6%	14.3 8.2%
Not Evaluable (NE) those without response data	9.1 5.2%	5.7 3.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus Dexamethasone, Placebo Plus Dexamethasone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Probability from Wilcoxon rank sum test

5. Secondary Outcome

Title	Myeloma Response Rates Based on the Reviewers Best Response Assessment (Later Cut-off Date of 02 March 2008)
Description	Complete Response (CR): Disappearance of monoclonal paraprotein and maintained for ≥ 6 weeks . Remission Response (RR):75-99% reduction in the level of the serum monoclonal paraprotein compared to baseline; 90-99% reduction in 24-hr urinary light chain excretion. Partial Response (PR): 50-74% reduction in the level of monoclonal paraprotein compared to baseline; 50-89% reduction in 24-hr urinary light chain excretion. Stable Disease (SD): Criteria for PR or PD have not been met. Plateau Phase: If PR, stable monoclonal paraprotein values (within 25% above or below nadir)/stable soft tissue plasmacytomas maintained for at least 3 months. Progressive Disease (PD): Reappearance of serum or urinary monoclonal paraprotein on immunofixation or electrophoresis on two consecutive occasions at least one week apart. Increase of percentage of plasma cells in bone marrow aspirate or biopsy to ≥ 5%. Development of at least one new lytic bone lesion or soft tissue plasmacytoma.
Time Frame	Randomization to data cut-off of 02 Mar 2008; up to 51 months

Outcome Measure Data

Analysis Population Description

Intent to Treat Population includes all participants who were randomized

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40 mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40 mg PO QD for Days 1-4 every 28 days. Participants with documented progressive disease were permitted to crossover to receive lenalidomide at the same doses mentioned. After the study was unblinded in August 2005 participants were given the option to add lenalidomide to their dexamethasone treatment regimen immediately or to add lenalidomide to their dexamethasone therapy at the time of disease progression.
Measure Participants	176	175
Complete Response (CR)	17.0 9.7%	4.0 2.3%
Partial Response (PR)	42.6 24.2%	19.4 11.1%
Stable Disease (SD)	28.4 16.1%	56.6 32.3%
Progressive Disease (PD)	3.4 1.9%	14.3 8.2%
Not Evaluable (NE) those without response data	8.5 4.8%	5.7 3.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus Dexamethasone, Placebo Plus Dexamethasone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Probability from Wilcoxon rank sum test

6. Secondary Outcome

Title	Number of Participants With Adverse Events (AE)
Description	An AE is any sign, symptom, illness, or diagnosis that appears or worsens during the course of the study. Treatment-emergent AEs (TEAEs) are any AE occurring or worsening on or after the first treatment of the study drug and within 30 days after the last cycle end date of study drug. A serious AE = any AE which results in death; is life-threatening; requires or prolongs existing inpatient hospitalization; results in persistent or significant disability is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE, Version 2.0): Grade 1 = Mild (no limitation in activity or intervention required); Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention required); Grade 3 = Severe (marked limitation in activity; medical intervention required, hospitalization possible); Grade 4 = Life-threatening; Grade 5 = Death.
Time Frame	From first dose of study drug through to 30 days after the last dose, until the data cut-off date of 25 June 2013; up to 90 months

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who received at least one dose of study drug regimen

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40 mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40 mg PO QD for Days 1-4 every 28 days. Participants with documented progressive disease were permitted to crossover to receive lenalidomide at the same doses mentioned. After the study was unblinded in August 2005 participants were given the option to add lenalidomide to their dexamethasone treatment regimen immediately or to add lenalidomide to their dexamethasone therapy at the time of disease progression.
Measure Participants	176	175
≥ 1 Adverse Event	176 100%	175 100%
≥ 1 Serious Adverse Event	105 59.7%	79 45.1%
≥ 1 AE leading to study drug discontinuation	46 26.1%	31 17.7%
≥ 1 AE leading to dose reduction or interruption	137 77.8%	100 57.1%
≥ 1 Drug-Related Adverse Event	160 90.9%	151 86.3%
≥ 1 Drug-Related Serious Adverse Event	54 30.7%	30 17.1%
≥Death within ≤ 30 days of last dose of study drug	17 9.7%	20 11.4%
≥ 1 Grade 1 or Higher Adverse Event	176 100%	175 100%
≥ 1 Grade 2 or Higher Adverse Event	168 95.5%	167 95.4%
≥ 1 Grade 3 or Higher Adverse Event	146 83%	119 68%
≥ 1 Grade 4 or Higher Adverse Event	52 29.5%	37 21.1%

7. Secondary Outcome

Title	Time to First Symptomatic Skeletal-related Event (SRE) (Clinical Need for Radiation or Surgery to Bone)
Description	Time from randomization to the date of the first occurrence of a symptomatic SRE (clinical need for radiotherapy or surgery to bone).
Time Frame	Up to unblinding data cut off of 03 August 2005; up to 24 months

Outcome Measure Data

Analysis Population Description

Analysis not performed due to an insufficient number of participants with SRE

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days.
Measure Participants	176	175
Number [participants]	NA NaN	NA NaN

8. Post-Hoc Outcome

Title	Kaplan-Meier Estimate of Duration of Response
Description	Duration of response was calculated for responders and defined as the time from the first observation of a response (e.g., the first time that the appropriate decrease in M-protein level was observed for confirmed responders) to the first documented progression or relapse. Response duration was censored at the last adequate assessment showing evidence of no progression.
Time Frame	Up to data cut off of 03 August 2005; up to 24 months

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all participants who were randomized to study drug.

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days.
Measure Participants	104	41
Median (95% Confidence Interval) [weeks]	67.6	33.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus Dexamethasone, Placebo Plus Dexamethasone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments
	Method	Log Rank
	Comments	The p-value is based on an unstratified log rank test of survival curve differences between the treatment groups
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.558
	Confidence Interval	(2-Sided) 95%; 0.338 to 0.921
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a proportional hazards model comparing the hazard functions associated with the treatment groups (lenalidomide/dexamethasone : placebo/dexamethasone).

9. Primary Outcome

Title	Kaplan-Meier Estimate of Time to Tumor Progression (TTP) (Later Cut-off Date of 02 Mar 2008)
Description	Time to progression was calculated as the time from randomization to the first occurrence of disease progression, as determined by a detailed review of all the myeloma response assessment data using the Bladé criteria (Bladé, 1998). Disease progression was also based on bone marrow findings, worsening lytic bone disease, progressively enlarging extramedullary plasmacytomas, or hypercalcemia.
Time Frame	From randomization up to cut-off date of 02 March 2008; up to 51 months

Outcome Measure Data

Analysis Population Description

Intent to treat included all participants who were randomized.

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Pulse dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40 mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40 mg PO QD for Days 1-4 every 28 days. Participants with documented progressive disease were permitted to crossover to receive lenalidomide at the same doses mentioned. After the study was unblinded in August 2005 participants were given the option to add lenalidomide to their dexamethasone treatment regimen immediately or to add lenalidomide to their dexamethasone therapy at the time of disease progression.
Measure Participants	176	175
Median (95% Confidence Interval) [weeks]	52.4	20.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus Dexamethasone, Placebo Plus Dexamethasone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The p-value is based on an unstratified log rank test of survival curve differences between the treatment groups.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.362
	Confidence Interval	(2-Sided) 95%; 0.27 to 0.478
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a proportional hazards model comparing the hazard functions associated with the treatment groups (CC-5013/Dex:Placebo/Dex)

10. Secondary Outcome

Title	Time to First Worsening on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
Description	The time to first worsening of the ECOG performance status was calculated as the time from randomization to the date of the first worsening compared with the last ECOG evaluation obtained prior to randomization. Data were censored at the last date that the participant was known to be unchanged or improved from before randomization for the participants who had not had worsened at the time of the analysis and for the patients who were lost to follow-up before worsening in the ECOG performance status was documented.
Time Frame	Randomization to cut off date of 03 August 2005; up to 24 months

Outcome Measure Data

Analysis Population Description

Intent to Treat includes all participants who were randomized to study drug; a total of six ECOG scores were missing at the time of the Aug 2005 cut-off.

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days.
Measure Participants	173	172
Median (95% Confidence Interval) [weeks]	10.1	12.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus Dexamethasone, Placebo Plus Dexamethasone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.271
	Comments	The p-value is based on an unstratified log rank test of survival curve differences between the treatment groups.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.166
	Confidence Interval	(2-Sided) 95%; 0.887 to 1.532
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a proportional hazards model comparing the hazard functions associated with the treatment groups (lenalidomide/dexamethasone: placebo/dexamethasone)

11. Secondary Outcome

Title	Time to First Worsening on the Eastern Cooperative Oncology Group (ECOG) Performance Scale (Later Cut-off Date of 02 March 2008)
Description	The time to first worsening of the ECOG performance status was calculated as the time from randomization to the date of the first worsening compared with the last ECOG evaluation obtained prior to randomization. Data were censored at the last date that the participant was known to be unchanged or improved from before randomization for the participants who had not had worsened at the time of the analysis and for the patients who were lost to follow-up before worsening in the ECOG performance status was documented.
Time Frame	Randomization to cut off date of 02 March 2008; up to 51 months

Outcome Measure Data

Analysis Population Description

Intent to Treat includes all participants who were randomized to study drug; six ECOG scores were missing at the March 2008 cut-off.

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40 mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40 mg PO QD for Days 1-4 every 28 days. Participants with documented progressive disease were permitted to crossover to receive lenalidomide at the same doses mentioned. After the study was unblinded in August 2005 participants were given the option to add lenalidomide to their dexamethasone treatment regimen immediately or to add lenalidomide to their dexamethasone therapy at the time of disease progression.
Measure Participants	173	172
Median (95% Confidence Interval) [weeks]	10.1	12.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus Dexamethasone, Placebo Plus Dexamethasone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.359
	Comments	The p-value is based on an unstratified log rank test of survival curve differences between the treatment groups.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.135
	Confidence Interval	(2-Sided) 95%; 0.866 to 1.486
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a proportional hazards model comparing the hazard functions associated with the treatment groups (CC-5013/Dex:Placebo/Dex)

12. Post-Hoc Outcome

Title	Kaplan-Meier Estimate of Duration of Response (Cut-off at a Later Date of 03 March 2008)
Description	Duration of response was calculated for responders and defined as the time from the first observation of a response (e.g., the first time that the appropriate decrease in M-protein level was observed for confirmed responders) to the first documented progression or relapse. Response duration was censored at the last adequate assessment showing evidence of no progression.
Time Frame	Up to data cut off of 03 Mar 2008; up to 51 months

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all participants who were randomized to study drug.

Arm/Group Title	Lenalidomide Plus Dexamethasone	Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.	Placebo PO daily on Days 1 to 28 of each 28 day cycle. Pulse dexamethasone 40 mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40 mg PO QD for Days 1-4 every 28 days. Participants with documented progressive disease were permitted to crossover to receive lenalidomide at the same doses mentioned. After the study was unblinded in August 2005 participants were given the option to add lenalidomide to their dexamethasone treatment regimen immediately or to add lenalidomide to their dexamethasone therapy at the time of disease progression.
Measure Participants	105	41
Median (95% Confidence Interval) [weeks]	68.1	33.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide Plus Dexamethasone, Placebo Plus Dexamethasone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments
	Method	Log Rank
	Comments	The p-value is based on an unstratified log rank test of survival curve differences between the treatment groups.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.619
	Confidence Interval	(2-Sided) 95%; 0.398 to 0.964
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a proportional hazards model comparing the hazard functions associated with the treatment groups (CC-5013/Dex:Placebo/Dex)

Adverse Events

Time Frame	From first dose of study drug to 30 days after the last visit. Up to 25 Jun 2013 (90 Months).
Adverse Event Reporting Description	Includes adverse events for those who received Lenalidomide after unblinding.
Arm/Group Title	Lenalidomide Plus Dexamethasone		Placebo Plus Dexamethasone
Arm/Group Description	Lenalidomide 25 mg by mouth (PO) daily (QD) on Days 1 to 21 and a matching placebo capsule QD on Days 22 to 28 of each 28-day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28 day cycle for cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD on Days 1 to 4 every 28 days for the remaining cycles.		Placebo PO daily on Days 1 to 28 of each 28 day cycle. Dexamethasone 40mg PO QD on Days 1-4, 9-12, and 17-20 of each 28-day cycle for Cycles 1 through 4. Beginning with Cycle 5, dexamethasone dosing schedule was reduced to 40mg PO QD for Days 1-4 every 28 days.
All Cause Mortality
	Lenalidomide Plus Dexamethasone		Placebo Plus Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lenalidomide Plus Dexamethasone		Placebo Plus Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	105/176 (59.7%)		79/175 (45.1%)
Blood and lymphatic system disorders
ANAEMIA NOS	4/176 (2.3%)		1/175 (0.6%)
THROMBOCYTOPENIA	2/176 (1.1%)		3/175 (1.7%)
NEUTROPENIA	3/176 (1.7%)		1/175 (0.6%)
FEBRILE NEUTROPENIA	4/176 (2.3%)		0/175 (0%)
PANCYTOPENIA	0/176 (0%)		2/175 (1.1%)
HYPERVISCOSITY SYNDROME	1/176 (0.6%)		0/175 (0%)
THROMBOTIC THROMBOCYTOPENIC PURPURA	1/176 (0.6%)		0/175 (0%)
Cardiac disorders
PULMONARY OEDEMA NOS	1/176 (0.6%)		3/175 (1.7%)
ATRIAL FIBRILLATION	2/176 (1.1%)		1/175 (0.6%)
MYOCARDIAL INFARCTION	1/176 (0.6%)		2/175 (1.1%)
ACUTE CORONARY SYNDROME	1/176 (0.6%)		0/175 (0%)
ACUTE MYOCARDIAL INFARCTION	1/176 (0.6%)		0/175 (0%)
ANGINA UNSTABLE	0/176 (0%)		1/175 (0.6%)
CARDIAC FAILURE ACUTE	0/176 (0%)		1/175 (0.6%)
CARDIAC FAILURE CONGESTIVE	1/176 (0.6%)		0/175 (0%)
CARDIAC FAILURE NOS	0/176 (0%)		1/175 (0.6%)
CARDIO-RESPIRATORY ARREST	0/176 (0%)		1/175 (0.6%)
CORONARY ARTERY STENOSIS	0/176 (0%)		1/175 (0.6%)
MYOCARDIAL ISCHAEMIA	0/176 (0%)		1/175 (0.6%)
VENTRICULAR BIGEMINY	0/176 (0%)		1/175 (0.6%)
Endocrine disorders
ACQUIRED HYPOTHYROIDISM	0/176 (0%)		1/175 (0.6%)
ADRENAL INSUFFICIENCY NOS	0/176 (0%)		1/175 (0.6%)
Eye disorders
CORNEAL ULCER	1/176 (0.6%)		0/175 (0%)
EXOPHTHALMOS NOS	0/176 (0%)		1/175 (0.6%)
Gastrointestinal disorders
DIARRHOEA NOS	2/176 (1.1%)		2/175 (1.1%)
CONSTIPATION	1/176 (0.6%)		1/175 (0.6%)
MELAENA	0/176 (0%)		2/175 (1.1%)
OESOPHAGEAL VARICES HAEMORRHAGE	1/176 (0.6%)		1/175 (0.6%)
OESOPHAGITIS NOS	1/176 (0.6%)		1/175 (0.6%)
UPPER GASTROINTESTINAL HAEMORRHAGE	0/176 (0%)		2/175 (1.1%)
ABDOMINAL PAIN NOS	1/176 (0.6%)		0/175 (0%)
ABDOMINAL PAIN UPPER	0/176 (0%)		1/175 (0.6%)
CAECITIS	1/176 (0.6%)		0/175 (0%)
COLOVESICAL FISTULA	0/176 (0%)		1/175 (0.6%)
DIVERTICULITIS INTESTINAL	0/176 (0%)		1/175 (0.6%)
DIVERTICULITIS NOS	1/176 (0.6%)		0/175 (0%)
GASTRIC ULCER	0/176 (0%)		1/175 (0.6%)
GASTRITIS NOS	1/176 (0.6%)		0/175 (0%)
GASTROENTERITIS NOS	1/176 (0.6%)		0/175 (0%)
GASTROINTESTINAL HAEMORRHAGE NOS	1/176 (0.6%)		0/175 (0%)
NAUSEA	1/176 (0.6%)		0/175 (0%)
OESOPHAGITIS ULCERATIVE	0/176 (0%)		1/175 (0.6%)
PEPTIC ULCER HAEMORRHAGE	1/176 (0.6%)		0/175 (0%)
VOMITING NOS	1/176 (0.6%)		0/175 (0%)
General disorders
PYREXIA	6/176 (3.4%)		7/175 (4%)
GENERAL PHYSICAL HEALTH DETERIORATION	4/176 (2.3%)		1/175 (0.6%)
ASTHENIA	2/176 (1.1%)		1/175 (0.6%)
DIFFICULTY IN WALKING	2/176 (1.1%)		0/175 (0%)
MULTI-ORGAN FAILURE	2/176 (1.1%)		0/175 (0%)
OEDEMA PERIPHERAL	2/176 (1.1%)		0/175 (0%)
PERFORMANCE STATUS DECREASED	1/176 (0.6%)		1/175 (0.6%)
CATHETER SITE INFLAMMATION	1/176 (0.6%)		0/175 (0%)
GRANULOMA NOS	1/176 (0.6%)		0/175 (0%)
INFLUENZA LIKE ILLNESS	0/176 (0%)		1/175 (0.6%)
NECROSIS NOS	0/176 (0%)		1/175 (0.6%)
PAIN NOS	0/176 (0%)		1/175 (0.6%)
SUDDEN DEATH	1/176 (0.6%)		0/175 (0%)
Hepatobiliary disorders
CHOLELITHIASIS	2/176 (1.1%)		0/175 (0%)
CHOLECYSTITIS ACUTE NOS	1/176 (0.6%)		0/175 (0%)
HEPATIC FAILURE	1/176 (0.6%)		0/175 (0%)
Infections and infestations
PNEUMONIA NOS	11/176 (6.3%)		7/175 (4%)
RESPIRATORY TRACT INFECTION NOS	4/176 (2.3%)		7/175 (4%)
SEPSIS NOS	3/176 (1.7%)		3/175 (1.7%)
SEPTIC SHOCK	2/176 (1.1%)		2/175 (1.1%)
UPPER RESPIRATORY TRACT INFECTION NOS	4/176 (2.3%)		0/175 (0%)
BRONCHOPNEUMONIA NOS	3/176 (1.7%)		0/175 (0%)
CELLULITIS	1/176 (0.6%)		2/175 (1.1%)
ARTHRITIS BACTERIAL	2/176 (1.1%)		0/175 (0%)
BRONCHITIS ACUTE NOS	2/176 (1.1%)		0/175 (0%)
HERPES ZOSTER	2/176 (1.1%)		0/175 (0%)
HERPES ZOSTER OPHTHALMIC	1/176 (0.6%)		1/175 (0.6%)
LOBAR PNEUMONIA NOS	2/176 (1.1%)		0/175 (0%)
PNEUMOCYSTIS CARINII PNEUMONIA	2/176 (1.1%)		0/175 (0%)
PNEUMONIA PNEUMOCOCCAL	1/176 (0.6%)		1/175 (0.6%)
URINARY TRACT INFECTION NOS	1/176 (0.6%)		1/175 (0.6%)
UROSEPSIS	1/176 (0.6%)		1/175 (0.6%)
BACTERAEMIA	0/176 (0%)		1/175 (0.6%)
BACTERIAL SEPSIS	1/176 (0.6%)		0/175 (0%)
BRONCHITIS CHRONIC NOS	0/176 (0%)		1/175 (0.6%)
BURSITIS INFECTIVE NOS	1/176 (0.6%)		0/175 (0%)
CENTRAL LINE INFECTION	1/176 (0.6%)		0/175 (0%)
CLOSTRIDIUM DIFFICILE SEPSIS	1/176 (0.6%)		0/175 (0%)
ESCHERICHIA URINARY TRACT INFECTION	0/176 (0%)		1/175 (0.6%)
GASTROINTESTINAL INFECTION NOS	0/176 (0%)		1/175 (0.6%)
LOWER RESPIRATORY TRACT INFECTION NOS	1/176 (0.6%)		0/175 (0%)
LUNG INFECTION NOS	0/176 (0%)		1/175 (0.6%)
MENINGITIS	1/176 (0.6%)		0/175 (0%)
MENINGITIS PNEUMOCOCCAL	1/176 (0.6%)		0/175 (0%)
NECROTISING FASCIITIS NOS	1/176 (0.6%)		0/175 (0%)
OTITIS MEDIA NOS	1/176 (0.6%)		0/175 (0%)
PNEUMONIA BACTERIAL NOS	1/176 (0.6%)		0/175 (0%)
PNEUMONIA LEGIONELLA	1/176 (0.6%)		0/175 (0%)
PYELONEPHRITIS ACUTE NOS	1/176 (0.6%)		0/175 (0%)
RESPIRATORY TRACT INFECTION VIRAL NOS	1/176 (0.6%)		0/175 (0%)
SALMONELLA INFECTION NOS	1/176 (0.6%)		0/175 (0%)
SINUSITIS NOS	1/176 (0.6%)		0/175 (0%)
STAPHYLOCOCCAL INFECTION	1/176 (0.6%)		0/175 (0%)
STAPHYLOCOCCAL SEPSIS	0/176 (0%)		1/175 (0.6%)
STREPTOCOCCAL SEPSIS	1/176 (0.6%)		1/175 (0.6%)
URINARY TRACT INFECTION BACTERIAL	1/176 (0.6%)		0/175 (0%)
Injury, poisoning and procedural complications
FEMUR FRACTURE	2/176 (1.1%)		0/175 (0%)
JOINT DISLOCATION	1/176 (0.6%)		0/175 (0%)
POST PROCEDURAL COMPLICATION	1/176 (0.6%)		0/175 (0%)
POST PROCEDURAL PAIN	1/176 (0.6%)		0/175 (0%)
SPINAL FRACTURE NOS	0/176 (0%)		1/175 (0.6%)
THORACIC VERTEBRAL FRACTURE	0/176 (0%)		1/175 (0.6%)
Investigations
BLOOD CREATININE INCREASED	0/176 (0%)		1/175 (0.6%)
BODY TEMPERATURE INCREASED	0/176 (0%)		1/175 (0.6%)
C-REACTIVE PROTEIN INCREASED	0/176 (0%)		1/175 (0.6%)
INTERNATIONAL NORMALISED RATIO DECREASED	1/176 (0.6%)		0/175 (0%)
WEIGHT DECREASED	1/176 (0.6%)		0/175 (0%)
Metabolism and nutrition disorders
HYPERGLYCAEMIA NOS	3/176 (1.7%)		2/175 (1.1%)
DEHYDRATION	1/176 (0.6%)		1/175 (0.6%)
ELECTROLYTE IMBALANCE	2/176 (1.1%)		0/175 (0%)
HYPERCALCAEMIA	0/176 (0%)		3/175 (1.7%)
HYPOCALCAEMIA	1/176 (0.6%)		1/175 (0.6%)
DIABETES MELLITUS INADEQUATE CONTROL	1/176 (0.6%)		0/175 (0%)
DIABETES MELLITUS NOS	0/176 (0%)		1/175 (0.6%)
Musculoskeletal and connective tissue disorders
BACK PAIN	5/176 (2.8%)		1/175 (0.6%)
BONE PAIN	5/176 (2.8%)		0/175 (0%)
MUSCLE WEAKNESS NOS	1/176 (0.6%)		3/175 (1.7%)
OSTEONECROSIS	3/176 (1.7%)		1/175 (0.6%)
PATHOLOGICAL FRACTURE	1/176 (0.6%)		2/175 (1.1%)
PAIN IN LIMB	1/176 (0.6%)		1/175 (0.6%)
CHEST WALL PAIN	1/176 (0.6%)		0/175 (0%)
JOINT SWELLING	1/176 (0.6%)		0/175 (0%)
MYALGIA	1/176 (0.6%)		0/175 (0%)
MYOPATHY	0/176 (0%)		1/175 (0.6%)
MYOPATHY STEROID	1/176 (0.6%)		0/175 (0%)
OSTEOPOROSIS NOS	0/176 (0%)		1/175 (0.6%)
PAIN IN JAW	1/176 (0.6%)		0/175 (0%)
SPONDYLITIS NOS	1/176 (0.6%)		0/175 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BASAL CELL CARCINOMA	1/176 (0.6%)		1/175 (0.6%)
BREAST CANCER IN SITU	1/176 (0.6%)		0/175 (0%)
GLIOBLASTOMA MULTIFORME	1/176 (0.6%)		0/175 (0%)
LUNG ADENOCARCINOMA NOS	1/176 (0.6%)		0/175 (0%)
NEOPLASM NOS	1/176 (0.6%)		0/175 (0%)
PROSTATE CANCER NOS	1/176 (0.6%)		0/175 (0%)
TRANSITIONAL CELL CARCINOMA	1/176 (0.6%)		0/175 (0%)
LUNG SQUAMOUS CELL CARCINOMA, STAGE UNSPECIFIED	1/176 (0.6%)		0/175 (0%)
Nervous system disorders
CEREBROVASCULAR ACCIDENT	3/176 (1.7%)		2/175 (1.1%)
MEMORY IMPAIRMENT	1/176 (0.6%)		1/175 (0.6%)
SPINAL CORD COMPRESSION NOS	2/176 (1.1%)		0/175 (0%)
ATAXIA	1/176 (0.6%)		0/175 (0%)
BRAIN OEDEMA	0/176 (0%)		1/175 (0.6%)
CEREBRAL ISCHAEMIA	1/176 (0.6%)		0/175 (0%)
ENCEPHALITIS NOS	0/176 (0%)		1/175 (0.6%)
EPIDURITIS	0/176 (0%)		1/175 (0.6%)
HYPOAESTHESIA	0/176 (0%)		1/175 (0.6%)
INTRACRANIAL PRESSURE INCREASED NOS	0/176 (0%)		1/175 (0.6%)
LEUKOENCEPHALOPATHY	1/176 (0.6%)		0/175 (0%)
PERIPHERAL MOTOR NEUROPATHY	0/176 (0%)		1/175 (0.6%)
PERIPHERAL NEUROPATHY NOS	1/176 (0.6%)		0/175 (0%)
POLYNEUROPATHY NOS	1/176 (0.6%)		0/175 (0%)
SUBDURAL HAEMATOMA	0/176 (0%)		1/175 (0.6%)
TREMOR	0/176 (0%)		1/175 (0.6%)
Psychiatric disorders
DEPRESSION	3/176 (1.7%)		1/175 (0.6%)
CONFUSIONAL STATE	1/176 (0.6%)		1/175 (0.6%)
BIPOLAR DISORDER	0/176 (0%)		1/175 (0.6%)
DELIRIUM	0/176 (0%)		1/175 (0.6%)
INSOMNIA	1/176 (0.6%)		0/175 (0%)
MANIA	0/176 (0%)		1/175 (0.6%)
MENTAL DISORDER NOS	0/176 (0%)		1/175 (0.6%)
Renal and urinary disorders
RENAL FAILURE ACUTE	4/176 (2.3%)		3/175 (1.7%)
RENAL FAILURE NOS	3/176 (1.7%)		4/175 (2.3%)
RENAL IMPAIRMENT NOS	0/176 (0%)		2/175 (1.1%)
FANCONI SYNDROME ACQUIRED	1/176 (0.6%)		0/175 (0%)
OLIGURIA	0/176 (0%)		1/175 (0.6%)
RENAL COLIC	1/176 (0.6%)		0/175 (0%)
RENAL FAILURE ACUTE ON CHRONIC	1/176 (0.6%)		0/175 (0%)
URINARY RETENTION	1/176 (0.6%)		0/175 (0%)
Reproductive system and breast disorders
BREAST MICROCALCIFICATION	1/176 (0.6%)		0/175 (0%)
Respiratory, thoracic and mediastinal disorders
PULMONARY EMBOLISM	7/176 (4%)		2/175 (1.1%)
ACUTE RESPIRATORY FAILURE	1/176 (0.6%)		1/175 (0.6%)
BRONCHITIS NOS	1/176 (0.6%)		1/175 (0.6%)
BRONCHOSPASM NOS	1/176 (0.6%)		1/175 (0.6%)
RESPIRATORY FAILURE	2/176 (1.1%)		0/175 (0%)
ACUTE RESPIRATORY DISTRESS SYNDROME	1/176 (0.6%)		0/175 (0%)
BRONCHOPNEUMOPATHY	0/176 (0%)		1/175 (0.6%)
COUGH	1/176 (0.6%)		0/175 (0%)
DYSPNOEA NOS	0/176 (0%)		1/175 (0.6%)
EPISTAXIS	0/176 (0%)		1/175 (0.6%)
LUNG CONSOLIDATION	1/176 (0.6%)		0/175 (0%)
MAXILLARY SINUSITIS	0/176 (0%)		1/175 (0.6%)
PNEUMONIA ASPIRATION	0/176 (0%)		1/175 (0.6%)
PULMONARY CONGESTION	1/176 (0.6%)		0/175 (0%)
Skin and subcutaneous tissue disorders
LEUKOPLAKIA NOS	1/176 (0.6%)		0/175 (0%)
Vascular disorders
DEEP VEIN THROMBOSIS	8/176 (4.5%)		6/175 (3.4%)
HYPOTENSION NOS	2/176 (1.1%)		2/175 (1.1%)
PHLEBITIS NOS	1/176 (0.6%)		2/175 (1.1%)
VENOUS THROMBOSIS NOS LIMB	2/176 (1.1%)		1/175 (0.6%)
PERIPHERAL ISCHAEMIA	2/176 (1.1%)		0/175 (0%)
CIRCULATORY COLLAPSE	1/176 (0.6%)		0/175 (0%)
PHLEBITIS SUPERFICIAL	1/176 (0.6%)		0/175 (0%)
PHLEBOTHROMBOSIS	1/176 (0.6%)		0/175 (0%)
Other (Not Including Serious) Adverse Events
	Lenalidomide Plus Dexamethasone		Placebo Plus Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	175/176 (99.4%)		173/175 (98.9%)
Blood and lymphatic system disorders
NEUTROPENIA	71/176 (40.3%)		17/175 (9.7%)
ANAEMIA	52/176 (29.5%)		49/175 (28%)
THROMBOCYTOPENIA	33/176 (18.8%)		19/175 (10.9%)
LEUKOPENIA	21/176 (11.9%)		11/175 (6.3%)
LYMPHOPENIA	17/176 (9.7%)		9/175 (5.1%)
Ear and labyrinth disorders
VERTIGO	12/176 (6.8%)		8/175 (4.6%)
Endocrine disorders
CUSHINGOID	9/176 (5.1%)		4/175 (2.3%)
Eye disorders
VISION BLURRED	13/176 (7.4%)		13/175 (7.4%)
Gastrointestinal disorders
CONSTIPATION	71/176 (40.3%)		41/175 (23.4%)
DIARRHOEA NOS	67/176 (38.1%)		45/175 (25.7%)
NAUSEA	40/176 (22.7%)		20/175 (11.4%)
DYSPEPSIA	23/176 (13.1%)		23/175 (13.1%)
ABDOMINAL PAIN UPPER	22/176 (12.5%)		11/175 (6.3%)
VOMITING NOS	20/176 (11.4%)		12/175 (6.9%)
ABDOMINAL PAIN NO	16/176 (9.1%)		10/175 (5.7%)
STOMATITIS	11/176 (6.3%)		6/175 (3.4%)
DRY MOUTH	10/176 (5.7%)		5/175 (2.9%)
GASTRITIS NOS	9/176 (5.1%)		4/175 (2.3%)
GASTROENTERITIS NOS	9/176 (5.1%)		5/175 (2.9%)
General disorders
ASTHENIA	64/176 (36.4%)		46/175 (26.3%)
FATIGUE	51/176 (29%)		41/175 (23.4%)
PYREXIA	50/176 (28.4%)		40/175 (22.9%)
OEDEMA PERIPHERAL	42/176 (23.9%)		34/175 (19.4%)
OEDEMA NOS	22/176 (12.5%)		15/175 (8.6%)
LETHARGY	15/176 (8.5%)		4/175 (2.3%)
CHEST PAIN	11/176 (6.3%)		7/175 (4%)
Infections and infestations
UPPER RESPIRATORY TRACT INFECTION NOS	29/176 (16.5%)		16/175 (9.1%)
URINARY TRACT INFECTION NOS	15/176 (8.5%)		13/175 (7.4%)
INFLUENZA	10/176 (5.7%)		8/175 (4.6%)
ORAL CANDIDIASIS	10/176 (5.7%)		9/175 (5.1%)
LOWER RESPIRATORY TRACT INFECTION NOS	9/176 (5.1%)		11/175 (6.3%)
RESPIRATORY TRACT INFECTION NOS	9/176 (5.1%)		6/175 (3.4%)
HERPES SIMPLEX	8/176 (4.5%)		12/175 (6.9%)
SINUSITIS NOS	6/176 (3.4%)		9/175 (5.1%)
Investigations
WEIGHT DECREASED	49/176 (27.8%)		46/175 (26.3%)
WEIGHT INCREASED	17/176 (9.7%)		24/175 (13.7%)
Metabolism and nutrition disorders
ANOREXIA	25/176 (14.2%)		14/175 (8%)
HYPOKALAEMIA	20/176 (11.4%)		10/175 (5.7%)
HYPERGLYCAEMIA NOS	19/176 (10.8%)		22/175 (12.6%)
HYPOCALCAEMIA	16/176 (9.1%)		5/175 (2.9%)
HYPOPHOSPHATAEMIA	11/176 (6.3%)		2/175 (1.1%)
HYPERURICAEMIA	4/176 (2.3%)		10/175 (5.7%)
Musculoskeletal and connective tissue disorders
MUSCLE CRAMP	56/176 (31.8%)		36/175 (20.6%)
BACK PAIN	45/176 (25.6%)		29/175 (16.6%)
BONE PAIN	34/176 (19.3%)		24/175 (13.7%)
ARTHRALGIA	33/176 (18.8%)		28/175 (16%)
MUSCLE WEAKNESS NOS	30/176 (17%)		28/175 (16%)
PAIN IN LIMB	27/176 (15.3%)		20/175 (11.4%)
MYALGIA	18/176 (10.2%)		16/175 (9.1%)
CHEST WALL PAIN	11/176 (6.3%)		14/175 (8%)
Nervous system disorders
HEADACHE	41/176 (23.3%)		35/175 (20%)
TREMOR	39/176 (22.2%)		14/175 (8%)
DIZZINESS	36/176 (20.5%)		16/175 (9.1%)
PARAESTHESIA	29/176 (16.5%)		29/175 (16.6%)
DYSGEUSIA	20/176 (11.4%)		16/175 (9.1%)
HYPOAESTHESIA	15/176 (8.5%)		7/175 (4%)
SOMNOLENCE	8/176 (4.5%)		10/175 (5.7%)
Psychiatric disorders
INSOMNIA	51/176 (29%)		63/175 (36%)
DEPRESSION	19/176 (10.8%)		18/175 (10.3%)
CONFUSIONAL STATE	14/176 (8%)		10/175 (5.7%)
ANXIETY	11/176 (6.3%)		14/175 (8%)
MOOD ALTERATION NOS	5/176 (2.8%)		10/175 (5.7%)
Respiratory, thoracic and mediastinal disorders
COUGH	41/176 (23.3%)		41/175 (23.4%)
DYSPNOEA NOS	36/176 (20.5%)		22/175 (12.6%)
NASOPHARYNGITIS	35/176 (19.9%)		23/175 (13.1%)
BRONCHITIS NOS	27/176 (15.3%)		26/175 (14.9%)
PHARYNGITIS	27/176 (15.3%)		16/175 (9.1%)
EPISTAXIS	12/176 (6.8%)		17/175 (9.7%)
HICCUPS	10/176 (5.7%)		8/175 (4.6%)
RHINITIS NOS	5/176 (2.8%)		9/175 (5.1%)
Skin and subcutaneous tissue disorders
RASH NOS	24/176 (13.6%)		9/175 (5.1%)
SWEATING INCREASED	17/176 (9.7%)		16/175 (9.1%)
DRY SKIN	16/176 (9.1%)		6/175 (3.4%)
PRURITUS	11/176 (6.3%)		9/175 (5.1%)
ERYTHEMA	8/176 (4.5%)		13/175 (7.4%)
Vascular disorders
HYPERTENSION NOS	17/176 (9.7%)		11/175 (6.3%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Investigator has the right to publish and/or present study data after multicentric publication or one year has elapsed until completion of this multicentric study provided that he/she (i) furnishes the sponsor a copy of any proposed publication or presentation before its submission, (ii) deletes any sponsor's confidential data as pointed out by sponsor, and (iii) delays any submission for generally up to ninety (90) days to permit the preparation and filing of intellectual property applications.