Conditions: Lupus Erythematosus, Systemic
Keywords: CC-220 Safety Efficacy Active Systemic Lupus Erythematosus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 289
Healthy volunteers: no

Brief summary:
The purpose of this Phase 2, multicenter, randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of an oral treatment regimen of CC-220 versus placebo in adult subjects with active systemic lupus erythematosus.

Approximately 280 subjects with a documented diagnosis of SLE will be randomized 2:2:1:2 to receive CC-220 (0.45 mg QD, 0.3 mg QD or 0.15 mg QD) or identically appearing placebo.

Detailed description:
The study consists of four phases:

* 4-week Screening Phase
* 24-week placebo-controlled phase Subjects will receive either 0.45 mg QD, 0.3 mg QD, 0.15 mg QD or placebo for the first 24 weeks of treatment.
* 28-week active treatment phase At Week 24, all subjects on placebo will be re-randomized to active treatment.
* 52-week long-term extension phase Subjects who complete the treatment phase may be eligible to roll over into a Long-term Extension of up to 52 weeks of treatment.
* 4 - 12-week observational follow-up All subjects who complete 52 weeks of treatment or discontinue the study early will enter a post-treatment observation follow-up phase. The Observational Follow-up Phase will consist of one visit 4 weeks following cessation of study drug for all subjects with an additional 12-week Observational Follow-up visit for males only.

Arms:
arm 1: * At Weeks 0 to 24: CC-220 Placebo Controlled Phase: CC-220 0.45 mg once daily (QD)
* At Weeks 24 to 52: CC-220 Active Treatment Phase: CC-220 0.45 mg once daily (QD)
* Long-term Extension Phase (52 weeks to 104 weeks): At Week 52 all subjects who elect to continue in the Long-term Extension will stay on the same dose they were on at the conclusion of the randomized, double-blind, active treatment phase. arm 2: * At Weeks 0 to 24: CC-220 Placebo Controlled Phase: CC-220 0.3 mg once daily (QD)
* At Weeks 24 to 52: CC-220 Active Treatment Phase: CC-220 0.30 mg once daily (QD)
* Long-term Extension Phase (52 weeks to 104 weeks): At Week 52 all subjects who elect to continue in the Long-term Extension will stay on the same dose they were on at the conclusion of the randomized, double-blind, active treatment phase. arm 3: * At Weeks 0 to 24: CC-220 Placebo Controlled Phase: CC-220 0.15 mg once daily (QD)
* At Weeks 24 to 52: CC-220 Active Treatment Phase: CC-220 0.15 mg once daily (QD)
* Long-term Extension Phase (52 weeks to 104 weeks): At Week 52 all subjects who elect to continue in the Long-term Extension will stay on the same dose they were on at the conclusion of the randomized, double-blind, active treatment phase. arm 4: Weeks 0 to 24: CC-220 Placebo Controlled Phase: placebo once daily (QD)

Interventions: intervention 1: CC-220 intervention 2: Placebo
Intervention descriptions: intervention 1: CC-220 intervention 2: Placebo QD PO

Protocol document:
Prot_000.pdf: 
EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
1
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
TITLE PAGE
A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF CC-220 
IN SUBJECTS WITH ACTIVE SYSTEMIC LUPUS 
ERYTHEMATOSUS
PROTOCOL NUMBER:
CC-220-SLE-002
DATE FINAL:
23 Feb 2017
AMENDMENT 1
18 Jun 2018
AMENDMENT 2
15 Aug 2018
EudraCT NUMBER:
2016-004574-17
IND NUMBER:
116088
SPONSOR NAME/ ADDRESS:
Celgene Corporation
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
2
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
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CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE


EDMS Doc. Number: 22932059 - 21574166
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Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
4
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
5
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
6
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PROTOCOL SUMMARY
Study Title
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the 
Efficacy and Safety of CC-220 in Subjects with Active Systemic Lupus Erythematosus 
Indication
Systemic Lupus Erythematosus (SLE)
Objectives

Primary Objective: 

To evaluate the clinical efficacy of three doses of CC-220 (0.45 mg once per day 
[QD], 0.3 mg QD or 0.15 mg QD) compared to placebo, for the treatment of 
active SLE using the SLE Responder Index at Week 24

Secondary Objectives:

To evaluate additional measures of clinical disease activity of CC-220 (0.45 mg 
once per day [QD], 0.3 mg QD or 0.15 mg QD) compared to placebo for the 
treatment of subjects with active SLE at Week 24

To assess the reduction in steroid use

To assess the reduction in fatigue 

To evaluate the safety and tolerability of three doses of CC-220 (0.45 mg QD, 0.3 
mg QD, and 0.15 mg QD) compared to placebo in subjects with active SLE 
 
 
 
 
 
 
 


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
7
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
Study Design
CC-220-SLE-002 is a Phase 2, randomized, placebo-controlled, double-blind, parallel group 
study with three active treatment groups (see Figure 1 for study design and Section 5 for Table of 
Events). 
The study consists of 5 phases:

Screening Phase up to 5 weeks

Randomized, Double-Blind, Placebo-Controlled Phase of up to 24 weeks

Randomized, Double-Blind, Active Treatment Phase of up to 28 weeks 

Long-term Extension Phase of up to 52 weeks

Observational Follow-up Phase of 4 weeks for females and 12 weeks for males
The total duration of the study is 113 weeks for females and 121 weeks for males. The total 
duration of the treatment period is 104 weeks. 
Approximately 280 subjects will be randomized 2:2:1:2 to receive CC-220 (0.45 mg QD, 0.3 mg 
QD or 0.15 mg QD) or identically appearing placebo. There will be approximately 80 subjects
randomized into the CC-220 0.45 mg QD and 0.3 mg QD dosing arms; 40 subjects randomized 
into the CC-220 0.15 mg QD dosing arm; and approximately 80 subjects in the placebo arm 
using an Interactive Response Technology (IRT). The treatment assignment will be stratified by 
Baseline corticosteroid dose (≥10 mg/d and < 10 mg/d) and screening SLEDAI 2K score (≥10 
points and < 10 points).
At Week 24, all placebo subjects will be re-randomized 1:1 in a blinded fashion by IRT to either 
CC-220 0.45 mg QD or 0.3 mg QD. All subjects who were initially randomized to CC-220 (0.45 
mg QD, 0.3 mg QD, or 0.15 mg QD) will be blindly re-randomized by IRT to the same dose 
group to which they were originally assigned. Once an optimal dose is identified by the Sponsor, 
subjects who have reached Week 24 will be transitioned to that dose. If more than one dose is 
identified for further investigation, subjects will be re-randomized accordingly as per the IRT.
Subjects who complete the 52-week treatment phase may be eligible for enrollment into a long-
term extension phase of up to 52 weeks in duration. 
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Study Population
Subjects are required to:

Have a diagnosis of SLE for at least 6 months prior to the Screening Visit and fulfill 
the 1997 update of the 1982 American College of Rheumatology (ACR) 
(Appendix E) Classification Criteria for SLE at the Screening Visit.

Have a SLEDAI 2K (Appendix B) score of ≥ 6 points at the Screening Visit at least 4 
points of which are a "clinical" SLEDAI 2K score.

A “clinical” score is the SLEDAI 2K assessment score without the inclusion of 
points attributed to any urine or blood laboratory results including immunologic 
measures.

Have a “clinical” SLEDAI 2K (Section 3.1) score of ≥ 4 points at the Baseline Visit


EDMS Doc. Number: 22932059 - 21574166
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Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
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CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018

Have at least one of the following positive antibodies per the central laboratory within 
the Screening Phase:

Positive antinuclear antibody (ANA) test with a titer of ≥ 1:40, associated with a 
diagnosis of SLE,

Anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies elevated to 
above normal,

Anti-Smith (anti-Sm) antibody elevated to above normal.
A positive ANA test from a local qualified laboratory performed in the last 6 months 
prior to or during the Screening Phase may be accepted for study entry and will be 
reviewed by the adjudication committee for eligibility purposes.

Enter the study on standard of care medications for SLE including antimalarials, 
immunosuppressants, and/or corticosteroids.
Subjects eligibility for enrollment will be adjudicated during the Screening Phase and prior to 
Randomization. The SLE disease activity measures will be adjudicated throughout the trial.
Length of Study
The length of study participation is 113 weeks for females and 121 weeks for males. This 
includes a 5-week Screening Phase, 52-week Treatment Phase, 52-week Long-term Extension 
Phase and a 4-week Observational Follow-Up Phase with an additional 12-week Observational 
Follow-Up Visit for males.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
posttreatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
Study Treatments
Subjects will be assigned to either CC-220 0.45 mg QD, CC-220 0.3 mg QD, CC-220 0.15 mg 
QD or placebo using 2:2:1:2 randomization ratio. Subjects assigned to the placebo group will 
receive matching placebo capsule(s) daily.
If a subject discontinues investigational product (IP) early (ie, prior to completing Visit 15 
during the core study or prior to completing Visit 28 during the Long-term Extension study), 
they will be required to complete an Early Termination Visit as soon as possible and enter into a 
4-week Observational Follow-up Phase with an additional 12-week Observational Follow-up 
Visit for males. In addition, if a subject completes through Visit 15, but opts not to enter the 
Long-term Extension Phase or completes the Long-term Extension Phase, the subject will enter 
into a 4-week Observational Follow-up Phase with an additional 12-week Observational Follow-
up Visit for males. 
Overview of Key Efficacy Assessments

SLE Responder Index consists of:

Systemic Lupus Erythematosus Disease Activity Index 2K (SLEDAI 2K)
(Appendix B)


EDMS Doc. Number: 22932059 - 21574166
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
British Isles Lupus Assessment Group 2004 (BILAG) (Appendix C)

Physician’s Global Assessment (PGA) (Appendix G)

Cutaneous Lupus Area and Severity Index (CLASI) (Appendix D)

Swollen and Tender Joint Counts (Appendix F)

Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Systemic Lupus Erythematosus (SLICC/ACR SLE) Damage Index 
(Appendix M)

BILAG-Based Composite Lupus Assessment (BICLA)

Lupus Low Disease Activity State (LLDAS)

Short Form-36 (SF-36) (Appendix N)

Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale 
(Appendix H)

Lupus patient reported outcome (LupusPRO™) (Appendix K)

Health assessment questionnaire-disability index (HAQ-DI) (Appendix L)
Overview of Key Safety Assessments

Adverse events (Section 6.8.1)

Vital signs (pulse, temperature, and blood pressure) (Section 6.8.2)

Hematology, chemistry, and urinalysis (Section 6.8.5)

Urine or serum beta-human chorionic gonadotropin (HCG) pregnancy tests (for 
females of childbearing potential [FCBP]) (Section 6.8.6)

12-lead electrocardiograms (ECGs) (Section 6.8.4)

Physical examinations, including height and weight (Section 6.8.3)

Concomitant medications and procedures (Section 6.7.4)

Hepatitis B and C screening (Section 6.8.8)

Human Immunodeficiency Virus (HIV) testing (Section 6.8.9)

Testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) for 
males only (Section 6.8.5)

Chest radiograph (for those subjects who have not had a chest radiograph in the 3 
months prior to the Screening Visit) (Section 6.8.11)
Statistical Methods
A two-group chi-square (continuity corrected) test with a 0.1 two-sided significance level will 
have approximately 80% power to detect a true 21% difference (55% versus 34%) between one 
of the CC-220 groups and the placebo group, for the proportion of subjects achieving an SLE 


EDMS Doc. Number: 22932059 - 21574166
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CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
Responder Index (SRI)(4) response at Week 24, when the sample size in each treatment group is 
80.
The primary efficacy endpoint is the SRI(4) response at Week 24.  The proportion of subjects 
who achieve SRI(4) response at Week 24 in each of the CC-220 0.45 mg QD, 0.3 mg QD or 0.15
mg QD group, will be compared with placebo group using a Cochran-Mantel-Haenszel (CMH)
test controlling for corticosteroid dose (≥ 10 mg/d and < 10 mg/d) at Baseline and SLEDAI 2K 
score (≥ 10 points and < 10 points) at Screening. Missing data for binary endpoints will be 
handled by nonresponder imputation (NRI), by which a subject will be considered a 
nonresponder at a given time point if the subject 1) does not have sufficient data (including the 
baseline data for the endpoints assessing the change from Baseline) assessed within the analysis 
visit window for response determination, or 2) has had an event of treatment failure (as per the 
prespecified criteria) before the date of assessment (or the date of the last assessment in the case 
of a composite endpoint involving multiple criteria that may be assessed on different dates) for 
the time point.


EDMS Doc. Number: 22932059 - 21574166
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Confidential and Proprietary
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CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
 
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................36


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3.
OVERALL STUDY DESIGN ................................................................................44
3.1.
Study Design ..........................................................................................................44
3.1.1.
Safety Management Team (SMT)...........................................................................45
3.1.2.
Independent External Data Monitoring Committee (DMC).....................................46
3.1.3.
Adjudication...........................................................................................................46
3.1.4.
Background Medication..........................................................................................46
3.2.
Study Duration for Subjects....................................................................................48
3.3.
End of Trial ............................................................................................................48
4.
STUDY POPULATION.........................................................................................49
4.1.
Number of Subjects ................................................................................................49
4.2.
Inclusion Criteria....................................................................................................49
4.3.
Exclusion Criteria...................................................................................................52
5.
TABLE OF EVENTS.............................................................................................56
6.
PROCEDURES......................................................................................................64
6.1.
Screening Phase......................................................................................................64
6.2.
Treatment Phase .....................................................................................................66
6.3.
Long-term Extension Phase ....................................................................................67
6.4.
End of Treatment/Early Termination.......................................................................68
6.6.
Unscheduled Visit for SLE Flare ............................................................................69
6.7.
General Assessments ..............................................................................................69
6.7.1.
Informed Consent ...................................................................................................69
6.7.2.
Inclusion/Exclusion Criteria....................................................................................69
6.7.3.
Complete Medical and Disease History...................................................................69
6.8.
Safety Assessments.................................................................................................70
6.8.1.
Adverse Event Assessment .....................................................................................70
6.8.2.
Vital Signs..............................................................................................................70
6.8.3.
Physical Examination .............................................................................................70
6.8.4.
Standard 12-lead ECGs...........................................................................................71
6.8.5.
Clinical Laboratory Evaluations..............................................................................71
6.8.6.
Pregnancy Test .......................................................................................................72
6.8.7.
Pregnancy Prevention and Counseling ....................................................................73


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6.8.8.
Hepatitis B and C....................................................................................................73
6.8.9.
Human Immunodeficiency Virus ............................................................................74
6.8.10.
QuantiFERON-TB..................................................................................................74
6.8.11.
Chest Radiograph ...................................................................................................74
6.9.
Clinical Efficacy Assessments ................................................................................74
6.9.1.
Functional Assessment of Chronic Illness Therapy (FACIT) – Fatigue Scale..........75
6.9.3.
LupusPRO™..........................................................................................................75
6.9.4.
HAQ-DI .................................................................................................................75
6.9.5.
SLEDAI 2K............................................................................................................76
6.9.6.
SLE Flare ...............................................................................................................76
6.9.7.
British Isles Lupus Assessment Group 2004 (BILAG) ............................................76
6.9.8.
Physician’s Global Assessment (PGA)....................................................................76
6.9.9.
CLASI Activity Score Assessment .........................................................................77
6.9.10.
CLASI Damage Score Assessment .........................................................................77
6.9.11.
Swollen and Tender Joint Count .............................................................................77
6.9.12.
SLICC/ACR SLE Damage Index............................................................................77
6.9.13.
Photography ...........................................................................................................77
7.
DESCRIPTION OF STUDY TREATMENTS........................................................80
7.1.
Description of Investigational Product(s)................................................................80
7.2.
Treatment Administration and Schedule .................................................................80
7.2.1.
Overdose ................................................................................................................80
7.2.1.1.
CC-220 Overdose ...................................................................................................81
7.2.2.
Dose Modifications and Interruptions .....................................................................81
7.3.
Method of Treatment Assignment...........................................................................81
7.4.
Packaging and Labeling..........................................................................................82
7.5.
Investigational Product Accountability and Disposal ..............................................82
7.6.
Investigational Product Compliance........................................................................82


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9.
STATISTICAL CONSIDERATIONS ....................................................................88
9.1.
Overview................................................................................................................88
9.2.
Study Population Definitions ..................................................................................88
9.3.
Sample Size and Power Considerations...................................................................88
9.4.
Background and Demographic Characteristics........................................................89
9.5.
Subject Disposition.................................................................................................89
9.6.
Efficacy Analysis....................................................................................................89
9.6.1.
Double-blind Placebo-controlled Phase...................................................................89
9.6.2.
Double-blinded Active Treatment Phase and Long-term Extension Phase...............90
9.6.3.
Subgroup Analysis..................................................................................................90
9.7.
Safety Analysis.......................................................................................................90
9.8.
Interim Analysis .....................................................................................................91
9.9.
Other Topics...........................................................................................................91
9.9.4.
Independent External Data Monitoring Committee .................................................91
10.
ADVERSE EVENTS..............................................................................................92
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................92


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10.2.
Evaluation of Adverse Events.................................................................................92
10.2.1.
Seriousness.............................................................................................................92
10.2.2.
Severity/Intensity....................................................................................................94
10.2.3.
Causality ................................................................................................................95
10.2.4.
Duration .................................................................................................................95
10.2.5.
Action Taken..........................................................................................................95
10.2.6.
Outcome.................................................................................................................95
10.3.
Abnormal Laboratory Values..................................................................................95
10.4.
Pregnancy...............................................................................................................96
10.4.1.
Females of Childbearing Potential: .........................................................................96
10.4.2.
Male Subjects.........................................................................................................97
10.5.
Reporting of Serious Adverse Events......................................................................97
10.5.1.
Safety Queries ........................................................................................................97
10.6.
Expedited Reporting of Adverse Events..................................................................97
11.
DISCONTINUATIONS .........................................................................................99
11.1.
Discontinuations.....................................................................................................99
11.2.
Investigational Drug Interruption and Stopping Rules.............................................99
11.2.1.
Pregnancy...............................................................................................................99
11.2.2.
Laboratory..............................................................................................................99
11.2.3.
AEs/SAEs.............................................................................................................100
11.2.4.
Study Stopping Criteria ........................................................................................101
12.
EMERGENCY PROCEDURES...........................................................................102
12.1.
Emergency Contact...............................................................................................102
12.2.
Emergency Identification of Investigational Products ...........................................102
13.
REGULATORY CONSIDERATIONS.................................................................103
13.1.
Good Clinical Practice..........................................................................................103
13.2.
Investigator Responsibilities .................................................................................103
13.3.
Subject Information and Informed Consent...........................................................104
13.4.
Confidentiality......................................................................................................104
13.5.
Protocol Amendments...........................................................................................104
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................104
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ..............105


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13.8.
Termination of the Study ......................................................................................105
14.
DATA HANDLING AND RECORDKEEPING...................................................106
14.1.
Data/Documents ...................................................................................................106
14.2.
Data Management.................................................................................................106
14.3.
Record Retention..................................................................................................106
15.
QUALITY CONTROL AND QUALITY ASSURANCE......................................108
15.1.
Study Monitoring and Source Data Verification....................................................108
15.2.
Audits and Inspections..........................................................................................108
15.3.
Product Quality Complaint ...................................................................................108
16.
PUBLICATIONS .................................................................................................110
18.
APPENDICES......................................................................................................114
APPENDIX A.
ABBREVIATIONS .....................................................................................114
APPENDIX J.
TOPICAL STEROID POTENCY TABLE....................................................128
APPENDIX M.
SLICC/ACR SLE DAMAGE INDEX.........................................................135


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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................36
Table 2:
Study Endpoints .....................................................................................................37
Table 3:
Double-Blind Placebo-Controlled Phase/Double-Blind Active Treatment 
Phase......................................................................................................................56
Table 4:
Pregnancy Testing Schedule for Females of Child Bearing Potential 
(FCBPs) Week 0 through Week 52.........................................................................60
Table 5:
Hematology Testing Schedule for Subjects Taking Immunosuppressants 
(mycophenolate mofetil, 6-mercaptopurine, mycophenolic acid, 
azathioprine, or calcineurin inhibitors) Week 0 through Week 52 ...........................60
Table 6:
Long-term Extension Phase ....................................................................................61
Table 7:
Abbreviations and Specialist Terms......................................................................114


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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................47




































EDMS Doc. Number: 22932059 - 21574166
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CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective

To evaluate the clinical efficacy of three doses of CC-220 (0.45 mg once per day 
[QD], 0.3 mg QD or 0.15 mg QD) compared to placebo, for the treatment of 
active systemic lupus erythematosus (SLE) using the SLE Responder Index at 
Week 24
Secondary Objectives

To evaluate additional measures of clinical disease activity of CC-220 (0.45 mg 
once per day [QD], 0.3 mg QD or 0.15 mg QD) compared to placebo for the 
treatment of subjects with active SLE at Week 24

To assess the reduction in steroid use

To assess the reduction in fatigue 

To evaluate the safety and tolerability of three doses of CC-220 (0.45 mg QD, 0.3 
mg QD, and 0.15 mg QD) compared to placebo in subjects with active SLE 
 
 
 
 
 
 


EDMS Doc. Number: 22932059 - 21574166
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Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary 
SLE 
Responder 
Index (SRI) (4)
Proportion of subjects who achieve SRI(4) response
Composite endpoint SRI(4), defined by the following 
criteria:

Reduction from Baseline of ≥ 4 points in the Systemic 
Lupus Erythematosus Disease Activity Index 
(SLEDAI) 2K score and

No new one or more British Isles Lupus Assessment 
Group (BILAG) A or new* 2 or more BILAG B items 
compared to Baseline using BILAG 2004 Index and

No worsening from Baseline defined by an increase of 
< 0.30 points from Baseline on a Physician's Global 
Assessment (PGA) visual analog scale (VAS) from 0-
3
*new excludes A to B
Week 24
Secondary
SLEDAI 2K
Proportion of subjects with SLEDAI 2K score 
improvement of ≥ 4 points from Baseline
Week 24
CLASI 
Proportion of subjects with a ≥50% reduction in Cutaneous 
Lupus Area and Severity Index (CLASI) activity score
from Baseline, in subjects with Baseline CLASI activity 
score ≥10
Week 24
BILAG
No new organ system affected as defined by 1 or more 
BILAG A or new* 2 or more BILAG B items compared to 
Baseline using BILAG 2004 Index
*new excludes A to B
Week 24 
PGA
Percentage of subjects with no worsening (increase of 
< 0.30 points from Baseline) in PGA compared to Baseline
Week 24
Joint Counts

Mean change from Baseline in swollen joint count in 
subjects with ≥2 swollen joints at Baseline

Mean change from Baseline in tender joint count in 
subjects with ≥2 tender joints at Baseline
Week 24 
PGA
Mean change from Baseline in PGA score
Week 24 
Fatigue
Change from Baseline in Functional Assessment of 
Chronic Illness Therapy (FACIT) Fatigue score
Week 24 


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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Corticosteroid 
Reduction

The percentage of subjects with a prednisone or 
equivalent dose of ≥10 mg/day at Baseline whose 
prednisone or equivalent dose has been reduced to ≤ 
7.5 mg/day by Week 16 and maintained through Week 
24 with no flares between Week 16 and Week 24

The percentage of subjects with a prednisone or 
equivalent dose of ≥10 mg/day at Baseline whose 
prednisone or equivalent dose has been reduced to < 10 
mg/day by Week 16 and maintained through Week 24 
with no flares between Week 16 and Week 24

Percent change from Baseline in oral corticosteroid 
(OCS) dose in subjects with prednisone or equivalent ≥ 
10 mg/day at Baseline

The total corticosteroid dose from Baseline through 
Week 24
Week 24
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
  
 
 
 
 
 
 
 
 
 
Safety 
Safety
Safety and tolerability as defined by the following:

Type, frequency, severity, and relationship of adverse 
events, clinical laboratory tests including urine 
cytology, 12-lead ECG, vital signs, and physical 
examination
Through 
Week 104
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 


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3.
OVERALL STUDY DESIGN
3.1.
Study Design
CC-220-SLE-002 is a Phase 2 randomized, placebo-controlled, double-blind, parallel group 
study with three active treatment groups (see Figure 1 for study design and Section 5 for Table of 
Events). 
The study consists of 5 phases:

Screening Phase up to 5 weeks

Randomized, Double-Blind, Placebo-Controlled Phase of up to 24 weeks

Randomized, Double-Blind, Active Treatment Phase of up to 28 weeks

Long-term Extension Phase of up to 52 weeks

Observational Follow-up Phase of 4 weeks for females and 12 weeks for males
The total duration of the study is 113 weeks for females and 121 weeks for males. The total 
duration of the treatment period is 104 weeks. 
Approximately 280 subjects will be randomized 2:2:1:2 to receive CC-220 (0.45 mg QD, 0.3 mg 
QD or 0.15 mg QD) or identically appearing placebo. There will be approximately 80 subjects 
randomized into the CC-220 0.45 mg QD and 0.3 mg QD dosing arms; 40 subjects randomized 
into the CC-220 0.15 mg QD dosing arm; and approximately 80 subjects in the placebo arm 
using an Interactive Response Technology (IRT). The treatment assignment will be stratified by 
Baseline corticosteroid dose (≥10 mg/d and < 10 mg/d) and screening SLEDAI 2K score (≥10 
points and < 10 points) (Furie, 2016).
Subjects will have a documented diagnosis of SLE, meet the ACR Classification Criteria 
(Appendix E), and meet the SLEDAI 2K entry criteria as described below.
The eligibility criteria require that: 

At the Screening Visit, subjects have a SLEDAI 2K score of ≥6 points, WITH at 
least 4 points being “clinical”. The “clinical” score excludes points attributable to any 
urine or laboratory results including immunologic measures.

At the Baseline Visit, subjects must have a “clinical” SLEDAI 2K score of ≥4 points. 
The “clinical” score excludes points attributable to any urine or laboratory results 
including immunologic measures.
The following SLEDAI 2K criteria qualify as “clinical”:

Alopecia*

Vasculitis

Arthritis

Myositis

Rash

Mucosal ulcers

Pleurisy

Pericarditis

Fever


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*Alopecia will count toward the “clinical” SLEDAI 2K score only if the CLASI activity 
score for alopecia is 2 or 3. Alopecia with a CLASI activity alopecia score of 1, will only 
count toward the total SLEDAI score.
Subjects with neurological manifestations of lupus are excluded from the study. As such, no 
neurologic descriptors of the SLEDAI 2K score (items 1 to 7) will be counted towards the 
SLEDAI study entry criteria. However, neurological manifestations of lupus which occur during 
the study, must be collected and scored accordingly.
During the screening phase and prior to the Baseline Visit, it is recommended that sites contact 
subjects to evaluate their concomitant medication. This call will be used to confirm that subjects 
are not taking any prohibited medications and to ensure that subjects taking any protocol 
permitted concomitant medications are on an appropriate dose and are maintaining stable dosing 
according to the protocol.
At Week 24, all remaining placebo subjects will be re-randomized 1:1 in a blinded fashion by 
IRT to either CC-220 0.45 mg QD or 0.3 mg QD. All subjects who were initially randomized to 
CC-220 (0.45 mg QD, 0.3 mg QD, or 0.15 mg QD) will be blindly re-randomized by IRT to the 
same dose group to which they were originally assigned.
Subjects who complete the Treatment Phase may be eligible to roll over into a Long-term 
Extension of up to 52 weeks in duration. Subjects who enter this phase will maintain the CC-220 
dosage they were re-randomized to at Week 24.
To maintain the blind at the site and subject level, the individual subject treatment assignments 
will not be revealed to the Investigators until after the 52-week database lock and after all final 
analyses are completed and the final results have been released. 
Once an optimal dose is identified, subjects will be transitioned to that dose. If more than one 
dose is identified for further study, subjects will be re-randomized accordingly as per the IRT.
If a subject discontinues investigational product (IP) early (ie, prior to completing Visit 15 
during the Active Treatment Phase or prior to completing Visit 28 during the Long-term 
Extension), they will be required to complete an Early Termination Visit as soon as possible and 
enter into a 4-week Observational Follow-up Phase with an additional 12-week Observational 
Follow-up visit for males. In addition, if a subject completes the Randomized, Double-Blind, 
Active Treatment Phase, but opts not to enter the Long-term Extension Phase or completes the 
Long-term Extension Phase, the subject will enter into a 4-week Observational Follow-up Phase 
with an additional 12-week Observational Follow-up Visit for males.
A 4-week Observational Follow-up Phase is included for all subjects to monitor subject safety 
after cessation of treatment. An additional 12-week Observational Follow-up Visit is included 
for males to monitor hormone levels (testosterone, LH, FSH).
The study will be conducted in compliance with the International Council for Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
3.1.1.
Safety Management Team (SMT)
In addition to daily safety monitoring conducted by Investigators and study personnel,
cumulative and interval blinded adverse events (AEs), SAEs, discontinuations, and laboratory 


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findings will be reviewed by a SMT. The SMT is comprised of lead representatives from 
multiple Sponsor functions engaged in the CC-220 development program. The scope, conduct,
processes, and accountabilities of the SMT are prespecified in a SMT charter.
3.1.2.
Independent External Data Monitoring Committee (DMC)
Although Sponsor study staff will monitor safety on an ongoing basis throughout the study, 
formal blinded safety assessments of the relevant study data will be performed by an external 
independent Data Monitoring Committee (DMC). The DMC will review unblinded data to 
evaluate safety during the study and data from the interim analysis for futility. The DMC is 
comprised of independent physician experts and a statistician for whom there is no identified 
conflict of interest. The DMC will be convened regularly, at least once a year, or ad hoc at the 
request of the SMT. Recommendations of the DMC based on the overall benefit/risk evaluation 
may include proceeding with the study per protocol, proceeding with the study with 
modification, or study suspension. The scope, conduct, membership, processes, and 
accountabilities of the DMC are specified in the DMC charter.
3.1.3.
Adjudication
Subjects eligibility for enrollment will be adjudicated during Screening and Randomization. No 
subject is allowed to be randomized into the study without the approval of the adjudication 
committee. Additionally, SLE disease activity measures will be adjudicated throughout the trial 
in a blinded fashion to ensure data quality. Details regarding the adjudication process are 
specified in a separate charter.
3.1.4.
Background Medication
Subjects will be required to be on standard of care medications for SLE, see Section 1.3.2.2. 
Subjects will remain on oral corticosteroids, immunosuppressants (methotrexate, sulfasalazine, 
azathioprine, 6-mercaptopurine, mycophenolate mofetil, mycophenolic acid, leflunomide, 
tacrolimus, cyclosporine) and/or antimalarials (hydroxychloroquine, quinacrine, chloroquine) 
during the study, as long as they have been treated for at least 4 weeks prior to the Screening 
Visit and on a stable dose for at least 2 weeks prior to their Baseline Visit for corticosteroids,
and/or treated for at least 12 weeks and on a stable dose for at least 8 weeks prior to their 
Baseline Visit for immunosuppressants/antimalarials (Section 8.1). 
See Inclusion Criteria, Section 4.2, and Section 8.1 for details of the allowed dose regimens.


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Figure 1:
Overall Study Design
Obs FU = Observational Follow Up Phase; QD = once per day; SLE = systemic lupus erythematosus; SRI(4) = SLE Responder Index(4); Wk = week.
*Female subjects will have a 4-week Observational Follow-Up Phase. Males will have a 12-week Observational Follow-Up Phase. 


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3.2.
Study Duration for Subjects 
The length of study participation is 113 weeks for females and 121 weeks for males. This 
includes a 5-week Screening Phase, 52-week Treatment Phase, 52-week Long-term Extension 
Phase and a 4-week Observational Follow-Up Phase with an additional 12-week Observational 
Follow-Up Visit for males.
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
posttreatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.


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4.
STUDY POPULATION
4.1.
Number of Subjects
Approximately 280 subjects will be enrolled at multiple (approximately 100) sites globally.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study. 
Age/Gender
1. Male or female 18 years of age or older at the time of signing the informed consent.
2. Understand and voluntarily sign informed consent forms (ICFs) prior to the initiation of 
any study specific assessments/procedures.
3. Able and willing to adhere to the visit schedule and other protocol requirements.
Disease Specific
4. Have a diagnosis of SLE for at least 6 months prior to the Screening Visit and fulfill the 
1997 update of the 1982 American College of Rheumatology (ACR) (Appendix E)
Classification Criteria for SLE at the Screening Visit.
5. A SLEDAI 2K score of ≥ 6 points, WITH at least 4 points being a "clinical" SLEDAI 2K 
score. The “clinical” score excludes points attributable to any urine or blood laboratory 
results including immunologic measures. As subjects with neurological manifestations of 
lupus are excluded from the study, no neurologic descriptors of the SLEDAI 2K score 
(items 1 to 7) will be counted towards the SLEDAI study entry criteria (see Appendix B).
The following SLEDAI 2K criteria qualify as “clinical”:

Alopecia*

Vasculitis

Arthritis

Myositis

Rash

Mucosal ulcers

Pleurisy

Pericarditis

Fever
* Alopecia will count toward the “clinical” SLEDAI 2K score only if the CLASI activity score for 
alopecia is 2 or 3 (Appendix D). Alopecia with a CLASI activity alopecia score of 1, will only count 
toward the total SLEDAI score.
6. At the Baseline Visit, a clinical SLEDAI 2K score of ≥ 4 points.
7. Have at least one of the following positive antibodies associated with SLE per the central 
laboratory within the Screening Phase:

Positive antinuclear antibody (ANA) test with a titer of ≥ 1:40, associated with a 
diagnosis of SLE,

Anti-dsDNA antibodies elevated to above normal,


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
Anti-Smith (anti-Sm) antibody elevated to above normal.
A positive ANA test from a local qualified laboratory performed in the last 6 months 
prior to or during the Screening phase may be accepted for study entry and will be 
reviewed by the adjudication committee for eligibility purposes.
8. All subjects must receive approval by the adjudication committee (Section 3.1.3) prior to 
enrollment into the study.
Pregnancy 
All male and female subjects should be counseled about pregnancy precautions and risks of 
fetal exposure as described in the Pregnancy Prevention Plan (provided separately)
(Section 6.8.7).
9. Females of childbearing potential (FCBP)1 must:

Have two negative pregnancy tests as verified by the Investigator prior to starting 
study therapy, one within 10 to 14 days prior to the first dose of CC-220 and again 
within 24 hours before taking the first dose of CC-220. She must agree to ongoing 
pregnancy testing during the course of the study, and after end of study treatment. 
This applies even if the subject practices true abstinence2 from heterosexual contact.

Either commit to true abstinence2 from heterosexual contact (which must be reviewed 
on a monthly basis and source documented) or agree to use two forms of reliable 
contraception simultaneously. One must be on a highly effective method and one 
additional effective (barrier) method (Section 6.8.7), and both must be practiced
without interruption, 28 days prior to starting investigational product, during the 
study therapy (including dose interruptions), and for 28 days after discontinuation of 
study therapy. 
10. Male subjects must: Practice true abstinence2 or agree to use a barrier contraception 
(male latex condom or non-latex condom NOT made out of natural [animal] membrane 
[for example, polyurethane]) during sexual contact with a pregnant female or a female of 
childbearing potential while participating in the study, during dose interruptions and for 
at least 90 days following investigational product discontinuation, even if he has 
undergone a successful vasectomy.
11. Male subjects must agree not to donate semen or sperm during therapy and for at least 90 
days following the discontinuation of IP.
12. All subjects must:

Understand that the IP could have potential teratogenic risk.
                                               
1 A female of childbearing potential is a sexually mature female who 1) has not undergone a hysterectomy (the 
surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been 
postmenopausal for at least 24 consecutive months (that is, has had menses at any time during the preceding 24 
consecutive months). 
2 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception).


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
Agree to abstain from donating blood while taking IP and for 28 days following 
discontinuation of the IP.

Agree not to share IP with another person.

Other than the subject, FCBP and males able to father a child should not handle the IP 
or touch the capsules unless gloves are worn.

Be counseled about pregnancy precautions and risks of fetal exposure as described in
the Pregnancy Prevention Plan.
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
For Long-term Extension Phase only:
18. Subjects have completed participation in the placebo-controlled and active treatment 
study phases.
Subjects eligibility to enter the long-term extension phase will be dependent on the 
ongoing adjudication review.


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4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment. In the event one or 
more of the laboratory criteria is not satisfied due to unexpected or unexplained reason, subjects 
may repeat the respective laboratory or ECG test one time during the Screening Phase.
If the result(s) do not satisfy eligibility criteria, subjects will be ineligible to enroll in the study 
and will be considered a screen failure. Subjects may be re-screened twice with the approval 
of the medical monitor.  
Concomitant Medications and Procedures
1. The subject has received immunomodulating or immunosuppressive therapy (except 
corticosteroids and permitted medications described in inclusion criterion 13 or 
Section 8), such as:
a.
Cyclophosphamide within 6 months of the Baseline Visit. Previous use of 
Melphalan or other alkylating agents is prohibited.
b. Etanercept within 8 weeks prior to the Baseline Visit.
c.
Belimumab within 3 months prior to the Baseline Visit.
d. B-cell depleting or modulating agents, such as rituximab or anti-CD22 therapy, 
within 1 year prior to the Baseline Visit.
e.
Any other biologic or non-biologic immunosuppressive agent within 2 months of 
5 pharmacokinetic half-lives (whichever is longer) prior to the Baseline Visit.
2. The subject has been treated with intra-articular, intralesional, subcutaneous, intradermal,
intramuscular or IV pulse corticosteroids 6 weeks prior to the Baseline Visit. 
3. The subject has received high potency topical or intralesional corticosteroids, topical 
immunosuppressants, and/or retinoids within 2 weeks of the Screening Visit (only Class 
6 or 7 are permitted [Section 8.1.2.3]).
4. The subject has undergone plasmapheresis within 3 months of the Baseline Visit.
5. The subject has received IV immunoglobulin within 3 months of the Baseline Visit.
6. The subject has participated in a clinical trial and has received an investigational product 
within 5 pharmacokinetic half-lives or 2 months, (whichever is longer) prior to the 
Baseline Visit. 
7. The subject has received strong inhibitors or inducers of CYP3A4/5, including grapefruit, 
St. John’s Wort or related products within two weeks prior to the Baseline Visit (Please 
refer to Appendix I for examples of medications). 
8. The subject has a planned or received immunization with a live or live attenuated vaccine 
within 2 months prior to the Baseline Visit and for 2 months after administration of the 
last dose of IP.
Disease Severity
9. The subject has an estimated glomerular filtration rate (eGFR) of < 45 mL/min/1.7 m2 or 
proteinuria > 2000 mg/day based on protein to creatinine ratio, or has active lupus 


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nephritis that in the opinion of the adjudication committee may require ‘induction’ 
therapy.
10. The subject has active, severe or unstable neuropsychiatric lupus disease (e.g., poorly 
controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, 
cerebellar ataxia or dementia related to SLE, psychosis, organic brain syndrome, 
cerebrovascular accident [CVA], cerebritis or central nervous system [CNS] vasculitis),
within 6 months of the Screening Visit. Please contact Medical Monitor if further 
clarification is needed.
Concomitant Disease
11. The subject has QTcF of > 450 milliseconds on the screening ECG.
12. The subject has serologic tests during Screening (see Section 6.8.8) consistent with 
infection with either hepatitis B or hepatitis C, and/or confirmed history of hepatitis B or 
hepatitis C infection. Subjects with isolated positive hepatitis B surface antibody are not 
excluded.
13. The subject has a history of congenital and/or acquired immunodeficiencies or any 
underlying condition that predisposes the subject to infection, or a positive laboratory test
for HIV infection during Screening (unless prohibited by local health authority or 
IRB/EC requirements).
14. The subject has active or history of recurrent bacterial, viral, fungal, mycobacterial or 
other infections (including, but not limited to, atypical mycobacterial disease and herpes 
zoster). The subject has any major episode of infection requiring hospitalization or 
treatment with intravenous or oral antibiotics within 4 weeks of the Screening Visit and at 
any time during the Screening Phase, up through the first dose of IP. Subjects with minor 
infections that meet these criteria may be discussed with the medical monitor for 
approval for study entry.
15. The subject has a history of latent or active TB, unless there is medical record 
documentation of successful completion of a standard course of treatment per local 
guidelines. The subject has a QuantiFERON®-TB Gold test result at Screening elevated 
to above normal as per the central laboratory, unless there is medical record 
documentation of successful completion of a standard course of treatment per local 
guidelines. Indeterminate QuantiFERON®-TB Gold test results should be repeated and if 
the result is indeterminate again then the subject should not be enrolled, unless there is 
medical record documentation of successful completion of a standard course of treatment
per local guidelines. 
16. The subject has an abnormal chest radiograph with evidence of active infection or 
possible malignancy. A chest radiograph should be taken prior to the Baseline Visit,
when most of the eligibility criteria are met, so that results are available prior to the 
Baseline Visit. A posterior-anterior (PA) radiograph is required. A lateral view is strongly 
recommended unless prohibited by local health authority requirements. Alternatively, PA 
or PA/lateral radiographs or chest computed tomography (CT) scans that were taken 
within the 3 months (or longer periods based on local health authority requirements) prior 
to the Screening Visit will be accepted for evaluation for participation in the study. Note: 
If screening chest radiograph shows abnormalities with no significant changes from 


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previous radiographs then the subject may be considered for enrollment. Please contact 
the medical monitor to discuss prior to entry.
17. The subject has a history of an organ transplant (eg, heart, lung, kidney, liver) or 
hematopoietic stem cell/marrow transplant. Subjects with other types of transplants may 
be discussed with the medical monitor for study entry approval.
18. The subject has malignancy or history of malignancy, except for:

treated (eg, cured) basal cell or squamous cell in situ
skin carcinomas

treated (eg, cured) cervical intraepithelial neoplasia Grade 1 and 2

treated (eg, cured) carcinoma in situ of the cervix with no evidence of disease within 
5 years of the Screening Visit.
Note: History of treated (ie, cured) cancer > 10 years before the Screening Visit and 
without recurrence can be considered based on the nature of the cancer and must be 
discussed with the medical monitor on a case-by-case basis.
19. Any subject who: 
a.
has a diagnosis or history consistent with Antiphospholipid Syndrome (APS) (See 
Appendix O for APS criteria)
b. has “triple positivity” (ie, a positive lupus anticoagulant, anticardiolipin, and anti-B2 
glycoprotein). Subjects with antiphospholipid antibodies without a diagnosis of APS 
will be reviewed by the adjudication committee for entry into the study based on the 
titer, the number of positive antibodies, and other risk factors.  
c.
is unwilling or unable to undergo protocol required thromboprophylaxis.
20. The subject has history of arterial or venous thrombosis.
21. The subject has a history or current diagnosis of peripheral neuropathy (sensory or motor)
≥Grade 2 (Appendix P).
22. The subject has a presence of active uveitis or any other ophthalmological finding that in 
the opinion of the Investigator is clinically significant.
23. The subject has concomitant fibromyalgia, which symptoms or therapy for, in the opinion 
of the PI, will significantly impact the assessment of SLE disease manifestations and 
activity.
24. The subject has dermatomyositis, polymyositis, scleroderma, rheumatoid arthritis or other
non-SLE driven inflammatory joint or skin disease or overlap syndromes as the primary
disease.
25. The subject has clinically significant or unstable or uncontrolled acute or chronic disease 
not due to SLE (eg, cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, 
renal, neurological, malignancy, psychiatric or infectious disease) or laboratory 
abnormality or planned surgical procedure which in the opinion of the Investigator could 
put the subject at undue risk or confounds the ability to interpret data from the study. 


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Laboratory Criteria (presence of any of the following at Screening will exclude subjects 
from enrollment) 
26. Laboratory criteria: 

Neutrophil count < 1.5 x 109/L

White blood cell (WBC) count > 20,000/µL (> 20 X 109/L)

Lymphocyte count < 450/mm3 (< 0.45 x 109/L)

Platelet count < 75 x 109/L and > 550 x 109/L

Hemoglobin < 8 g/dL or > 18 g/dL

Total bilirubin > 1.5 x upper limit of normal (ULN) (unless due to Gilbert’s 
syndrome)

Aspartate transaminase (AST [serum glutamic oxaloacetic transaminase, SGOT]) > 2 
x ULN 

Alanine transaminase (ALT [serum glutamic pyruvic transaminase, SGPT]) > 2 x 
ULN 
General
27. The subject is pregnant or a nursing (breast-feeding) female. 
28. The subject is unlikely to comply with the study protocol or is unsuitable for any other 
reason, as judged by the Investigator, medical monitor or adjudication committee. 
29. The subject has a history of known substance abuse within six months of the Screening 
Visit which, in the opinion of the Investigator, would interfere with the subject’s safety or 
ability to comply with the study procedures. Marijuana use (whether or not medically 
prescribed) is not allowed within 6 weeks of Screening and during the study.
30. The subject has a history of severe allergic reactions to or hypersensitivity to any 
component of the IP or placebo.
31. The subject has received CC-220 in previous trials. 
For Long-term Extension Phase only:
32. Subjects will not be eligible to enter the long-term extension phase if they required an 
increased dose of immunosuppressant medication above the maximum dose permitted in 
the protocol (see Section 8.1.4.1) during the last 2 months of the active treatment phase.


EDMS Doc. Number: 22932059 - 21574166
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5.
TABLE OF EVENTS
Table 3:
Double-Blind Placebo-controlled Phase/Double-Blind Active Treatment Phase
Double-Blind Placebo-Controlled Treatment Phaseb
Double-Blind Active Treatment Phaseb
Visit(s)
±1 Day (Visits 2-30)
1
Screening
Phase a
2
Baseline
3
4
5
6
7
8
9
10
11
12
13
14
15
Days
-35 to 0
0
28
56
84
112
140
168
196
224
252
280
308
336
364
Week(s)
-5 to 0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
General Assessments
Informed Consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/Exclusion Criteria
X
X
-
-
-
-
-
-
-
-
-
-
-
-
X
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical/Disease History
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior/Concomitant Meds and 
Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy Assessments
SF-36
-
X
-
-
X
-
-
X
-
-
-
-
-
-
X
FACIT Fatigue 
-
X
-
-
X
-
-
X
-
-
X
-
-
-
X
LupusPRO™
-
X
-
-
-
-
-
X
-
-
-
-
-
-
X
HAQ-DI
-
X
-
-
-
-
-
X
-
-
-
-
-
-
X
SLEDAI 2Kc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SLEDAI Flare Index
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BILAG 2004
-
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PGAc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLASI Activity
X
X
X
X
X
X
X
X
-
-
-
X
-
-
X


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
57
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
Table 3:
Double-Blind Placebo-controlled Phase/Double-Blind Active Treatment Phase (Continued)
Double-Blind Placebo-Controlled Treatment Phaseb
Double-Blind Active Treatment Phaseb
Visit(s)
±1 Day (Visits 2-30)
1
Screening
Phase a
2
Baseline
3
4
5
6
7
8
9
10
11
12
13
14
15
Days
-35 to 0
0
28
56
84
112
140
168
196
224
252
280
308
336
364
Week(s)
-5 to 0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
CLASI Damage
-
X
-
-
-
-
-
X
-
-
-
-
-
-
X
Swollen and Tender Joint 
Assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SLICC/ACR SLE Damage 
Index
-
X
-
-
-
-
-
-
-
-
-
-
-
-
X
Safety Assessments
12-Lead ECG
X
X
X
-
-
-
-
X
X
-
-
-
-
-
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry, Hematologye
eGFR, Urine 
Protein/Creatinine, and 
Urinalysisf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IgA,IgM,IgG
-
X
-
-
-
-
-
X
-
-
-
-
-
-
X
ESR and hs-CRP
-
X
-
-
X
-
-
X
-
-
X
-
-
-
X
Lupus Autoantibody Panelg
X
X
-
-
-
-
-
X
-
-
-
-
-
-
X
ds-DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complement Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lupus Antiphospholipid 
Profile
X
X
-
-
X
-
-
X
-
-
X
-
-
-
X
Testosterone, FSH and LHh
-
X
-
-
-
-
-
X
-
-
-
-
-
-
X
Pregnancy Testsi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis B and C Tests
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
58
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
Table 3:
Double-Blind Placebo-controlled Phase/Double-Blind Active Treatment Phase (Continued)
Double-Blind Placebo-Controlled Treatment Phaseb
Double-Blind Active Treatment Phaseb
Visit(s)
±1 Day (Visits 2-30)
1
Screening
Phase a
2
Baseline
3
4
5
6
7
8
9
10
11
12
13
14
15
Days
-35 to 0
0
28
56
84
112
140
168
196
224
252
280
308
336
364
Week(s)
-5 to 0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
QuantiFERON®-TB Gold 
testj
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
HIV test
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Celgene Pregnancy 
Prevention Counseling 
Program (CPPCP)k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest radiographj
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
 
 
Photographsm
-
X
X
X
X
X
-
X
-
-
X
-
-
-
X
Investigational Product
Dispense IP
-
X
X
X
X
X
X
X
X
X
X
X
X
X
Xn
IP Accountability/Compliance
-
-
X
X
X
X
X
X
X
X
X
X
X
X
X
ANA = antinuclear antibody; BILAG = British Isles Lupus Assessment Group; CLASI = Cutaneous Lupus Area and Severity Index; ECG = Electrocardiogram; eGFR = Estimated 
Glomerular Filtration Rate; ESR = Erythrocyte Sedimentation Rate; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FSH = Follicle Stimulating 
Hormone; HAQ-DI = Health Assessment Questionnaire-Disability Index; hs-CRP = High-Sensitivity C-Reactive Protein; IgA = Immunoglobulin A; IgG = Immunoglobulin G; 
IgM = Immunoglobulin M; IP = Investigational Product; LH = Luteinizing Hormone; LupusPRO = Lupus Patient Reported Outcome Tool; PD = Pharmacodynamics; PG =
Pharmacogenetics: PGA = Physician’s Global Assessment; PK = Pharmacokinetics; SF-36 = Short Form-36; SLEDAI = Systemic Lupus Erythematosus Disease Activity Index;
SLICC/ACR SLE Damage Index = Systemic Lupus International Collaborating Clinics/American College of Rheumatology Systemic Lupus Erythematosus Damage Index; TB =
Tuberculosis.


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
59
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
a During the Screening Phase and prior to the Baseline Visit, it is recommended that sites contact subjects to evaluate their concomitant medication. This call will be used to 
confirm that subjects are not taking any prohibited medications and to ensure that subjects taking any protocol permitted concomitant medications are on an appropriate dose and 
are maintaining stable dosing according to the protocol.
b Subjects who discontinue the Treatment Phase early should complete the Week 104 (Visit 28) Early Termination Visit as soon as possible and enter into the Observational 
Follow-up Phase (Visit 29/Week 108 [males must also complete Visit 30/Week 116]).
c A SLEDAI 2K score and PGA must be assessed at any visit where a steroid taper is being considered or at any visit, including an unscheduled visit, where a steroid burst is 
being considered. For the purposes of a steroid taper or steroid burst, the “clinical” SLEDAI 2K score will be used.
d Height at the Screening Visit only.
e Subjects taking concomitant mycophenolate mofetil, 6-mercaptopurine, mycophenolic acid, azathioprine, or calcineurin inhibitors must have hematology assessments 
weekly between Visit 2 (Baseline) through Visit 3 (Week 4) and Visit 8 (Week 24) through Visit 9 (Week 28). In addition, these subjects must have hematology 
measurements two weeks after Visit 3 [Week 4], Visit 4 [Week 8], Visit 9 [Week 28], and Visit 10 [Week 32]).
f Microscopic analysis of the urine will be performed only when the dipstick is positive.
g This will include ANA, anti-Smith, anti-Ro, anti-LA, anti-ribonucleoprotein (RNP), and rheumatoid factor. Rheumatoid factor will be assessed at Screening (Visit 1) only.
h Collection of these analytes must occur at the same time of day (± 1 hour) at the Baseline (Visit 2), Week 24, and Week 52 for males only. For example, if collected at the 
Baseline Visit at 9 AM, the Week 24 and Week 52 sample must be collected between 8 and 10 AM.
i FCBP are required to have 2 pregnancy tests during the Screening Phase.  The first pregnancy test must be a serum or urine β-HCG performed within 10 to 14 days 
prior to the start of IP. The second test (urine) must be performed within 24 hours before starting IP.  The subject may not receive IP until the Investigator has 
verified that the results of these pregnancy tests are negative. See Section 6.8.6 and Table 4 for more detail.
j Please see Section 6.8.10 and Section 6.8.11 for greater detail on the QuantiFERON®-TB Gold test and chest radiograph.
k All male and FCBP subjects must be counseled about pregnancy precautions and risks of fetal exposure as described in the Pregnancy Prevention Plan.  All subjects must also be 
counseled against sharing investigational product and donating blood during treatment with and within 28 days of discontinuing investigational product.
l PK blood samples will be collected prior to subjects taking their IP dose at the site on the study visit day.
 
n For subjects who decide to enter the Observational Follow-up Phase, there will be no dispensation of IP at this visit. 


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
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Confidential and Proprietary
60
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
Table 4:
Pregnancy Testing Schedule for Females of Child Bearing Potential (FCBPs) Week 0 through Week 52
Double-Blind Placebo-Controlled Treatment Phase
Double-Blinded Active Treatment Phase
Visit(s)
1
SCR
Phase
2
BL
LAB 
ONLY
LAB 
ONLY
LAB 
ONLY
3
LAB 
ONLY
4
LAB 
ONLY
5
LAB 
ONLY
6
LAB 
ONLY
7
LAB 
ONLY
8
LAB 
ONLY
LAB 
ONLY
LAB 
ONLY
9
LAB 
ONLY 10
LAB 
ONLY 11
LAB 
ONLY 12
LAB 
ONLY 13
LAB 
ONLY 14
LAB 
ONLY 15
Days
-35 
to 0
0
7
14
21
28
35
56
70
84
98
112
126
140
154
168
175
182
189
196
210
224
238
252
266
280
294
308
322
336
350
364
Week(s)
-5
to 0
0
1
2
3
4
6
8
10
12
14
16
18
20
22
24
25
26
27
28
30
32
34
36
38
40
42
44
46
48
50
52
FCBPs 
with 
regular 
menses
Xa
X
X
X
X
X
-
X
-
X
-
X
-
X
-
X
X
X
X
X
-
X
-
X
-
X
-
X
-
X
-
X
FCBPs 
with 
irregular 
menses
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BL = Baseline; IP = investigational product; SCR = Screening.
a FCBPs must have a serum or urine pregnancy test within 10 to 14 days prior to the start of IP.
“LAB ONLY” indicates time points when subjects have only pregnancy testing done.
Pregnancy Testing Schedule for Females of Child Bearing Potential (FCBPs) Week 52 through Week 104
All FCBPs with reported regular menses will have pregnancy tests every 28 days throughout the Long-term Extension Phase. All FCBPs with 
irregular or no menses will be required to have pregnancy tests every 2 weeks throughout the Long-term Extension Phase.
Table 5:
Hematology Testing Schedule for Subjects Taking Immunosuppressants (mycophenolate mofetil, 6-
mercaptopurine, mycophenolic acid, azathioprine, or calcineurin inhibitors) Week 0 through Week 52
Double-Blind Placebo-Controlled Treatment Phase
Double-Blinded Active Treatment Phase
Visit(s)
±1 Day 
1
SCR
2
BL
LAB 
ONLY
LAB 
ONLY
LAB 
ONLY
3
LAB 
ONLY
4
LAB 
ONLY
5
6
7
8
LAB 
ONLY
LAB 
ONLY
LAB 
ONLY
9
LAB 
ONLY
10
LAB 
ONLY
11
12
13
14
15
Days
-35 to 0
0
7
14
21
28
35
56
70
84
112
140
168
175
182
189
196
210
224
238
252
280
308
336
364
Week(s)
-5 to 0
0
1
2
3
4
6
8
10
12
16
20
24
25
26
27
28
30
32
34
36
40
44
48
52
Hematology testing 
for subjects taking 
immunosuppressants
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BL = Baseline; SCR = Screening.


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
61
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
“LAB ONLY” indicates time points when subjects have only hematology testing done.
All subjects (regardless of background concomitant medication) will have hematology tests every 28 days from Week 52 through Week 104.
Table 6:
Long-term Extension Phase
Long-term Extension Phase 
Observational Follow-up Phase
Visit(s)
±1 Day – for all visits
16a
17
18
19
20
21
22
23
24
25
26
27
Final Treatment 
Visit/Early 
Termination 
Visita
28
29
30h
Days
392
420 448 476
504
532
560
588
616
644
672
700
728
756
812
Week(s)
56
60
64
68
72
76
80
84
88
92
96
100
104
108
116
General Assessments
Concomitant Meds and 
Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
Efficacy Assessments
SF-36/ FACIT Fatigue 
-
-
-
-
-
X
-
-
-
-
-
-
X
X
-
HAQ-DI
-
-
-
-
-
-
-
-
-
-
-
-
X
X
-
LupusPRO™ 
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
SLEDAI 2K
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
SLEDAI Flare Index
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
BILAG 2004
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
PGA
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
CLASI activity
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
CLASI Damage
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
Swollen and Tender 
Joint Assessments
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
SLICC/ACR SLE 
Damage Index
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
62
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
Table 6:
Long-term Extension Phase (Continued)
Long-term Extension Phase 
Observational Follow-up 
Phase
Visit(s)
±1 Day – for all visits
16a
17
18
19
20
21
22
23
24
25
26
27
Final Treatment 
Visit/Early 
Termination Visita
28
29
30h
Days
392
420
448
476
504
532
560
588
616
644
672
700
728
756
812
Week(s)
56
60
64
68
72
76
80
84
88
92
96
100
104
108
116
Safety Assessments
12-Lead ECGg
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
Vital Signs
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
Physical Exam
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
Chemistry, Urinalysis, 
eGFR Urine 
Protein/Creatinine
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
IgA,IgM,IgG  
-
-
-
-
-
X
-
-
-
-
-
-
X
-
-
ESR and hs-CRP
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
Lupus Autoantibody Panelc
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
ds-DNA
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
Complement Panel
-
-
X
-
-
X
-
-
X
-
-
-
X
X
-
Lupus Antiphospholipid
Profile
-
-
X
-
-
X
-
-
X
-
-
-
X
-
-
Testosterone, FSH and LHb
-
-
-
-
-
X
-
-
-
-
-
-
X
-
X
Pregnancy Testd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
QuantiFERON®-TB Gold 
teste
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Celgene Pregnancy 
Prevention Counseling 
Program (CPPCP)f
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-


EDMS Doc. Number: 22932059 - 21574166
CC-220
Protocol CC-220-SLE-002
Celgene Corporation
Confidential and Proprietary
63
CC-220-SLE-002 Amendment 2.0 Final: 15 Aug 2018
Table 6:
Long-term Extension Phase (Continued)
Long-term Extension Phase 
Observational Follow-up 
Phase
Visit(s)
±1 Day – for all visits
16a
17
18
19
20
21
22
23
24
25
26
27
Final Treatment
Visit/Early 
Termination Visita
28
29
30h
Days
392
420
448
476
504
532
560
588
616
644
672
700
728
756
812
Week(s)
56
60
64
68
72
76
80
84
88
92
96
100
104
108
116
Investigational Product
Dispense IP
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
IP 
Accountability/Compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
ANA = antinuclear antibodies; BILAG = British Isles Lupus Assessment Group; CLASI = Cutaneous Lupus Area and Severity Index; ECG = Electrocardiogram; eGFR =
Estimated Glomerular Filtration Rate; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FCBP = female of child bearing potential; FSH = Follicle
Stimulating Hormone; HAQ-DI = Health Assessment Questionnaire-Disability Index; IgA = Immunoglobulin A; IgG = Immunoglobulin G; IgM = Immunoglobulin M; IP =
Investigational Product; LH = Luteinizing Hormone; LupusPRO = Lupus Patient Reported Outcome Tool; PGA = Physician’s Global Assessment; SF-36 = Short Form-36; 
SLEDAI = Systemic Lupus Erythematosus Disease Activity Index; SLICC/ACR SLE Damage Index = Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Systemic Lupus; Erythematosus Damage Index; TB = tuberculosis.
a Subjects who discontinue from the study during the Long-term Extension Phase should complete the Week 104 (Visit 28) Early Termination Visit as soon as possible and enter 
into the Observational Follow-up Phase (Visit 29/Week 108 [males must also complete Visit 30/Week 116]).
b Collection of these analytes must occur at the same time of day (± 1 hour) at Week 76, Week 104 (End of Treatment or Early Termination Visit), and Week 116 for males only. 
For example, if collected at the Week 64 at 9 AM, the Week 76, Week 88, Week 104, and Week 116 sample must be collected between 8 and 10 AM.
c This will include ANA, anti-Smith, anti-Ro, anti-LA, and anti-ribonucleoprotein (RNP).
d FCBP may not receive IP until the Investigator has verified that the subject’s urine pregnancy test results are negative. Serum pregnancy tests may be performed as
needed. FCBP with reported regular cycles must have pregnancy testing every 28 days during the Long-term Extension Phase, at study discontinuation and at 28 days 
after the last dose of IP.  If menstrual cycles are irregular, pregnancy testing must occur every 14 days while on IP, at study discontinuation and at 14 and 28 days 
following study discontinuation.
e Please see Section 6.8.10 for greater detail on the QuantiFERON®-TB Gold test.
f All male and FCBP subjects must be counseled about pregnancy precautions and risks of fetal exposure as described in the Pregnancy Prevention Plan. All subjects must also be
counseled against sharing investigational product and donating blood during treatment with and within 28 days of discontinuing investigational product.
g ECGs may be performed at any time during the Long-term Extension Phase if clinically warranted.
h Visit 30 is only for males to collect male hormones (LH, FSH, and testosterone). 


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6.
PROCEDURES
Signed informed consent forms (ICFs) must be obtained before any study evaluations or 
procedures are performed and any samples are collected per local regulations during the course 
of the study.
Waivers to the protocol will not be granted during the conduct of this trial.
Any questions regarding the protocol should be directed to the Medical Monitor or designee.
6.1.
Screening Phase
Screening evaluations will be performed for all subjects to determine eligibility. These 
evaluations should be completed within 5 weeks of Baseline (Visit 2). In the event that the 
subject will exceed the 5-week Screening Phase the medical monitor must be contacted.
Subjects are permitted to be re-screened two times should they fail to meet the study entry 
criteria. Note: Subjects who fail entry criteria due to a positive hepatitis B, hepatitis C, HIV or 
TB test result should not be rescreened for the study. 
Safety laboratory analyses will be performed by the contracted central laboratory. The central 
laboratory will provide a separate manual for the collection and processing of the samples for 
this study. Screening laboratory values must demonstrate subject eligibility, but may be repeated 
once within the Screening Phase, if necessary.
During the Screening Phase and prior to the Baseline Visit, it is recommended that sites contact 
subjects to evaluate their concomitant medication. This call will be used to confirm that subjects 
are not taking any prohibited medications and to ensure that subjects taking any protocol 
permitted concomitant medications are on an appropriate dose and are maintaining stable dosing 
according to the protocol. The Screening Visit should be registered using IRT.
The following order of procedures should be considered after informed consent has been 
obtained:

Inclusion/exclusion criteria eligibility (see Section 4.2 and Section 4.3)

Demographics (initials, date of birth, sex, race, ethnicity [if allowed by local 
regulations])

Disease history including specific information regarding SLE

Complete medical history (all relevant medical conditions diagnosed and those 
occurring prior to Screening)

Prior and concomitant medication evaluation (including any non-SLE medications 
taken within one month prior to Screening)

Prior and concomitant SLE medication evaluation (previous use of antimalarial, 
immunosuppressant, biologic or other medication relevant to the SLE management 
should be recorded, regardless of when it was administered. For steroids, a reporting 
period of 3 months for orals and 6 months for IV or IM preparations prior to 
Screening is sufficient.)

Prior procedures evaluation 

Vital signs, weight, and height (see Section 6.8.2)

Physical examination (see Section 6.8.3)


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
Standard 12-lead ECGs (see Section 6.8.4)

The following laboratory assessments (Section 6.8.5) will be collected:

Hematology panel 

Chemistry panel 

Urinalysis 

Lupus antiphospholipid profile

Lupus autoantibody panel 

ds-DNA

Complement panel

Pregnancy test (a serum or urine β-HCG must be performed within 10 to 14 days 
prior to the start of IP and a second pregnancy test [urine] must be performed within 
24 hours before starting IP) (see Section 6.8.6)

Hepatitis B and C testing (Section 6.8.8)

HIV test (Section 6.8.9)

QuantiFERON®-TB Gold (see Section 6.8.10)

Counseling about pregnancy precautions and the potential risks of fetal exposure (see 
Section 6.8.7)

Efficacy assessments (see Section 6.9 for the recommended order).

Adverse event assessment (begins when the subject signs the informed consent and is 
assessed continuously throughout the study until 28 days following cessation of IP)
(see Section 6.8.1)

Chest radiograph (see Section 6.8.11) (A chest radiograph should be taken prior to the 
Baseline Visit, when most of the eligibility criteria are met, so that results are 
available prior to Baseline Visit).
All clinically significant abnormal ECG, laboratory and physical exam findings identified during 
the Screening Phase will be captured on the medical history page of the electronic case report 
form (eCRF). Refer to Section 10 for details pertaining to AEs. Adverse event assessment begins 
when the subject signs the informed consent form. If a subject is hospitalized for a serious 
adverse event, additional information will be collected regarding reason and duration of 
hospitalization and to which unit the subject was admitted.
At a minimum the informed consent date, demographics, and reason why the subject did not 
qualify for the study will be collected for all subjects determined to be screen failures. Adverse 
events experienced by screen failure subjects will be collected from the date of signing consent 
to the day the subject is confirmed to be a screen failure. This information will be captured in the 
subject’s source documents and appropriate CRF(s).
For purposes of study eligibility, inclusion and exclusion criteria/results should be reviewed 
again prior to randomization (Baseline [Visit 2]) to ensure the subject continues to meet criteria 
for entry into the study (Section 4.2 and Section 4.3). Subjects eligibility for enrollment will be 
adjudicated during the Screening Phase and prior to Randomization.


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6.2.
Treatment Phase
The subject will begin treatment upon confirmation of eligibility by the adjudication committee.
Investigational product is provided as a 28-day supply. Therefore, only a ± 1-day window for all 
study visits is allowed.
On study visit days, pregnancy testing should be done prior to taking IP. 
At Weeks 4, 12, and 24 subjects must take their IP at the study site after PK samples have been 
collected.
Site personnel responsible for conducting efficacy assessments are not permitted to see subjects’ 
completed QOL questionnaires. 
The following order of procedures should be considered: 

Pregnancy test (urine or serum) (see Section 6.8.6)

Pharmacokinetic testing (see Section 6.10)

Adverse event assessment (see Section 6.8.1)

Disease history including specific information regarding SLE

Concomitant procedures and medications

Quality-of-life assessments (see Section 6.9)

Physical examination (see Section 6.8.3)

Vital signs and weight (see Section 6.8.2)

Efficacy assessments (see Section 6.9)

The following laboratory assessments (Section 6.8.5) will be collected:

Hematology panel 
o Subjects taking concomitant mycophenolate mofetil, 6-mercaptopurine, 
mycophenolic acid, azathioprine, or calcineurin inhibitors must have weekly 
hematology assessments between Visit 2 [Baseline] through Visit 3 [Week 4] 
and Visit 8 [Week 24] through Visit 9 [Week 28]. In addition, these subjects 
must have hematology measurements two weeks after Visit 3 [Week 4], Visit 4
[Week 8], Visit 9 [Week 28], and Visit 10 [Week 32]).

Chemistry panel

Complement panel

Testosterone, FSH and LH

Lupus autoantibody panel

ds-DNA

Immunoglobulin assessment 

Erythrocyte sedimentation rate (ESR) and high-sensitivity c-reactive protein (hs-
CRP)

Lupus antiphospholipid profile 

Pharmacodynamic and pharmacogenetic testing (see Section 6.11)

Urinalysis 

Counseling about pregnancy precautions and the potential risks of fetal exposure (see 
Section 6.8.7)

Standard 12-lead ECGs (see Section 6.8.4)


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
IP compliance assessment (all used and unused blister cards must be returned at every 
visit)

Dispensation of IP

Photography (only for subjects at selected sites in the US)
6.3.
Long-term Extension Phase
Participation in the Long-term Extension Phase is optional. Subjects who elect not to continue in 
the Long-term Extension Phase at the completion of the Blinded Active Treatment Phase, should 
enter the Observational Follow-up Phase as detailed in Section 6.5. In order to enter the Long-
term Extension Phase subjects must meet entry criteria specified for the Long-term Extension 
Phase in Section 4.2 and Section 4.3. For all Long-term Extension Phase visits, IP is provided as 
a 28-day supply. Therefore only ± 1-day window for all visits is allowed.
On study visit days, pregnancy testing should be done prior to taking IP. 
Worsening of a subject’s SLE should be considered as worsening of the disease under study, and 
should not be captured as an adverse event unless it meets the criterion of a SAE.
Site personnel responsible for conducting efficacy assessments are not permitted to see subjects’ 
completed QOL questionnaires. 
The following order of procedures should be considered:  

Pregnancy test (urine or serum) (see Section 6.8.6)

Adverse event assessment (see Section 6.8.1)

Concomitant procedures and medications

Quality-of-life assessments (see Section 6.9)

Physical examination (see Section 6.8.3)

Vital signs and weight (see Section 6.8.2)

Efficacy assessments (see Section 6.9)

The following laboratory assessments (Section 6.8.5) will be collected:

Hematology panel 

Chemistry panel

Complement panel

Testosterone, FSH and LH

Lupus autoantibody panel

ds-DNA 

Immunoglobulin assessment 

Lupus antiphospholipid profile 

Urinalysis 

QuantiFERON®-TB Gold (see Section 6.8.10)

Counseling about pregnancy precautions and the potential risks of fetal exposure (see 
Section 6.8.7)

Standard 12-lead ECGs (see Section 6.8.4). 

IP compliance assessment (all used and unused medication containers must be 
returned at every visit)

Dispensation of IP


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6.4.
End of Treatment/Early Termination
An early termination visit will be performed for subjects who are withdrawn from treatment for 
any reason as soon as possible after the decision to permanently discontinue treatment has been 
made. 
The following order of procedures should be considered:  

Pregnancy test (urine or serum) (see Section 6.8.6)

Adverse event assessment 

Concomitant procedures and medications

Quality-of-life assessments (see Section 6.9)

Physical examination

Vital signs 

Efficacy assessments (see Section 6.9)

The following laboratory assessments (Section 6.8.5) will be collected:

Hematology panel 

Chemistry panel 

Complement panel

Testosterone, FSH and LH

Lupus autoantibody panel

ds-DNA

Immunoglobulin assessment 

Lupus antiphospholipid profile 

Urinalysis 

Counseling about pregnancy precautions and the potential risks of fetal exposure (see 
Section 6.8.7)

Standard 12-lead ECGs 

IP compliance assessment (all used and unused blister cards must be returned at every 
visit)
 
 
 
 
 
 
 


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6.6.
Unscheduled Visit for SLE Flare
Subjects experiencing SLE flares must meet steroid burst criteria (Section 8.1.2) in order to 
receive a steroid burst. In the event a SLE flare requiring an increase in steroids occurs outside of 
a protocol specified visit, subjects should come to the site for an unscheduled visit in order to 
qualify for a steroid burst.
The following evaluations will be performed as specified:

Adverse event assessment (see Section 6.8.1)

Concomitant procedures and medications (Section 6.7.4)

The following laboratory assessments (Section 6.8.5) will be collected:

Hematology panel 

Chemistry panel 

ds-DNA

Complement panel

Urinalysis 

SLEDAI2K, BILAG, and PGA (see Section 6.9).
6.7.
General Assessments
6.7.1.
Informed Consent
Informed consent must be obtained by the Investigator or designee for all subjects prior to the 
initiation of any study procedures. All subjects must review the ICF prior to the initiation of any 
study procedures and indicate whether or not they consent to participate in this portion of the 
study.
6.7.2.
Inclusion/Exclusion Criteria
Subjects must meet all inclusion criteria (Section 4.2) and must not have any of the conditions 
specified in the exclusion criteria (Section 4.3). The subjects’ source documents must support 
his/her qualifications for the study (eg, for females not of childbearing potential [FNCBP] who 
do not require pregnancy testing or birth control because of hysterectomy, the date of the 
hysterectomy must be included in the medical history [Section 6.8.6]).
6.7.3.
Complete Medical and Disease History
Medical history should be recorded, including previous surgeries. History of SLE will be 
reported in a disease-specific electronic case report form (eCRF) including diagnosis date and 
date of skin and joint manifestations (if applicable).


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6.7.4.
Prior and Concomitant Medications
Information regarding prior/concomitant medication usage will be collected for each subject. All 
medications and therapies (including systemic and topical medications, prescription, and non-
prescription, including herbal supplements) taken by the subject up to 30 days prior to Visit 1 
should be recorded, including the stop dates for medications prohibited in the study, at the time 
of consent. 
Previous use of antimalarial, immunosuppressant, biologic or other medication relevant to the 
SLE management should be recorded, regardless of when they were administered. For steroids, 
reporting period of 3 months for orals and 6 months for IV or IM preparations prior to Screening 
Visit is sufficient.
At the Screening and Baseline Visits, concomitant medications should be checked against the list 
of prohibited medications to ensure the protocol requirements have been met. Refer to Protocol 
Section 8.1 for permitted and Section 8.2 for prohibited medications. If a subject does not meet 
the medication requirements, the study visit must be rescheduled.  
6.8.
Safety Assessments
The following assessments will be performed as outlined in Section 5.
6.8.1.
Adverse Event Assessment
Adverse event assessment begins when the subject signs the informed consent form (see 
Section 10.1 for information on definition and attribution of AEs). Information regarding all AEs 
regardless of causal relationship to IP (CC-220 or placebo) will be collected. The time frames for 
recording all AEs are indicated in Section 5. Worsening of a subject’s SLE or SLE flares should 
be considered as worsening of the disease under study and not recorded as an AE unless the 
event meets the definition of a SAE.
6.8.2.
Vital Signs
Vital signs include temperature, pulse, and seated blood pressure. Blood pressure will be 
measured after the subject has been seated and resting quietly for 5 minutes. If body temperature 
is measured orally, since drinking hot or cold beverages (including water) has a significant 
impact on recorded oral body temperature, no beverages should be ingested within 15 minutes of 
the measurement.  Investigators are to report any clinical significant abnormal findings as AEs.
6.8.3.
Physical Examination
Physical examinations will include height (Screening only) and weight (to be done in street 
clothes, no shoes), mucocutaneous, eyes, ears, respiratory, cardiovascular, gastrointestinal,
neurological, lymphatic, and musculoskeletal system evaluations. Physical examinations should 
also be guided by the subject’s symptomology. Results of the physical examinations will be 
recorded only in the source documents. Clinically significant abnormal findings identified during 
the Screening physical examination will be recorded on the eCRF as medical history. 
Gynecological and urogenital examinations will not be done unless for cause. The frequency of 
these assessments is detailed in Section 5.


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6.8.4.
Standard 12-lead ECGs 
All ECGs will be performed after the subject has been in the supine position for 3 minutes. All 
ECG recordings will be manually over-read on an ongoing basis by a cardiologist at the core 
ECG laboratory for QT measurement and QTc calculation using Fridericia’s formula (QTcF). 
The central cardiologist will interpret all ECGs with respect to PR interval, QRS duration, heart 
rate and R-R interval, QT and QTcF intervals and for arrhythmia, ischemia or any relevant 
finding. Details regarding the ECG recordings are described in a separate manual.
6.8.5.
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed as indicated in Section 5.
A central laboratory will be used for this study. The Principal Investigator or medically-qualified 
designee will review and assess all clinical laboratory results for each subject participating at 
their sites, and indicate whether the results are clinically significant. Repeat clinical safety 
laboratory evaluations should be performed if judged clinically appropriate by the PI or by a 
medically-qualified designee. The laboratory reports should be initialled and dated by the 
Investigator or medically-qualified designee to indicate that they have been reviewed. Any 
clinically significant abnormal laboratory result that is not part of the disease under study should 
be reported as a separate AE and should be followed to resolution (eg, stabilizes, returns to 
baseline, or improves and considered as no longer clinically significant).
Clinical laboratory evaluations will include:
Category
Parameters
Hematologya
Complete Blood Count (CBC): hematocrit, hemoglobin, platelets, red blood cell 
count (RBC), and white blood cell count (WBC) with differential (basophils, 
eosinophils, lymphocytes, monocytes, and neutrophils [percent and absolute 
count])
Serum Chemistry
Albumin, alanine aminotransferase (ALT; serum glutamic pyruvic transaminase 
[SGPT]), alkaline phosphatase, aspartate aminotransferase (AST; serum 
glutamic oxaloacetic transaminase [SGOT]), bicarbonate, blood urea nitrogen, 
calcium, chloride, creatinine, creatinine kinase, glucose, lactate dehydrogenase, 
magnesium, phosphorus, potassium, sodium, total bilirubin, direct bilirubin, 
indirect bilirubin, total cholesterol, total protein, triglycerides, lipase, and 
amylase
Dipstick Urinalysisb
Color, bilirubin, blood, glucose, ketones, leukocyte esterase, nitrite, pH, protein, 
specific gravity, and urobilinogen
Microscopic 
Urinalysis
RBCs, WBCs, casts, crystals, bacteria, and epithelial cells
Immunoglobulins
IgG, IgM, and IgA
Hormones
Testosterone, FSH, and LH
Collection of these analytes must occur at the same time of day (± 1 hour) for 
males only. For example, if collected at the Baseline Visit at 9 AM, subsequent 
samples must be collected between 8 and 10 AM.


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Category
Parameters
Hepatitis
Hepatitis B and C 
Serological tests for hepatitis B and C will be performed at the Screening Visit. 
HIV
Serological tests for HIV-1 and HIV-2 will be performed at the Screening Visit.
Inflammation
ESR and hs-CRP
Lupus 
autoantibodies
ANA, anti-dsDNAc, anti-Smith, anti-Ro, anti-LA, anti-ribonucleoprotein 
(RNP), and rheumatoid factord
Complement Panel
C3, C4, and CH50
Lupus 
antiphospholipid 
profile
Lupus anticoagulant, anti-cardiolipin antibodies, and beta-2–glycoprotein I
antibodies
a Subjects taking concomitant mycophenolate mofetil, 6-mercaptopurine, mycophenolic acid, azathioprine, or 
calcineurin inhibitors must have weekly hematology assessments between Visit 2 [Baseline] through Visit 3 
[Week 4] and Visit 8 [Week 24] through Visit 9 [Week 28]. In addition, these subjects must have hematology 
measurements two weeks after Visit 3 [Week 4], Visit 4 [Week 8], Visit 9 [Week 28], and Visit 10 [Week 32]).
b Use clean catch technique for urine sample.
c Anti-dsDNA will be collected at every visit in the Placebo-Controlled and Active Treatment Phase while ANA, 
anti-Smith, anti-Ro, anti-LA, and anti-ribonucleoprotein will be collected at Visits 1, 2, 8, and 15. In the Long-
Term Extension Phase, anti-dsDNA will be collected at Visits 18, 21, 24, 28, and in the Observational Follow-up  
Phase at Visit 29 while ANA, anti-Smith, anti-Ro, anti-LA, and anti-ribonucleoprotein will be collected at Visit 
28. 
d Rheumatoid factor will be assessed only at Screening (Visit 1).
6.8.6.
Pregnancy Test 
A pregnancy test (urine or serum) is required for all female subjects of childbearing potential
throughout the study as specified in Section 5. All FCBP are required to have 2 negative 
pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting IP. A serum or urine β-
HCG pregnancy test must be performed within 10 to 14 days prior to the start of IP and a
second pregnancy test (urine) must be performed within 24 hours before starting IP. The 
subject may not receive IP until the Investigator has verified that the results of these 
pregnancy tests are negative.
FCBP with reported regular cycles must have pregnancy testing weekly for the first 28 days of 
study participation and then every 28 days while on study, at study discontinuation, and at Visit
29 (Week 108) following IP discontinuation (if urine pregnancy test is positive at Visit 29 (Week 
108), a serum pregnancy test must be conducted to confirm result). Weekly pregnancy tests must 
be obtained between Visit 2 (Baseline) through Visit 3 (Week 4) and Visit 8 (Week 24) through 
Visit 9 (Week 28). The physician in concert with the subject should determine whether the 
subject has irregular menses. For those FCBP with menstrual cycles that are irregular, pregnancy 
testing must occur weekly (as described above) and then every 14 days while on study, at study 
discontinuation and at 14 and 28 days following study discontinuation. At every visit, the 
Investigator must verify that the results of these pregnancy tests are negative prior to providing 
the subject with IP.
Females who are not of childbearing potential (FNCBP) and do not require pregnancy testing or
birth control must provide sufficient evidence such as, but not limited to, history of


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hysterectomy, bilateral oophorectomy, and/or being postmenopausal for at least 24 consecutive 
months (that is, has not had menses at any time during the preceding 24 consecutive months).
6.8.7.
Pregnancy Prevention and Counseling
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted for all subjects as described in the Pregnancy Prevention Plan (provided separately).
Females of childbearing potential enrolled in this protocol must agree to use two reliable forms 
of contraception simultaneously or to practice complete abstinence (True abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence [eg, calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal 
are not acceptable methods of contraception.) from heterosexual contact during the following 
time periods related to this study: 1) for at least 28 days before starting CC-220; 2) while taking 
CC-220; 3) during dose interruptions; and 4) for at least 28 days after the last dose of CC-220. 
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. If the below contraception methods are not appropriate for 
the FCBP, she must be referred to a qualified provider of contraception methods to determine the 
medically effective contraception method appropriate to the subject. The following are examples 
of highly effective and additional effective methods of contraception:
Examples of highly effective methods:
Intrauterine device (IUD)
Hormonal (birth control pills, injections, implants, levonorgestrel-releasing intrauterine 
system [IUS], medroxyprogesterone acetate depot injections, ovulation inhibitory 
progesterone-only pills [eg, desogestrel]). Estrogen-free formulations are recommended.
Tubal ligation
Partner’s vasectomy
Examples of additional effective methods:
Male condom
Diaphragm
Cervical Cap
Male subjects must practice complete abstinence (True abstinence is acceptable when this is in 
line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg, calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable methods 
of contraception.) or agree to use a condom during sexual contact with a pregnant female or a 
FCBP while taking CC-220, during dose interruptions and for at least 90 days following the last 
dose of CC-220, even if he has undergone a successful vasectomy. 
6.8.8.
Hepatitis B and C
Hepatitis B and hepatitis C testing will be performed at Screening. The hepatitis screen includes 
testing for hepatitis B surface antigen and antibody, hepatitis B core antibodies (IgG/IgM), and 


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antibodies to hepatitis C. The Investigator should refer the subject to his/her general practitioner 
or other appropriate healthcare provider for further follow-up, if testing is positive.
6.8.9.
Human Immunodeficiency Virus 
The HIV testing will be performed at Screening unless prohibited by local health authority 
guidelines. The HIV test uses an antigen/antibody combination immunoassay that detects HIV-1 
and HIV-2 antibodies and HIV-1 p24 antigen to screen for established infection with HIV-1 or 
HIV-2 and for acute HIV-1 infection. The Investigator should refer the subject to his/her general 
practitioner or other appropriate healthcare provider for further follow-up and counseling (per the 
Investigator’s medical practice procedure and local guidelines), if testing is positive.
6.8.10.
QuantiFERON-TB
All subjects will be required to have a QuantiFERON-TB Gold at their Screening Visit to ensure 
they do not have active or latent mycobacterium tuberculosis infection. This test is an Interferon-
Gamma Release Assay which uses whole-blood to help diagnose Mycobacterium 
tuberculosis infection. Subjects with a QuantiFERON-TB Gold test result at Screening elevated 
to above normal as per the central laboratory will not be permitted to enter the study.
6.8.11.
Chest Radiograph
Subjects must have a normal chest radiograph. Results must be within normal limits or not 
clinically significant in order to allow a subject to enroll in the study. A chest radiograph should 
be taken prior to the Baseline Visit, when most of the eligibility criteria are met, so that results 
are available prior to the Baseline Visit. A posterior-anterior (PA) radiograph is required. A 
lateral view is strongly recommended unless prohibited by local health authority requirements.
Alternatively, PA or PA/lateral radiographs or chest CT scans that were taken within the 3 
months (or longer periods based on local health authority requirements) prior to the Screening 
Visit will be accepted for evaluation for participation in the study. Additional chest radiographs 
should be performed as indicated by local health authorities or treatment guidelines. Chest 
radiographs should be performed when clinically indicated. If the screening chest radiograph is 
indeterminate, please contact the medical monitor to discuss.
Note: If screening chest radiograph shows abnormalities with no significant changes from 
previous radiographs, then the subject may be considered for enrollment. Please contact the 
medical monitor to discuss prior to entry.
6.9.
Clinical Efficacy Assessments
Efficacy assessments should be conducted by the same qualified person throughout the study. 
Cutaneous Lupus Area and Severity Index (CLASI), Swollen and Tender Joint Counts, SLEDAI
2K, SLICC/ACR SLE Damage Index, PGA and BILAG 2004 assessments must be conducted by 
a physician, physician assistant, or qualified nurse practitioner. Efficacy assessments should be 
conducted by the same qualified person throughout the study. The CLASI, SLEDAI 2K, and 
BILAG 2004 assessments must be performed by a physician, physician assistant, or qualified 
nurse practitioner who has been certified through the online instrument training specific to the 
study. Any qualified personnel who has a valid certification through the LFA website will not be 
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It is recommended that health assessment questionnaires be completed prior to any other study 
activities so that responses most accurately reflect subjects’ experiences before the study visit. If 
the subject needs help in completing the questionnaires, assistance should only be provided by 
study staff and not by family members.
6.9.1.
Functional Assessment of Chronic Illness Therapy (FACIT) – Fatigue Scale
The FACIT-Fatigue scale (Yellin, 1997; Appendix H) is a 13-item self-administered 
questionnaire that assesses both the physical and functional consequences of fatigue. Each 
question is answered on a 5-point scale, where 0 means “not at all,” and 4 means “very much.” 
The total FACIT-Fatigue score ranges from 0 to 52. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9.3.
LupusPRO™
The LupusPRO™(Appendix K) is a disease targeted patient reported outcome tool for patients 
with SLE. It was developed from ethnically diverse US patients with SLE. It has been validated 
for use in the US. It has 49 items of which 30 items are for health related quality of life. The 
instrument has a 6 point Likert response format, where 0=None of the time, 1= A little of the 
time, 2= Some of the time, 3=Most of the time, 4= All of the time, and 5= Not applicable. Scores 
for this tool range from 0 (worst QoL) to 100 (best QoL) (Jolly, 2008; Cervera, 2009).
6.9.4.
HAQ-DI
The HAQ-DI (Appendix L; Fries, 1980) is a 20-question, self-administered instrument that 
measures the subject’s functional ability on a 4-level difficulty scale (0 to 3, with 0 representing 


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normal or no difficulty; and 3 representing an inability to perform). Eight categories of 
functioning are included: dressing, rising, eating, walking, hygiene, reach, grip, and usual 
activities (Bruce, 2003). This scale is sensitive to change and is a good predictor of future 
disability (Aletaha, 2006).
6.9.5.
SLEDAI 2K
The SLEDAI 2K score (Appendix B; Gladman, 2002) measures disease activity through 
assessment of 24 lupus manifestations using a weighted score of 1 to 8 points. A manifestation is 
recorded if it is present over the previous 30 days regardless of severity or whether it has 
improved or worsened. A SLEDAI 2K score of 3 to 4 points is representative of active disease 
and a decrease of 1 to 2 points is considered clinically meaningful. In addition to capturing 
changes in disease activity, the SLEDAI 2K captures the occurrence of SLE flares using the SLE 
Flare Index. The SLE Flare Index is defined by an increase in the SLEDAI of 3 or more points 
(mild or moderate flare) or a SLEDAI score greater than 12 (severe), a 0 to 3 visual analogue 
scale (VAS) with anchors for the physician global assessment (none, mild, moderate or severe 
flare) with an increase in 1 (for mild/moderate) or 2.5 (for severe) and adding NSAIDs or 
hydroxychloroquine (for mild) or steroids, but no more than 0.5 mg/kg/day and/or adding a new 
immunosuppressant (for severe) (Pope, 2014).  
6.9.6.
SLE Flare
The occurrence of SLE flares will be captured by the SLEDAI 2K, BILAG, and PGA. Subjects 
experiencing SLE flares should come to the site for an unscheduled visit. All flares will be 
adjudicated by reviewing the SLEDAI Flare index and BILAG in a blinded fashion for severity 
(mild, moderate, severe).
6.9.7.
British Isles Lupus Assessment Group 2004 (BILAG) 
The BILAG 2004 (Isenberg, 2005; Appendix C) is a composite index that is based on the Classic 
BILAG index. It is a clinical measure of lupus disease activity. This tool assesses the changing 
severity of clinical manifestations of SLE using an ordinal scale scoring system that contain 9 
systems (constitutional, mucocutaneous, neuropsychiatric, musculoskeletal, cardiorespiratory, 
gastrointestinal, ophthalmic, renal and hematological). Activity in each organ system is scored 
as: A=most active disease; B=intermediate activity; C=mild, stable disease; D=previous 
involvement, currently inactive; E=no previous activity.
6.9.8.
Physician’s Global Assessment (PGA)
The PGA (Appendix G; Furie, 2009) uses a visual analog scale with scores between 0 and 3 to 
indicate worsening of disease. The scoring is as follows:

0 = none

1 = mild disease

2 = moderate disease

3 = severe disease


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6.9.9.
CLASI Activity Score Assessment
The CLASI Activity Score (Appendix D; Albrecht, 2005) ranges from 0 to 70. To generate the 
activity score erythema is scored on a scale of 0 (absent) to 3 (dark red; 
purple/violaceous/crusted/hemorrhagic) and scale/hypertrophy are scored on a scale of 0 (absent) 
to 2 (verrucous/hypertrophic). Both the erythema and scale/hypertrophy scores are assessed in 13 
different anatomical locations. In addition, the presence of mucous membrane lesions is scored 
on a scale of 0 (absent) to 1 (lesion or ulceration), the occurrence of recent hair loss is captured 
(1=yes; 0=no) and non-scarring alopecia is scored on a scale of 0 (absent) to 3 (focal or patchy in 
more than one quadrant). To calculate the activity score, all scores for erythema, 
scale/hypertrophy, mucous membrane lesions and alopecia are added together. 
6.9.10.
CLASI Damage Score Assessment
The CLASI Damage Score (Appendix D; Albrecht, 2005) ranges from 0 to 56. To generate the 
damage score, dyspigmentation is scored on a scale of 0 (absent) to 1 (dyspigmentation) and 
scarring/atrophy/panniculitis are scored on a scale of 0 (absent) to 2 (severely atrophic scarring 
or panniculitis). Both the dyspigmentation and scarring/atrophy/panniculitis scores are assessed 
as usually lasting greater than or less than 12 months for the subject. If the dyspigmentation 
usually lasts greater than 12 months, the dyspigmentation scoring conducted for the 13 
anatomical areas is doubled. In addition, scarring of the scalp (judged clinically), is scored on a 
scale of 0 (absent) to 6 (affects the whole skull). To calculate the damage score, all scores for 
dyspigmentation, scarring/atrophy/panniculitis, and scarring of the scalp are added together. 
6.9.11.
Swollen and Tender Joint Count
Joint tenderness and swelling will be noted as “present” or “absent,” with no quantitation of 
severity. The 28 assessed joints are illustrated in Appendix F. In order to maintain consistency 
throughout the study, the same evaluator should perform the joint assessments for a given subject 
at a study site at each study visit.
6.9.12.
SLICC/ACR SLE Damage Index
The SLICC/ACR Damage Index (Appendix M; Stoll, 2004) measures irreversible impairment 
since onset of SLE which has to be present for at least 6 months. Damage is defined for 12 
separate organ systems: ocular (range 0-2), neuropsychiatric (0-6), renal (0-3), pulmonary (0-5), 
cardiovascular (0-6), peripheral vascular (0-5), gastrointestinal (0-6), musculoskeletal (0-7), skin 
(0-3), endocrine (diabetes) (0-1), gonadal (0-1) and malignancies (0-2). The maximum score for 
this assessment is 47 points.
6.9.13.
Photography
Photographic assessments may be done at selected sites in the United States to provide 
supportive evidence of efficacy as scheduled in Table 3. In order to be eligible for photography, 
subjects must have a CLASI activity score of at least 10 at Screening. Subjects with no Baseline 
photographs should not have subsequent photographs taken. The procedure for taking the 
photographs and processing photographs will be described in a separate procedure manual 
distributed to investigational sites performing photographic assessments. Photographic 


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assessments are an optional part of this study. Subjects enrolled at the selected photography sites 
will be asked to provide separate consent prior to being photographed.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
CC-220 has a chemical structure of 2,6-piperidinedione, 3-[1,3-dihydro-4-[[4-(4-
morpholinylmethyl)phenyl]methoxy]-1-oxo-2H-isoindol-2-yl]-, (3S)-, hydrochloride (1:1). It has 
a molecular weight of 485.96 g/mol. 
CC-220 will be provided by the sponsor as 0.15 mg (size #4), 0.3 mg (size #4), and 0.45 mg (size 
#3) formulated capsules (equivalent to 0.162 mg, 0.324 mg, and 0.486 mg hydrochloric acid salt, 
respectively) and will be labeled appropriately as investigational material. Excipients of the 
formulated capsules include anhydrous lactose, pregelatinized starch, stearic acid and gelatin 
capsules.
In addition, the sponsor will provide size #4 matching placebo identical in appearance to CC-220 
0.15 mg, and 0.3 mg, and size #3 matching placebo identical in appearance to CC-220 0.45 mg
formulated capsules labeled appropriately as investigational material.
Each daily dose will consist of one size #3 capsule (either placebo or 0.45 mg) and one size #4 
capsule (either placebo or 0.15 mg or 0.3 mg) depending on the assigned treatment.
7.2.
Treatment Administration and Schedule
Investigational product will be taken orally once daily without respect to food or drink at 
approximately the same time every day in the morning.
To maintain the blind at the site and subject level, the original individual subject treatment 
assignments at randomization will not be revealed to the Investigators until after the 52 Week 
database lock and after all final analyses are completed and the final results have been released.
Capsules of CC-220 will be counted at every visit starting at Visit 3 through the completion of 
the study. If a dose of IP is missed for the entire day, the subject should not take an extra dose 
the next day or take an unscheduled dose. Subjects who take more than the prescribed dose of IP 
should be instructed to contact study staff immediately and seek emergency medical care if 
needed.
Any interruption in the IP will not alter the current dose or dose interval, nor will the length of 
the study be extended to account for days of missed IP. 
The sponsor asks to be notified in advance of planned IP dosage interruptions or modifications; 
however, the decision to modify IP dosing will be based on the Investigator’s clinical judgment. 
7.2.1.
Overdose
Overdose, as defined for this protocol, applies to protocol-required dosing of the IP (CC-220) 
only. Therefore, for a drug to be subject to the overdose definition it must be both required and 
an IP. In this study the only required IP is CC-220 and placebo, hence the overdose definition 
will apply to only CC-220 (or matching placebo). Other required or optional non-IP intended for 
prophylaxis of certain side effects, to treat the disease, etc, are excluded from this definition. 
On a per dose basis, an overdose is defined as any amount over the protocol-specified dose of 
CC-220 given to a subject, regardless of any associated adverse events or sequelae.


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On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.
The reporting cutoff was intentionally set very low; the intent is to collect any deviation from the 
protocol dosing rules, and not to specify a medically meaningful cutoff based on PK, PD, or 
clinical data.
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the electronic case report form 
(eCRF). See Section 10.1 for the immediate reporting of adverse events associated with 
overdose.
7.2.1.1.
CC-220 Overdose
There is no information available about the appropriate dose of CC-220 in humans nor is there 
any available information regarding overdose. There is no experience in the management of 
human CC-220 overdose. In the event of overdose, subjects should be managed by symptomatic 
and supportive care. 
7.2.2.
Dose Modifications and Interruptions
This is a dose-finding study; therefore, no dose reductions or increases will be permitted. 
However, in the event a subject experiences a study drug-related adverse event (Section 11.2.3)
or abnormal laboratory test (Section 11.2.2), a temporary IP interruption may be required. The 
Sponsor should be notified in advance of the dosage interruption if possible; however, the 
decision to interrupt IP dosing will be based on the Investigator’s clinical judgment. If a subject 
missed 4 or more consecutive days of dosing, the Sponsor must be contacted to decide whether 
dosing should resume or whether the subject should be terminated from the study, return for an 
Early Termination Visit, and enter into the Observational Follow-up Phase. If a dose of IP is 
missed, it should be taken as soon as possible on the same day. If the dose is missed for the entire 
day, the subject should not take an extra dose the next day or take an unscheduled dose.
7.3.
Method of Treatment Assignment
Designated study personnel at the investigational sites will be assigned password protected, 
coded identification, which give them authorization to log on to the IRT to screen and/or 
randomize subjects, as well as re-supply and discontinue subjects from the study.
After the informed consents have been signed, subjects will be assigned a subject identification 
(ID) by IRT consisting of a 7-digit number where the first 3 digits are the site ID number 
concatenated with a 1 and then a 3-digit consecutive run-in number. For example, the first 
subject entering the study at Site 002 will receive a Subject ID number 0021001. In cases were a 
subject is screen-failed and later rescreened, the original subject number, concatenated with a “2” 
is assigned (eg, Subject ID number 0022001). In the event the subject is screen-failed for a 
second time and then rescreened, the original number, concatenated with a “3” is assigned (eg, 
Subject ID number 0023001).  Confirmation of the subject ID will be sent to the investigational 
site, the Sponsor and/or its representative.
At the Baseline Visit (Day 1), the system will present a menu of questions by which the study 
personnel will identify the subject and confirm eligibility. When all questions have been 


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answered, subjects who meet the eligibility criteria shall be randomized by the IRT to receive 
either the assigned CC-220 dose or placebo.
Authorized study personal will log into the IRT at each study visit whereupon site personnel will 
be notified which coded kits to dispense to the subject. The pharmacy or authorized study 
personnel at the investigational site will dispense coded investigational product kits in 
accordance with the medication identification number(s) assigned by the IRT. 
7.4.
Packaging and Labeling
The label(s) for IP will include Sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
The Investigator(s) or designee (s) is responsible for taking an inventory of each IP shipment 
received. All drug shipments will be acknowledged by the site on the IRT verifying the 
information contained on the shipping acknowledgement form contained in the shipment/on the 
IRT shipment acknowledgement screen. The Investigator(s) or designee (s) will retain a copy of 
the shipping acknowledgement form in the study file. 
At the investigational site, all IP will be stored in a locked, safe area to prevent unauthorized 
access.
Investigational product should be stored according to instructions on the labeled drug product, 
away from direct sunlight and protected from excessive heat and cold.
7.5.
Investigational Product Accountability and Disposal 
The Sponsor (or designee) will review with the Investigator and relevant site personnel the 
process for investigational product and/or medical device materials, if applicable, return, 
disposal, and/or destruction including responsibilities for the site versus the Sponsor (or 
designee).
Site staff must make every effort to retrieve all IP supplies from subjects. 
7.6.
Investigational Product Compliance
Accurate recording of all IP administration (including dispensing and dosing) will be made in the 
appropriate section of the subject’s eCRF and source documents.
Capsules of CC-220 will be counted at every visit starting at Visit 3 through the completion of 
the study. Overall compliance is defined as taking between 75% and 120% of dispensed IP.  In 
the event of gross compliance problems (eg, missing 4 or more consecutive days of dosing in the 
absence of a clinically significant adverse event or taking less than 75% or greater than 120% of 
the doses between study visits) the sponsor must be contacted to decide whether dosing should 
resume or whether the subject should be terminated from the study and enter into the 
Observation Follow-up Period.












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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a Phase 2, randomized, placebo-controlled, double-blind study to evaluate efficacy and
safety of three doses of CC-220 in subjects with systemic lupus erythematosus. The treatment 
assignment will be stratified by Baseline corticosteroid dose (≥10 mg/d and < 10 mg/d) and 
Screening SLEDAI 2K score (≥10 points and < 10 points) (Furie, 2016). These proposed strata 
are to ensure that patients with more severe disease are balanced across treatment groups. This 
study consists of a 24-week Placebo-Controlled Treatment Phase, a 28-week Double-Blinded 
Active Treatment Phase, a Long-term Extension Phase of up to 52 weeks, and a 4-week 
Observational Follow-up Phase with an additional 12-week Observational Follow-Up Visit for 
males.
This section outlines the statistical analysis strategy and details will be documented in a separate 
Statistical Analysis Plan (SAP).
9.2.
Study Population Definitions
The safety population will include all randomized subjects who received at least one dose of IP.  
The analysis of safety data in this study will be based on the safety population and subjects will 
be included in the treatment group they actually received.
The intent-to-treat (ITT) population will include all randomized subjects who receive at least one 
dose of IP.  The analysis of efficacy data in this study will be based on the ITT population unless 
otherwise specified and subjects will be included in the treatment group to which they are 
randomized.
The Per Protocol (PP) population will include all randomized subjects who received at least one 
dose of IP, and have no important protocol deviations that may substantially affect the efficacy 
results. The final determination of the important protocol deviation criteria will be made prior to 
the unblinding of the database and will be separately documented.
9.3.
Sample Size and Power Considerations
Approximately 280 subjects will be randomized 2:2:1:2 to receive CC-220 (0.45 mg QD, 0.3 mg 
QD or 0.15 mg QD) or placebo. There will be approximately 80 subjects randomized into each 
CC-220 0.45 mg QD, CC-220 0.3 mg QD, and placebo arm and approximately 40 subjects into
the CC-220 0.15 mg QD arm. 
A sample size of 80 subjects in the CC-220 0.45 mg QD, CC-220 0.3 mg QD, and placebo dose 
groups provides approximately 80% power to detect a true 21% difference (55% versus 34%) 
between one of the CC-220 group and the placebo group, using a two-group chi-square test with 
a 0.1 two-sided significance level, for the proportion of subjects achieving an SRI(4) response at 
Week 24 as defined in Section 2. Based upon clinical trials of Belimumab and Anifrolumab in a 
similar patient population with SLE, the observed placebo response rate ranged from 34% to 
44%. A 21% treatment effect provides a clinically meaningful improvement compared to 
placebo and approximately 50% higher than the treatment differences achieved in published 
trials in SLE (Human Genome Sciences, Inc., 2010; Furie, 2016). 


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The sample size of the 0.15 mg QD dose group is limited to 40 subjects to assess and determine 
the lowest effective dose and limit the chance of a false negative result. Details of the rationale 
will be described in the statistical analysis plan (SAP).
9.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations. Medical history data will be summarized using frequency tabulations by system 
organ class and preferred term.
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent by study phase. A 
summary of subjects enrolled by site will be provided. Protocol violations and deviations will be 
summarized using frequency tabulations.
9.6.
Efficacy Analysis
No multiplicity adjustment will be conducted for this Phase 2 study.  However, in the absence of 
multiplicity adjustment, p-values and confidence intervals (CIs) from any efficacy analyses 
should be interpreted with caution.  All efficacy analyses will be conducted using the ITT
population. The primary efficacy endpoint analysis will be conducted using a PP population in 
addition to the ITT population (Section 9.2). 
9.6.1.
Double-blind Placebo-controlled Phase 
The primary efficacy endpoint is the SRI(4) response at Week 24.  The proportion of subjects 
who achieve SRI(4) response at Week 24 in each of the CC-220 0.45 mg QD, 0.3 mg QD or 0.15
mg QD groups, will be compared with placebo group using a Cochran-Mantel-Haenszel (CMH) 
test controlling for corticosteroid dose (≥ 10 mg/d and < 10 mg/d) at Baseline and SLEDAI 2K 
score (≥ 10 points and < 10 points) at Screening. P-values and 95% confidence intervals for the 
comparisons will be provided. Missing data for binary endpoints will be handled by 
nonresponder imputation (NRI), by which a subject will be considered a nonresponder at a given 
time point if the subject 1) does not have sufficient data (including the Baseline data for the 
endpoints assessing the change from Baseline) assessed within the analysis visit window for 
response determination, or 2) has had an event of treatment failure (as per the prespecified 
criteria) before the date of assessment (or the date of the last assessment in the case of a 
composite endpoint involving multiple criteria that may be assessed on different dates) for the 
time point.
Binary variables such as ≥50% reduction in CLASI activity score at Week 24 will be analyzed
in a similar way to the primary efficacy endpoint.
For continuous endpoints assessed by mean change or percent change from Baseline, a 
longitudinal data analysis (LDA) model (in the absence of severe departures from normality) or 
multiple imputation in conjunction with a robust regression that uses M-estimation (in the 
presence of severe departures from normality) will be used.  The LDA model assumes a common 


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mean across treatment groups at Baseline and a different mean for each treatment group at each 
of the post-baseline time points.  In this model, the response vector consists of the Baseline and 
post-baseline values for the analysis of the change from Baseline, or the Baseline value and the 
post-baseline percent changes from Baseline for the analysis of the percent change from 
Baseline.  Time is treated as a categorical variable so that no restriction is imposed on the 
trajectory of the means over time.  Where specified, the model will also adjust for randomization 
stratification factors (corticosteroid dose [≥ 10 mg/d and < 10 mg/d] at Baseline, SLEDAI 2K 
score [≥ 10 points and < 10 points] at Screening).
The time-to-event endpoints will be analyzed by the Kaplan-Meier method, the stratified log-
rank test, and the Cox proportional hazards model adjusting for treatment group and 
randomization stratification factors.
9.6.2.
Double-blinded Active Treatment Phase and Long-term Extension Phase
The efficacy endpoints in the Double-Blinded Active Treatment Phase will be analyzed in a 
similar way to those in the Placebo-Controlled Treatment Phase, except that no formal treatment 
comparisons will be performed between the CC-220 doses. The efficacy endpoints in the Long-
term Extension Phase will be summarized.
9.6.3.
Subgroup Analysis
Subgroup analyses for SRI(4) response will be based upon Baseline demographic and disease 
characteristics. All subgroup analyses will be summarized by individual and pooled (0.45 mg 
QD and 0.3 mg QD) treatment groups.
9.7.
Safety Analysis
The safety analyses will be performed using the safety population as defined in Section 9.2.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system. Adverse events occurring during the 24-week Placebo-Controlled Phase, the 28-
week Double-Blinded Active Treatment Phase, and the 4-week Observational Follow-up Phase
for females and 12-week Observational Follow-up Phase for males will be tabulated. All adverse 
events will be summarized by system organ class, preferred term, severity and relationship to IP. 
Adverse events leading to death or to discontinuation from treatment and serious adverse events 
will also be tabulated. In the by-subject analysis, a subject having the same event more than once 
will be counted only once and by greatest severity.
Laboratory data will be summarized by visit descriptively (n, mean, median, standard deviation, 
minimum, and maximum). In addition, shift tables showing the number of subjects with values 
low, normal, and high compared to the normal references pretreatment versus posttreatment will 
be provided. Shift tables will also be provided for ECGs.
Vital sign measurements will be summarized by visit descriptively (n, mean, median, standard 
deviation, minimum, and maximum). In addition, shift tables showing the number of subjects 
with values low, normal, and high compared to the normal reference ranges pretreatment versus 
posttreatment will be provided.


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9.8.
Interim Analysis 
Unblinded interim analyses may be performed by a group that is independent of the study team. 
The purpose of the interim analysis is to determine if any treatment group should be 
discontinued, and whether to terminate the study for futility. The interim analysis will be 
conducted after approximately 50 percent of the subjects have completed or discontinued prior to 
the Week 24 Visit. The details of this analysis including the scope of distribution will be 
documented in a separate charter/analysis plan.
9.9.
Other Topics
 
 
 
 
9.9.4.
Independent External Data Monitoring Committee
Although the Sponsor study staff will monitor safety on an ongoing basis throughout the study, 
formal blinded safety assessments of the relevant study data will be performed by an external 
independent Data Monitoring Committee (DMC). The DMC will review unblinded data to 
evaluate safety during the study and data from the interim analysis for futility. The DMC is 
comprised of independent physician experts and a statistician for whom there is no identified 
conflict of interest. The DMC will be convened regularly, at least once a year, or ad hoc at the 
request of the SMT. Recommendations of the DMC based on the overall benefit/risk evaluation 
may include proceeding with the study per protocol, proceeding with the study with 
modification, or study suspension. The scope, conduct, membership, processes, and 
accountabilities of the DMC are specified in the DMC charter.


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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (eg, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Worsening of a subject’s SLE or SLE flares should be considered as worsening of the disease 
under study and not recorded as an AE unless the event meets the definition of a SAE 
(Section 6.8.1).
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF. (See Section 7.2.1 for the definition of overdose.) Any sequela 
of an accidental or intentional overdose of an investigational product should be reported as an 
AE on the AE CRF. If the sequela of an overdose is an SAE, then the sequela must be reported 
on an SAE report form and on the AE CRF. The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and CRF but should not be reported 
as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary.  There is no known specific antidote for CC-220 overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 28 days after the last dose of IP as well as those SAEs made known to the Investigator at 
any time thereafter that are suspected of being related to IP. AEs and SAEs will be recorded on 
the AE page of the CRF and in the subject’s source documents. All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form.  
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:


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
Results in death;

Is life-threatening (eg, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);

Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 

routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.

hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

a procedure that is planned (eg, planned prior to start of treatment on study); must be 
documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from Baseline. 

emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form 
must be completed.


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For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/ intensity of the event. 
Mild

Asymptomatic or mild symptoms; clinical or diagnostic observations only

Intervention not indicated

Activities of daily life (ADLs) minimally or not affected

No or minimal intervention/therapy may be required 
Moderate 

Symptom(s) cause moderate discomfort

Local or noninvasive intervention indicated

More than minimal interference with ADLs but able to carry out daily social and 
functional activities.

Drug therapy may be required
Severe (could be non-serious or serious) 

Symptoms causing severe discomfort/pain

Symptoms requiring medical/surgical attention/intervention

Interference with ADLs including inability to perform daily social and functional 
activities (eg, absenteeism and/or bed rest)

Drug therapy is required
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.


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10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by the Sponsor, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation or interruption, as appropriate) and report if concomitant and/or additional 
treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

results in discontinuation from the study;

requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or


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
is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All male and female subjects should be counseled about pregnancy precautions and risks of fetal 
exposure as described in the Pregnancy Prevention Plan (provided separately).
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.  
In the event of a pregnancy occurring in a female subject of childbearing potential or female 
partner of a male subject, Celgene will follow up with the clinical Investigator each trimester of 
pregnancy and for 1 year following the birth of the infant (if applicable). Please reference the 
pregnancy information consent (permission) forms for data collection for additional information.
The exposure of any pregnant female (eg, caregiver, pharmacist, study coordinator or monitor) to 
CC-220 is also an immediately reportable event.
10.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on CC-220, or within 28 days of the subject’s last dose of CC-220, are considered immediately 
reportable events.  Investigational product is to be discontinued immediately and the subject 
instructed to return any unused portion of the IP to the Investigator. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety immediately by 
email, phone or facsimile, or other appropriate method, using the Pregnancy Initial Report Form, 
or approved equivalent form.  
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.


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All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
10.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP 
should notify the Investigator, and the pregnant female partner should be advised to call their 
healthcare provider immediately.  
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg, via email), using the SAE Report Form, or approved equivalent 
form.  This instruction pertains to initial SAE reports as well as any follow-up reports.
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP) or any 
SAE made known to the Investigator at any time thereafter that are suspected of being related to 
IP.  Serious adverse events occurring prior to treatment (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with the Sponsor and the IRB/EC.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to CC-220 based on the Investigator Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.


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For countries within the European Economic Area, the Sponsor or its authorized representative 
will report in an expedited manner to Regulatory Authorities and Ethics Committees concerned, 
SUSARs in accordance with Directive 2001/20/EC and the Detailed Guidance on collection, 
verification and presentation of adverse reaction reports arising from clinical trials on 
investigational products for human use (ENTR/CT3) and also in accordance with country-
specific requirements.  
The Sponsor or its authorized representative shall notify the Investigator of the following 
information:

Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (eg, SUSAR);

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with the Sponsor and the IRB/EC.  (See Section 14.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.


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11.
DISCONTINUATIONS
11.1.
Discontinuations
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study:

Adverse event

Lack of efficacy

Non-compliance with study drug

Withdrawal of consent by subject

Study terminated by the sponsor

Protocol violation

Death

Lost to follow-up

Other (to be specified on the CRF)
The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor. However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
11.2.
Investigational Drug Interruption and Stopping Rules
11.2.1.
Pregnancy
Any subject who is pregnant or has a positive pregnancy test must be discontinued immediately 
from the study. The subject must complete an Early Termination Visit as soon as possible and 
enter the Observational Follow-up Phase.
Any subject who has a borderline positive serum pregnancy test must hold IP and repeat the 
serum pregnancy test. If the repeat pregnancy test remains borderline, consult the Medical 
Monitor.
If pregnancy or a positive pregnancy test occurs in the partner of a male subject, the Investigator 
must be notified immediately.
11.2.2.
Laboratory 

Absolute Neutrophil Count (ANC) < 500 cells/μL (with or without signs or symptoms 
of infection):
o
IP must be held immediately and the neutrophil count retested as soon as 
possible, preferably within 3 days. If the retest is < 500 cells/μL, the subject 


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must be discontinued from the study. If the retest is ≥ 500 cells/μL, the subject 
should continue to hold IP until the ANC rises above 1000 cells/μL, while 
retesting the neutrophil counts weekly, or as determined necessary based on 
the level of neutropenia. The IP can be resumed once the neutrophil count is ≥ 
1000 cells/μL.

ANC ≥ 500 cells/μL and < 1000 cells/μL without signs or symptoms of infection:
o
IP should be held until the ANC rises above 1000 cells/μL, while retesting the 
neutrophil counts weekly, or as determined necessary based on the level of 
neutropenia. If the ANC falls < 500 cells/μL, the subject must be discontinued 
from the study. The IP can be resumed once the neutrophil count is ≥ 1000 
cells/μL. 

ANC ≥ 500 cells/μL and < 1000 cells/μL with signs or symptoms of infection:
o
IP must be held immediately, and the neutrophil count retested as soon as 
possible, preferably within 3 days. The Investigator should discuss with the 
Medical Monitor if the subject should continue study participation.

If the neutrophil count drops repeatedly below 1000 cells/μL after IP is resumed, or 
the neutrophil count remains below 1000 cells/μL after 4 weeks off IP, the 
Investigator should discuss with the Medical Monitor if the subject should continue 
study participation.

If growth factors must be administered during any IP dose interruption triggered by 
low ANC, the subject should be discontinued from the study.

Subjects who are discontinued from the study must complete an Early Termination 
Visit as soon as possible, and enter the Observational Follow-up Phase.
For any questions regarding abnormal laboratory values, the investigator may contact the 
Medical Monitor.
11.2.3.
AEs/SAEs
Subjects who develop one of the following AEs/SAEs must be discontinued:

A thromboembolic event (eg, deep vein thrombosis, pulmonary embolism, thrombotic 
cerebrovascular or cardiovascular events). In such events, an antiphospholipid panel 
should be collected, if possible, before initiation of any therapy.
Subjects who develop one of the following AEs/SAEs, should suspend IP and contact the 
Medical Monitor to discuss continued eligibility of the subject:

Recurrent infections or systemic opportunistic infections requiring hospitalization
and/or parenteral antibiotics 

Life-threatening or disabling rash or blistering

Subjects may have a skin biopsy to confirm if the rash is not a manifestation 
of the disease under study (SLE). 

Uveitis or other clinically significant ophthalmological findings


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11.2.4.
Study Stopping Criteria
In the event that > 3% of subjects exposed to CC-220 experience a ≥ Grade 3 thromboembolic 
event or > 5% of subjects exposed to CC-220 experience a ≥ Grade 2 thromboembolic event (as 
defined by CTCAE version 4.03) (Appendix Q):

All screening and randomization activities will be suspended 

IP will be held for all enrolled subjects

The DMC will be convened to assess the risk/benefit of IP. The final decision on 
study continuation will be made by the Sponsor in consultation with the DMC.


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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call the 
Sponsor/contract research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
The blind must not be broken during the course of the study unless in the opinion of the 
Investigator, it is absolutely necessary to safely treat the subject.  If it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued if, in the opinion of 
the Investigator, continuing IP can negatively affect the outcome of the subject’s treatment.
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, the Investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject. 
The Investigator should ensure that the code is broken only in accordance with the protocol. The 
Investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the Investigator in the 
subject’s source documentation.
Emergency unblinding should only be performed by the Investigator or designee as indicated in 
the Delegation of Authority log. The Investigator or designee will log into the IRT to perform 
emergency unblinding in order to obtain the subject’s unblinded dose information.


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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator abide by GCP, as described in ICH Guideline E6 and in 
accordance with the general ethical principles outlined in the Declaration of Helsinki. The study 
will receive approval from an IRB/EC prior to commencement. The Investigator will conduct all 
aspects of this study in accordance with applicable national, state, and local laws of the pertinent 
regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Sponsor staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Sponsor information. The Investigator should maintain 
a list of Sub-Investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by the Sponsor on public registry websites) is considered Sponsor
confidential information.  Only information that is previously disclosed by the Sponsor on a 
public registry website may be freely disclosed by the Investigator or its institution, or as 
outlined in the Clinical Trial Agreement.  The Sponsor protocol, amendment and IB information 
is not to be made publicly available (for example on the Investigator’s or their institution’s 
website) without express written approval from the Sponsor.  Information proposed for posting 
on the Investigator’s or their institution’s website must be submitted to the Sponsor for review 
and approval, providing at least 5 business days for review.
At the time results of this study are made available to the public, the Sponsor will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.


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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
The Sponsor affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). The Sponsor
requires the Investigator to permit the Sponsor's representatives and, when necessary, 
representatives from regulatory authorities, to review and/or copy any medical records relevant 
to the study in accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Sponsor’s Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
IP can only be supplied to an Investigator by the Sponsor or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 


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the Sponsor or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by the Sponsor and 
the IRB/EC prior to use.  
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible; 

Periodic reports on the progress of the study;

Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
The Sponsor reserves the right to terminate this study prematurely at any time for reasonable 
medical or administrative reasons. Any premature discontinuation will be appropriately 
documented according to local requirements (eg, IRB/EC, regulatory authorities, etc).
In addition, the Investigator or the Sponsor has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:

Unsatisfactory enrollment;

GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.


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14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
14.2.
Data Management
Data will be collected via CRF and entered into the clinical database per the Sponsor’s Standard 
Operating Procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team.  Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary.  Resolutions 
to these issues will be reflected in the database.  An audit trail within the system will track all 
changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:

Signed ICFs for all subjects;

Subject identification code list, screening log (if applicable), and enrollment log;

Record of all communications between the Investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the Investigator, the Sponsor, and their 
authorized representative(s);

List of Sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of CRFs (if paper) and of documentation of corrections for all subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc.); 


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
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify the Sponsor if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from the Sponsor prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask the 
Sponsor for permission to make alternative arrangements. Details of these arrangements should 
be documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.


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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by the Sponsor or its authorized 
representative for compliance with applicable government regulations with respect to current 
GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
The Sponsor ensures that appropriate monitoring procedures are performed before, during and 
after the study.  All aspects of the study are reviewed with the Investigator and the staff at a 
study initiation visit and/or at an Investigators’ Meeting.  Prior to enrolling subjects into the 
study, a Sponsor representative will review the protocol, CRFs, procedures for obtaining 
informed consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring 
will include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Sponsor representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within the Sponsor.  Representatives of this unit will conduct audits of clinical 
research activities in accordance with Sponsor SOPs to evaluate compliance with Good Clinical 
Practice guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, EMA, Health Canada) and 
company authorized representatives.  The Investigator should make every effort to be available 
for the audits and/or inspections.  If the Investigator is contacted by any regulatory authority 
regarding an inspection, he/she should contact the Sponsor immediately.
15.3.
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
purity, or performance of any drug product manufactured by or on behalf of Celgene Corporation 
after it is released for distribution. The PQCs may reduce the usability of the product for its 
intended function or affect performance of the product and therefore, pose a significant risk to 
the patient. Examples of PQCs include (but are not limited to): mixed product, mislabeling, lack 


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of effect, seal/packaging breach, product missing/short/overage, contamination, suspected 


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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by the Sponsor on public registry websites, is considered 
Sponsor confidential information and is not to be used in any publications.  Sponsor protocol-
related information proposed for use in a publication must be submitted to the Sponsor for 
review and approval, and should not be utilized in a publication without express written approval 
from the Sponsor, or as described in the Clinical Trial Agreement.
The Sponsor will ensure Celgene-sponsored studies are considered for publication in the 
scientific literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this 
applies to results from all Phase 3 clinical studies, and any other study results of significant 
medical importance.  This also includes results relating to investigational medicines whose 
development programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.  
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.








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18.
APPENDICES
APPENDIX A. ABBREVIATIONS
Table 7:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ACR
American College of Rheumatology
ADLs
Activities of daily living
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
ANA
Antinuclear antibody
ANC
Absolute neutrophil count
APS
Antiphospholipid Syndrome
AST
Aspartate aminotransferase (SGOT)
ATEP
Active Treatment Extension Phase
AUC
Area under the curve
β-hCG
β-subunit of human chorionic gonadotropin
BILAG
British Isles Lupus Assessment Group
CBC
Complete blood count
CD
Cluster of differentiation
CFR
Code of Federal Regulations
CI
Confidence interval
CLASI
Cutaneous Lupus Area and Severity Index
Cmax
Maximum plasma concentration of drug
CMH
Cochran-Mantel-Haenszel
CNS
Central nervous system
CPPCP
Celgene Pregnancy Prevention Counseling Program
CRBN
Cereblon
CRF
Case report form
CT
Computed tomography
DMC
Data Monitoring Committee
ds-DNA
Double-stranded deoxyribonucleic acid
EC
Ethics Committee


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Table 7:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
ESR
Erythrocyte sedimentation rate
FACIT
Functional Assessment of Chronic Illness Therapy
FCBP
Female of child bearing potential
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
HAQ-DI
Health assessment questionnaire – disability index
HIV
Human immunodeficiency virus
Hs-CRP
High sensitivity – c-reactive protein
IA
Intra-articular
ICF
Informed consent form
ICH
International Council for Harmonisation
ID
Identification 
IFN
Interferon
Ig
Immunoglobulin
IKZF
Ikaros
IL
Interleukin
IM
Intramuscular
IND
Investigational New Drug
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-treat
IV
Intravenous
LDA
Longitudinal data analysis
LH
Luteinizing hormone


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Table 7:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
LupusPRO
Lupus patient reported outcome
MAF
Minor allele frequency
MCS
Mental Component Summary 
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
mRNA
Messenger ribonucleic acid
NSAID
Nonsteroidal anti-inflammatory drug
PA
Posterior-anterior
PBMCs
Peripheral blood mononuclear cells
PCS
Physical Component Summary
PD
Pharmacodynamic
pDC
Plasmacytoid dendritic cell
PG
Pharmacogenetic
PGA
Physician’s Global Assessment
PK
Pharmacokinetic
PO
Oral
PP
Per protocol
PQC
Product Quality Compliant
OCS
Oral corticosteroid dose
QD
Once a day
QOL
Quality-of- life
OR
Odds ratio
RBC
Red blood cell
RNP
Ribonucleoprotein
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SF-36
Short Form-36


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Table 7:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SLE
Systemic lupus erythematosus
SLEDAI (2K)
Systemic Lupus Erythematosus Disease Activity Index (2K)
SLICC/ACR 
Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology 
SMT
Safety management team
SNP
Single nucleotide polymorphism
SOP
Standard operating procedure
SRI
Systemic lupus erythematosus Responder Index
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Half-life
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
Tfh
Follicular helper T cells
Th
T cell helper
TNF-α
Tumor necrosis factor-alpha
ULN
Upper limit of normal
US
United States 
VAS
Visual analog scale
WBC
White blood cell 
































































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SAP_001.pdf: 
Official Title of Study: 
A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF CC-220 IN SUBJECTS WITH 
ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS 
NCT Number: NCT03161483 
Document Date (Date in which document was last revised): June 20, 2019 


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-002
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STATISTICAL ANALYSIS PLAN
A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF CC-220 IN SUBJECTS WITH 
ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS
STUDY DRUG:
CC-220
PROTOCOL NUMBER:
CC-220-SLE-002
DATE FINAL:
20 Jun 2019
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.


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TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
2.
INTRODUCTION..................................................................................................10
3.
STUDY OBJECTIVES...........................................................................................11
4.
INVESTIGATIONAL PLAN .................................................................................12
4.1.
Overall Study Design and Plan ...............................................................................12
4.2.
Study Endpoints .....................................................................................................13
4.2.1.
Primary Endpoint....................................................................................................13
4.2.2.
Secondary Endpoints ..............................................................................................14
4.2.4.
Safety Endpoints.....................................................................................................31
4.3.
Stratification, Randomization, and Blinding............................................................36
4.4.
Sample Size Determination.....................................................................................36
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................37
5.1.
Reporting Conventions ...........................................................................................37
5.2.
Safety Analysis Periods ..........................................................................................37
5.3.
Time Points ............................................................................................................39
5.3.1.
Screening Value and Baseline Value Definitions ....................................................39
5.3.2.
Analysis Visit Windows .........................................................................................39
5.4.
Analysis Populations ..............................................................................................40
5.4.1.
Intent-to-treat Population........................................................................................40
5.4.2.
Safety Population....................................................................................................40
5.4.3.
Per-protocol Population ..........................................................................................40
5.4.5.
CC-220 Subjects as Randomized Population...........................................................40
5.4.6.
CC-220 Subjects as Treated Population ..................................................................40
5.4.7.
Extension Phase Population....................................................................................41
5.5.
Missing Data ..........................................................................................................41
5.6.
Treatment Failures..................................................................................................44
6.
SUBJECT DISPOSITION......................................................................................45


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7.
PROTOCOL DEVIATIONS ..................................................................................46
8.
DEMOGRAPHIC AND BASELINE CHARACTERISTICS..................................47
8.1.
Demographic and Baseline Characteristics..............................................................47
8.2.
Medical History......................................................................................................50
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................52
9.1.
Treatment Duration.................................................................................................52
9.2.
Overdose ................................................................................................................52
9.3.
Treatment Compliance............................................................................................52
10.
EFFICACY ANALYSIS ........................................................................................54
10.1.
Multiplicity.............................................................................................................54
10.2.
Primary Endpoint....................................................................................................55
10.3.
Secondary Endpoints ..............................................................................................58
10.3.1.
SLEDAI 2K............................................................................................................58
10.3.2.
CLASI....................................................................................................................59
10.3.3.
BILAG 2004...........................................................................................................59
10.3.4.
PGA .......................................................................................................................59
10.3.5.
Joint Counts............................................................................................................61
10.3.6.
Fatigue ...................................................................................................................61
10.3.7.
Corticosteroid Reduction ........................................................................................61


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10.5.
Subgroup Analysis..................................................................................................74
11.
SAFETY ANALYSIS ............................................................................................76
11.1.
Adverse Events.......................................................................................................76
11.2.
Clinical Laboratory Tests........................................................................................77
11.3.
Vital Signs and Weight...........................................................................................77
11.4.
ECG .......................................................................................................................78
 
13.
INTERIM ANALYSIS...........................................................................................82
14.
CHANGES TO THE STATISTICAL SECTION OF THE PROTOCOL ................83
16.
APPENDICES........................................................................................................85
APPENDIX A.
ANALYSIS VISIT WINDOWS ....................................................................86
APPENDIX B.
HANDLING OF PARTIAL OR COMPLETELY MISSING DATES ............92
APPENDIX C.
DERIVATIOIN OF DAILY ORAL CORTICOSTEROID DOSES................94
APPENDIX D.
LABORATORY MARKED ABNORMALITY CRITERIA ..........................95
APPENDIX E.
VITAL SIGNS MARKED ABNORMALITY CRITERIA .............................96
APPENDIX F.
ECG POTENTIALLY CLINICALLY SIGNIFICANT 
VALUES/CHANGES FROM BASELINE .............................................................97


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LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2:
Study Objectives.....................................................................................................11
Table 3:
Analysis Visit Windows .........................................................................................86
Table 4:
Imputation Rules for Partial or Completely Missing Start Dates of Adverse 
Events.....................................................................................................................93
Table 5:
Conversions to Prednisone-equivalent Doses ..........................................................94
Table 6:
Laboratory Marked Abnormality Criteria................................................................95
Table 7:
Vital Signs Marked Abnormality Criteria................................................................96
Table 8:
ECG Potentially Clinically Significant Values/Changes from Baseline ...................97
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................13




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1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation
Description
ACR
American College of Rheumatology
AE
Adverse event
ALT
Alanine aminotransferase/ serum glutamic-pyruvic transaminase (SGPT)
AST
Aspartate aminotransferase/ serum glutamic-oxaloacetic transaminase (SGOT)
ATC
Anatomical Therapeutic Chemical
AUC
Area Under Curve
BILAG
British Isles Lupus Assessment Group 2004
BMI
Body mass index
CI
Confidence interval
CLASI
Cutaneous Lupus Area and Severity Index
CMH
Cochran-Mantel-Haenszel
CP
Conditional power
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DMC
Data Monitoring Committee
ds-DNA
Double-stranded deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
ESR
Erythrocyte sedimentation rate
Hgb
Hemoglobin
hs-CRP
High sensitivity C-reactive protein
IFN
Interferon
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M


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Abbreviation
Description
IKZF
Ikaros
IL
Interleukin
IP
Investigational product
ITT
Intent-to-treat
LupusPRO
Lupus patient reported outcome
MCMC
Markov Chain Monte Carlo 
MCS
Mental Component Summary
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
mRNA
Messenger ribonucleic acid
PD
Pharmacodynamic
pDC
Plasmacytoid dendritic cell
PG
Pharmacogenetic
PGA
Physician’s Global Assessment
PK
Pharmacokinetic
PP
Per protocol
PCS
Physical Component Summary
PT
Preferred term
QD
Once daily
SAP
Statistical analysis plan
SD
Standard deviation
SE
Standard error 
SF-36
Short Form 36
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SLE
Systemic lupus erythematosus
SLEDAI
Systemic lupus erythematosus Disease Activity Index
SLEDAI 2K
Systemic Lupus Erythematosus Disease Activity Index 2K


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Abbreviation
Description
SLICC
Systemic Lupus International Collaborating Clinics
SOC
System Organ Class
SRI
SLE Responder Index
SRI(4)
SLE Responder Index response with 4 point reduction in the SLEDAI 2K score
SNP
Single Nucleotide Polymorphism
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
WBC
White blood cells
WHODD
World Health Organization Drug Dictionary


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3.
STUDY OBJECTIVES
Table 2:
Study Objectives
Primary Objective

To evaluate the clinical efficacy of three doses of CC-220 (0.45 mg once per day 
[QD], 0.3 mg QD or 0.15 mg QD) compared to placebo, for the treatment of 
active systemic lupus erythematosus (SLE) using the SLE Responder Index at 
Week 24
Secondary Objectives

To evaluate additional measures of clinical disease activity of CC-220 (0.45 mg 
once per day [QD], 0.3 mg QD or 0.15 mg QD) compared to placebo for the 
treatment of subjects with active SLE at Week 24

To assess the reduction in steroid use

To assess the reduction in fatigue 

To evaluate the safety and tolerability of three doses of CC-220 (0.45 mg QD, 0.3 
mg QD, and 0.15 mg QD) compared to placebo in subjects with active SLE 
 
 
 
 
 
 


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4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
CC-220-SLE-002 is a phase 2 randomized, placebo-controlled, double-blind, parallel group 
study with three active treatment groups. 
The study consists of 5 phases:

Screening Phase up to 5 weeks

Randomized, Double-Blind, Placebo-Controlled Phase of up to 24 weeks

Randomized, Double-Blind, Active Treatment Phase of up to 28 weeks

Long-term Extension Phase of up to 52 weeks 

Observational Follow-up Phase of 4 weeks for females and 12 weeks for males
The total duration of the study is 113 weeks for females and 121 weeks for males. The total 
duration of the treatment period is 104 weeks. 
Approximately 280 subjects will be randomized 2:2:1:2 to receive CC-220 (0.45 mg QD, 0.3 mg 
QD or 0.15 mg QD) or identically appearing placebo. There will be approximately 80 subjects 
randomized into the CC-220 0.45 mg QD and 0.3 mg QD dosing arms; 40 subjects randomized 
into the CC-220 0.15 mg QD dosing arm; and approximately 80 subjects in the placebo arm 
using an Interactive Response Technology (IRT). The treatment assignment will be stratified by 
baseline corticosteroid dose (≥ 10 mg/d and < 10 mg/d) and screening SLEDAI 2K score (≥ 10 
points and < 10 points).
At Week 24, all remaining placebo subjects will be re-randomized 1:1 in a blinded fashion by 
IRT to either CC-220 0.45 mg QD or 0.3 mg QD. All subjects who were initially randomized to 
CC-220 (0.45 mg QD, 0.3 mg QD, or 0.15 mg QD) will be blindly re-randomized by IRT to the 
same dose group to which they were originally assigned. 
Subjects who complete the Treatment Phase may be eligible to roll over into a Long-term 
Extension of up to one-year in duration. Subjects who enter this phase will maintain the CC-220 
dosage they were re-randomized to at Week 24. 
To maintain the blind at the site and subject level, the individual subject treatment assignments 
will not be revealed to the Investigators until after the 52-week database lock and after all final 
analyses are completed and the final results have been released. 
Once an optimal dose is identified, subjects will be transitioned to that dose. If more than one 
dose is identified for further study, subject will be re-randomized accordingly as per the IRT.
If a subject discontinues investigational product (IP) early (ie, prior to completing Visit 15 
during the Active Treatment Phase or prior to completing Visit 28 during the Long-term 
Extension), they will be required to complete an Early Termination Visit as soon as possible and 
enter into a 4-week Observational Follow-up Phase with an additional 12-week Observational 
Follow-up visit for males. In addition, if a subject completes the Randomized, Double-Blind, 
Active Treatment Phase, but opts not to enter the Long-term Extension Phase or completes the 
Long-term Extension Phase, the subject will enter into a 4-week Observational Follow-up Phase 
with an additional 12-week Observational Follow-up visit for males. 


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A 4-week Observational Follow-up Phase is included for all subjects to monitor subject safety 
after cessation of treatment. An additional 12-week Observational Follow-up visit is included for 
males to monitor hormone levels (testosterone, LH, FSH).
Figure 1:
Overall Study Design
*Female subjects will have a 4-week Observational Follow-Up Phase. Males will have a 12-week Observational 
Follow-Up Phase. 
Obs FU= Observational Follow Up Phase; QD=once per day; SRI(4)=SLE Responder Index(4); Wk=week.
4.2.
Study Endpoints
4.2.1.
Primary Endpoint
The primary endpoint is the percentage of subjects who achieve SRI(4) at Week 24. A subject 
achieves SRI(4) if the following criteria are all met:

Change of ≤ -4 from baseline in the SLEDAI 2K score at Week 24
The SLEDAI 2K score will be calculated as the sum of the scores of individual items.

No new BILAG 2004 A score or more than one new BILAG 2004 B score compared 
to baseline at Week 24
New A or B scores are determined for each organ system, rather than based on the 
total number of A or B scores across all organ systems. An A score is new if the 
baseline score for the same organ system is B, C, D or E. A B score is new if the 
baseline score for the same organ system is C, D, or E.

Change of < 0.30 from baseline in the PGA score at Week 24

No event of treatment failure (Section 5.6) before the date of the last SRI assessment
(ie, SLEDAI 2K, BILAG 2004, or PGA, if they are assessed on different dates) at 
Week 24


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Missing data handling is described in Section 5.5.
4.2.2.
Secondary Endpoints
4.2.2.1.
SLEDAI 2K
The secondary endpoint evaluating SLEDAI 2K is the percentage of subjects with an
improvement of ≥ 4 from baseline in the SLEDAI 2K score at Week 24, which is a component of 
the primary endpoint. A subject achieves this endpoint if the following criteria are all met:

Change of ≤ -4 from baseline in the SLEDAI 2K score at Week 24
The SLEDAI 2K score will be calculated as the sum of the scores of individual items.

No event of treatment failure (Section 5.6) before the date of the SLEDAI 2K 
assessment at Week 24
Missing data handling is described in Section 5.5.
4.2.2.2.
CLASI
The secondary endpoint evaluating CLASI is the percentage of subjects with an improvement of 
≥ 50% from baseline in the CLASI activity score at Week 24, in subjects with baseline CLASI 
activity score ≥ 10. A subject achieves this endpoint if the following criteria are all met:

Percent change of ≤ -50% from baseline in the CLASI activity score at Week 24
The CLASI activity score will be calculated as the sum of the individual activity 
scores (erythema in 13 locations, scale/hypertrophy in 13 locations, mucous 
membrane lesions, recent hair loss, and non-scarring alopecia).

No event of treatment failure (Section 5.6) before the date of the CLASI assessment 
at Week 24
Missing data handling is described in Section 5.5.
4.2.2.3.
BILAG 2004
The secondary endpoint evaluating BILAG 2004 is the percentage of subjects with no new 
BILAG 2004 A score or more than one new BILAG 2004 B score compared to baseline at Week 
24, which is a component of the primary endpoint. A subject achieves this endpoint if the 
following criteria are all met:

No new BILAG 2004 A score or more than one new BILAG 2004 B score compared
to baseline at Week 24
New A or B scores are determined for each organ system, rather than based on the 
total number of A or B scores across all organ systems. An A score is new if the 
baseline score for the same organ system is B, C, D or E. A B score is new if the 
baseline score for the same organ system is C, D, or E.

No event of treatment failure (Section 5.6) before the date of the BILAG 2004 
assessment at Week 24
Missing data handling is described in Section 5.5.


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4.2.2.4.
PGA
Percentage of subjects with no worsening from baseline (defined as change of < 0.30 from 
baseline) in the PGA score at Week 24
This endpoint is a component of the primary endpoint. A subject achieves this endpoint if the 
following criteria are all met:

Change of < 0.30 from baseline in the PGA score at Week 24

No event of treatment failure (Section 5.6) before the date of the PGA assessment at 
Week 24
Missing data handling is described in Section 5.5.
Change from baseline in the PGA score at Week 24
This endpoint will be evaluated by the mean change from baseline in the PGA score at Week 24.
Data after the date of treatment failure will be considered missing for the efficacy analysis.
4.2.2.5.
Joint Counts
The secondary endpoints evaluating joint counts are the mean change from baseline in swollen 
joint count at Week 24 in subjects with ≥2 swollen joints at baseline and the mean change from
baseline in tender joint count at Week 24 in subjects with ≥2 tender joints at baseline. The 
handling of missing joint assessments is described in Section 5.5. Data after the date of treatment 
failure will be considered missing for the efficacy analysis.
4.2.2.6.
Fatigue
The secondary endpoint evaluating fatigue is the mean change from baseline in the 
FACIT-Fatigue score at Week 24. Data after the date of treatment failure will be considered 
missing for the efficacy analysis. The FACIT-Fatigue score will be calculated as the sum of the 
13 item scores ranging from 0 to 4.
4.2.2.7.
Corticosteroid Reduction
Percentage of subjects with oral corticosteroid (OCS) dose reduced to ≤ 7.5 mg/day by
Week 16 and maintained through Week 24 with no flares between Week 16 and Week 24, 
in subjects with baseline OCS dose ≥10 mg/day
A subject achieves this endpoint if the following criteria are all met:

Daily OCS doses ≤ 7.5 mg/day from the date after the last SRI assessment (ie, 
SLEDAI 2K, BILAG 2004, or PGA, if they are assessed on different dates) at Week 
16 to the date of the last SRI assessment at Week 24
If no SRI assessment is found at Week 16 or Week 24 and thus the date of the last 
SRI assessment at Week 16 or Week 24 cannot be derived, the subject will be 
considered not achieving this endpoint.

No flares as defined by the SLE Flare Index between Week 16 and Week 24, 
inclusive
Missing flare assessments will not be imputed and will be considered as no flares.


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
No event of treatment failure (Section 5.6) before the date of the last SRI assessment
at Week 24
The baseline OCS dose is defined as the daily OCS dose on the date of the first dose of IP. The 
calculation of daily OCS doses is detailed in Appendix C.
Percentage of subjects with OCS dose reduced to < 10 mg/day by Week 16 and maintained 
through Week 24 with no flares between Week 16 and Week 24, in subjects with baseline 
OCS dose ≥ 10 mg/day
This endpoint will be derived in the same way as the one above, with < 10 mg replacing ≤7.5 
mg.
Percent change from baseline in OCS dose at Week 24 in subjects with the baseline OCS 
dose ≥10 mg/day
This endpoint will be evaluated by the mean percent change and median percent change from 
baseline in OCS dose at Week 24 in subjects with the baseline OCS dose ≥10 mg/day. The 
baseline OCS dose is defined as the daily OCS dose on the date of the first dose of IP. The OCS 
dose at each post-baseline analysis visit is defined as the OCS dose on the date after the last SRI 
assessment (ie, SLEDAI 2K, BILAG 2004, or PGA, if they are assessed on different dates) at the 
analysis visit. Subjects without an OCS dose on the specified dates will have a dose of 0 at the 
corresponding analysis visit. The calculation of daily OCS doses is detailed in Appendix C. If no 
SRI assessment is found at an analysis visit and thus the date of the last SRI assessment at the 
analysis visit cannot be derived, the OCS dose at the analysis visit will be considered missing. 
OCS data after the date of treatment failure will still be used for this endpoint.
Standardized total OCS dose in Weeks 0-24
This endpoint will be evaluated by the mean standardized total OCS dose in Weeks 0-24.
The total OCS dose in Weeks 0-24 will be calculated using the records subjected to the 
calculation of daily OCS doses in Appendix C that have the calculated daily doses between the 
date of the first dose of IP and the date of the Week 24 visit, inclusive, ie, the start date is before 
the date of the first dose of IP and the end date (or the “effective” end date as described in 
Appendix C) is on or after the date of the first dose of IP or ongoing, or the start date is between 
the date of the first dose of IP and the date of the Week 24 visit, inclusive.
For each of these records, the duration (days) will be calculated as min(end date, date of the 
Week 24 visit) – max(start date, date of the first dose of IP) + 1, where the end date can be an 
“effective” end date as described in Appendix C, or date of the Week 24 visit – max(start date, 
date of the first dose of IP) + 1 if ongoing. The total dose for each record will be calculated as the 
calculated daily dose (mg/day) multiplied by the duration (days), and the total dose in Weeks 0-
24 will be calculated as the sum of the total doses of these records. The standardized total dose in 
Weeks 0-24 will be calculated as the total dose in Weeks 0-24 divided by the actual number of 
days in Weeks 0-24 (date of the Week 24 visit – date of the first dose of IP + 1) multiplied by the 
normalizing duration of 168 (ie, 7 days/week × 24 weeks).
For subjects with no calculated daily doses between the date of the first dose of IP and the date 
of the Week 24 visit, inclusive, the standardized total dose in Weeks 0-24 will be 0.


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For subjects who do not have the Week 24 visit, whether or not completing the placebo-
controlled phase according to the placebo-controlled phase disposition eCRF, the date of 
completion or the date of discontinuation as collected in the placebo-controlled phase disposition 
eCRF will replace the date of the Week 24 visit in the above calculation.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




























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4.2.4.
Safety Endpoints
4.2.4.1.
Adverse Events
Adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA). Treatment-emergent AEs (TEAEs) will be flagged for the safety analysis 
periods (Section 5.2) according to their start dates. Imputation rules of partial or completely 
missing start dates of AEs are given in Appendix B. AE intensity, relationship to IP, and 
seriousness will be ensured to be non-missing during medical monitoring.
Exposure-adjusted incidence rate (EAIR) per 100 person-years is defined as 100 times the 
number of subjects with the specific event divided by the total time (in years) at risk among 
subjects included in the analysis. Subjects with multiple occurrences of the specific event in the 
specific analysis period will be counted only once in the numerator. The time (in days) at risk for 
a subject without the specific event is the duration of the specific analysis period as described in 
Section 5.2, whereas the time (in days) at risk for a subject with the specific event is the duration 
of the specific analysis period up to the start date (inclusive) of the first occurrence of the 
specific event. The total time (in years) at risk will be calculated by dividing the sum of time (in 
days) at risk over all subjects included in the analysis by 365.25.
In the summary of TEAEs by time interval, the time intervals relative to the date of the first dose 
of IP (or the date of the first dose of CC-220) are the following:

Placebo-controlled phase (Section 5.2): ≤4, > 4 to 8, > 8 to 12, > 12 weeks

Weeks 0-52 CC-220-exposure period (Section 5.2): ≤4, > 4 to 8, > 8 to 12, > 12 to 
24, > 24 to 36, > 36 weeks
For each time interval, a subject is counted once in the numerator of the percentage or EAIR for 
each applicable specific event if an occurrence starts in the time interval (eg, if the study day of 


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the start of an occurrence is 80, then the occurrence starts in the time interval of > 8 to 12 
weeks). The denominator of the percentage is the number of subjects with the time at risk 
reaching the lower bound of the time interval, and the denominator of the EAIR is the sum of the 
time at risk during the time interval (up to the start date [inclusive] of the first occurrence of the 
specific event for each subject with an occurrence starting in the time interval) among the same 
number of subjects as in the denominator of the corresponding percentage.
In the summary of TEAEs by maximum severity, a subject with multiple occurrences of a 
specific event within a safety analysis period (Section 5.2) will be counted only once by the 
maximum severity in the safety analysis period.
4.2.4.2.
Clinical Laboratory Tests
The endpoints of clinical laboratory tests include:

The change from baseline by time point (including the follow-up visit) in the 
protocol-specified laboratory analytes of hematology, serum chemistry, immunology, 
and dipstick urinalysis (numeric parameters only) in subjects with a baseline value 
and a value at the respective post-baseline time point

Shifts from baseline by time point (including each post-baseline time point, the 
maximum value, the minimum value, and the last value in a safety analysis period 
[Section 5.2]) in abnormality category (low/normal/high, or normal/abnormal where 
applicable, eg, for some urinalysis parameters) according to the reference range for 
the protocol-specified laboratory analytes of hematology, serum chemistry, 
immunology, and dipstick urinalysis
For the summary of the maximum and minimum values, all data in the period, 
including any multiple values within the same analysis visit window, will be used to 
derive this endpoint. Percentages will be based on subjects with a baseline value and 
at least one post-baseline value in the period (at the respective time point for the 
summary by time point).

The number and percentage of subjects with laboratory marked abnormalities 
(Appendix D) by time point and at least once in a safety analysis period (Section 5.2)
For the summary of at least once in a given safety analysis period, all data in the 
period, including any multiple values within the same analysis visit window, will be 
used to derive this endpoint. Percentages will be based on subjects with a baseline 
value and at least one post-baseline value in the period (at the respective time point 
for the summary by time point) for the marked abnormality criteria referencing the
baseline, or subjects with at least one post-baseline value in the period (at the 
respective time point for the summary by time point) for the marked abnormality 
criteria not referencing the baseline.

Neutrophil (“neutrophils, segmented and band form”), lymphocyte, and hemoglobin
shifts from baseline by time point (including each post-baseline time point, the 
minimum value, and the last value in a safety analysis period [Section 5.2]) in 
CTCAE grade for overall subjects and by baseline use of methotrexate (yes, no), 


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azathioprine (yes, no), mycophenolic compounds (yes, no), oral tacrolimus or oral 
cyclosporine (yes, no)
For the summary of the minimum value, all data in the period, including any multiple 
values within the same analysis visit window, will be used to derive this endpoint. 
Percentages will be based on subjects with a baseline value and at least one post-
baseline value in the period (at the respective time point for the summary by time 
point).

Time (days) to the first neutropenia (“neutrophils, segmented and band form”) of 
CTCAE grade 3 or above (ie, < 1 109/L)
The time (days) to the first neutropenia of CTCAE grade 3 or above is defined as the 
study day as defined in Section 5.3.2 for the first neutropenia of CTCAE grade 3 or 
above. For subjects who do not have a neutropenia of CTCAE grade 3 or above in a 
given safety analysis period (Section 5.2), the time will be censored on the date of the 
last neutrophil collection in the period.
Only the data in a given safety analysis period (Section 5.2) will be included in the analysis of 
that period.
4.2.4.3.
Vital Signs and Weight
The endpoints of vital signs and weight include:

The change from baseline by time point (including the follow-up visit) in the vital 
signs (including weight) in subjects with a baseline value and a value at the respective
post-baseline time point

Shifts from baseline by time point (including each post-baseline time point, the 
maximum value, the minimum value, and the last value in a safety analysis period 
[Section 5.2]) in abnormality category (low/normal/high) according to the reference 
range for the applicable vital signs
For the summary of the maximum and minimum values, all data in the period, 
including any multiple values within the same analysis visit window, will be used to 
derive this endpoint. Percentages will be based on subjects with a baseline value and 
at least one post-baseline value in the period (at the respective time point for the 
summary by time point). The reference ranges are defined as: 60 to 100 beats/min for 
pulse, 90 to 140 mmHg for systolic blood pressure, and 60 to 90 mmHg for diastolic 
blood pressure.

The number and percentage of subjects with vital signs marked abnormalities 
(Appendix E) by time point and at least once in a safety analysis period (Section 5.2)
For the summary of at least once in a given safety analysis period, all data in the 
period, including any multiple values within the same analysis visit window, will be 
used to derive this endpoint. Percentages will be based on subjects with a baseline 
value and at least one post-baseline value in the period (at the respective time point 
for the summary by time point) for the marked abnormality criteria referencing the
baseline, or subjects with at least one post-baseline value in the period (at the 


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respective time point for the summary by time point) for the marked abnormality 
criteria not referencing the baseline.
Only the data in a given safety analysis period (Section 5.2) will be included in the analysis of 
that period.
4.2.4.4.
ECG
The ECG endpoints include:

The change from baseline by time point in the following ECG variables in subjects 
with a baseline value and a value at the respective post-baseline time point:
o
Summary (mean) heart rate (beats/min)
o
Summary (mean) PR duration (msec)
o
Summary (mean) QRS duration (msec)
o
Summary (mean) QT duration (msec)
o
Summary (mean) RR duration (sec)
o
QTcB - Bazett's correction formula (msec)
o
QTcF - Fridericia's correction formula (msec)

Shifts from baseline by time point (including each post-baseline time point, the worst 
result, and the last result in a safety analysis period [Section 5.2]) in abnormality 
category (normal/abnormal, not clinically significant/abnormal, clinically significant 
ECG interpretation results)
For the summary of the worst result, all data in the period, including any multiple 
results within the same analysis visit window, will be used to derive this endpoint. 
Percentages will be based on subjects with a baseline result and at least one post-
baseline result in the period (at the respective time point for the summary by time 
point). The ECG interpretation result will be based on the investigator’s clinical 
interpretation.

The number and percentage of subjects with ECG potentially clinically significant
values/changes from baseline (Appendix F) by time point and at least once in a safety 
analysis periods (Section 5.2)
For the summary of at least once in a given safety analysis period, all data in the 
period, including any multiple values within the same analysis visit window, will be 
used to derive this endpoint. Percentages will be based on subjects with a baseline 
value and at least one post-baseline value in the period (at the respective time point 
for the summary by time point) for the potentially clinically significant changes from 
baseline, or subjects with at least one post-baseline value in the period (at the 
respective time point for the summary by time point) for the potentially clinically 
significant values. 
Only the data in a given safety analysis period (Section 5.2) will be included in the analysis of 
that period.


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4.3.
Stratification, Randomization, and Blinding
Approximately 280 subjects will be randomized 2:2:1:2 to receive CC-220 (0.45 mg QD, 0.3 mg 
QD or 0.15 mg QD) or identically appearing placebo. There will be approximately 80 subjects 
randomized into the CC-220 0.45 mg QD and 0.3 mg QD dosing arms; 40 subjects randomized 
into the CC-220 0.15 mg QD dosing arm; and approximately 80 subjects in the placebo arm 
using an Interactive Response Technology (IRT). The treatment assignment will be stratified by 
baseline corticosteroid dose (≥ 10 mg/d and < 10 mg/d) and screening SLEDAI 2K score (≥ 10 
points and < 10 points).
At Week 24, all remaining placebo subjects will be re-randomized 1:1 in a blinded fashion by 
IRT to either CC-220 0.45 mg QD or 0.3 mg QD. All subjects who were initially randomized to 
CC-220 (0.45 mg QD, 0.3 mg QD, or 0.15 mg QD) will be blindly re-randomized by IRT to the 
same dose group to which they were originally assigned.
Subjects who complete the Treatment Phase may be eligible to roll over into a Long-term 
Extension of up to one-year in duration. Subjects who enter this phase will maintain the CC-220 
dosage they were re-randomized to at Week 24.
To maintain the blind at the site and subject level, the individual subject treatment assignments 
will not be revealed to the Investigators until after the 52-week database lock and after all final 
analyses are completed and the final results have been released.
Once an optimal dose is identified, subjects will be transitioned to that dose. If more than one 
dose is identified for further study, subject will be re-randomized accordingly as per the IRT.
4.4.
Sample Size Determination
Approximately 280 subjects will be randomized 2:2:1:2 to receive CC-220 (0.45 mg QD, 0.3 mg 
QD or 0.15 mg QD) or placebo. There will be approximately 80 subjects randomized into each 
CC-220 0.45 mg QD, CC-220 0.3 mg QD, and placebo arm and approximately 40 subjects into
the CC-220 0.15 mg QD arm. 
A sample size of 80 subjects in the CC-220 0.45 mg QD, CC-220 0.3 mg QD, and placebo dose 
groups provides approximately 80% power to detect a true 21% difference (55% versus 34%) 
between one of the CC-220 group and the placebo group, using a two-group chi-square test with 
a 0.1 two-sided significance level, for the percentage of subjects achieving an SRI(4) response at 
Week 24. Based upon clinical trials of belimumab and anifrolumab in a similar patient 
population with SLE, the observed placebo response rate ranged from 34% to 44%. A 21% 
treatment effect provides a clinically meaningful improvement compared to placebo and is 
approximately 50% higher than the treatment differences achieved in published trials in SLE 
(Human Genome Sciences, Inc., 2010; Furie, 2016).
The sample size of the 0.15 mg QD dose group is limited to 40 subjects to assess and determine 
the lowest effective dose. 


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5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
All statistical analyses will be conducted using SAS® Version 9.2 or higher.
All analyses adjusting for the randomization stratification factors and the subgroup analyses with 
respect to the randomization stratification factors will use the actual stratifications derived from 
the clinical database, rather than the stratifications as randomized in the IRT.
P-values will be 2-sided and presented with 3 decimal places. P-values that are rounded to 0.000 
will be presented as “< 0.001” and p-values that are rounded to 1 “> 0.999”. Confidence intervals 
(CIs) will be presented as 2-sided 95% CIs and formatted to one more decimal place than the 
measured value.
Descriptive statistics for continuous variables include sample size (n), mean, standard deviation 
(SD), median, minimum, the 25th (Q1) and 75th (Q3) percentiles, and maximum. All mean,
median, Q1, Q3, and SD values will be formatted to one more decimal place than the measured 
value. Minimum and maximum values will be presented to the same number of decimal places as 
the measured value. A frequency summary for categorical variables includes number and 
percentage. Number and percentage will be presented in the form XX (XX.X), where the 
percentage is in the parentheses. All percentages will be rounded to one decimal place, except 
100% which will be displayed without any decimal places. Percentages will not be displayed for 
zero counts.
The change from baseline is calculated as the post-baseline value minus the baseline value. The 
percent change from baseline is calculated as the change from baseline divided by the baseline 
value multiplied by 100.
All laboratory data will be reported using standard international units.
Listings will be sorted by treatment group and subject number.
5.2.
Safety Analysis Periods
For the safety analysis, the following analysis periods for the post-baseline data are defined. 
Safety data in these periods are considered treatment-emergent.

Placebo-controlled phase: This period encompasses the post-baseline data through 
Week 24. It starts on the date of the first dose of IP, and ends on the date before the 
first Week 24 dose of CC-220 for subjects who receive at least one dose of CC-220 
after Week 24, or 28 days after the last dose of IP or on the date of the last follow-up, 
whichever comes first, for subjects who do not receive at least one dose of CC-220 
after Week 24. See Appendix B for the imputation of partial or completely missing 
dates of the last dose of IP.
For the analysis of measured (ie, visit-based) safety data (ie, labs, vital signs, and 
ECG), this period is exclusive of the date of the first dose of IP and inclusive of the 
date of the first Week 24 dose of CC-220.


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At the time of the interim analysis or the Week 24 analysis, if the date of the first 
Week 24 dose of CC-220 (derived from the Study Drug Exposure eCRF which may 
not be entered by sites until the next visit after Week 24) is not yet available for 
subjects with CC-220 dispensed at Week 24 and on or before the (possibly derived) 
date of the last dose of IP as of the time of analysis (ie, no evidence that the subject 
has discontinued without receiving at least one dose of CC-220 after Week 24), the 
date of CC-220 dispensing at Week 24 will replace the date of the first Week 24 dose 
of CC-220 in the above definition for these subjects.

Weeks 0-52 CC-220-exposure period: This period encompasses all CC-220-exposure 
data through Week 52, irrespective of when the CC-220 exposure starts (at Week 0 or 
Week 24). It starts on the date of the first dose of CC-220, and ends on the date before 
the first Week 52 dose of CC-220 for subjects who receive at least one dose of CC-
220 after Week 52, or 28 days after the last dose of IP or on the date of the last 
follow-up, whichever comes first, for subjects who do not receive at least one dose of 
CC-220 after Week 52.
For the analysis of measured (ie, visit-based) safety data (ie, labs, vital signs, and 
ECG), this period is exclusive of the date of the first dose of CC-220 and inclusive of 
the date of the first Week 52 dose of CC-220.
At the time of the Week 52 analysis, if the date of the first Week 52 dose of CC-220 
(derived from the Study Drug Exposure eCRF which may not be entered by sites until 
the next visit after Week 52) is not yet available for subjects with CC-220 dispensed 
at Week 52 and on or before the (possibly derived) date of the last dose of IP as of the 
time of analysis (ie, no evidence that the subject has discontinued without receiving at 
least one dose of CC-220 after Week 52), the date of CC-220 dispensing at Week 52 
will replace the date of the first Week 52 dose of CC-220 in the above definition for 
these subjects.

Weeks 0-104 CC-220-exposure period: This period encompasses all CC-220-
exposure data through Week 104, irrespective of when the CC-220 exposure starts (at 
Week 0 or Week 24). It starts on the date of the first dose of CC-220, and ends 28 
days after the last dose of IP or on the date of the last follow-up, whichever comes 
first.
For the analysis of measured (ie, visit-based) safety parameters (ie, labs, vital signs, 
and ECG), this period is exclusive of the date of the first dose of CC-220.

Extension phase: This period encompasses the data in Weeks 52-104. It starts on the 
date of the first Week 52 dose of CC-220, and ends 28 days after the last dose of IP or 
on the date of the last follow-up, whichever comes first.
Testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) that are 
collected at the 12-week follow-up visit for males only will be included in the above safety 
analysis periods, irrespective of their timing relative to the end of the respective period.


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5.3.
Time Points
5.3.1.
Screening Value and Baseline Value Definitions
Where applicable (eg, the screening SLEDAI 2K score), the screening value is defined as the last 
non-missing value with the recorded visit being the screening visit.
Unless otherwise specified, the baseline value is defined as the last non-missing value on or 
before the date of the first dose of IP. For the safety analysis, the baseline value is defined as the 
last non-missing value on or before the date of the first dose of IP for the analysis of the placebo-
controlled phase, and the last non-missing value on or before the date of the first dose of CC-220
for the analysis of an CC-220-exposure period.
For the above definitions, in case of multiple non-missing values on the same date, the one with 
the earliest time will be used if the time of assessment/collection is available (eg, lab and ECG); 
otherwise the average of the multiple non-missing values will be used.
5.3.2.
Analysis Visit Windows
All visit-based data, except for those with the recorded visit being a follow-up visit, will be 
assigned to analysis visits based on study day (the date of assessment/collection relative to the 
reference date) and the defined analysis visit windows (Appendix A), rather than the recorded
visit. The only exception is that data with the recorded visit being a follow-up visit will be 
assigned to the analysis visit corresponding to the follow-up visit.
Unless otherwise specified, study day is defined as date of assessment/collection – date of the 
first dose of IP + 1 if the date of assessment/collection is on or after the date of the first dose of 
IP, or date of assessment/collection – date of the first dose of IP if the date of 
assessment/collection is before the date of the first dose of IP. For visit-based safety data (ie, 
labs, vital signs, and ECG) in the CC-220-exposure period for subjects who switch from placebo 
to CC-220 at Week 24, study day is defined as date of assessment/collection – date of the first 
dose of CC-220 + 1 so that the time points for the analyses of visit-based safety data in the CC-
220-exposure period are relative to the same reference date, ie, the date of the first dose of CC-
220.
Unless otherwise specified, the analysis visit windows are continuous, mutually exclusive, and 
stretch from the date after the reference date to the midpoint between the first two scheduled 
visits for the endpoint in question, from midpoint to midpoint between each successive pair of 
scheduled visits, and from the last midpoint onward for the last scheduled visit.
For visit-based analyses, if multiple non-missing values are within the same analysis visit 
window, then the value closest to the scheduled study day of the analysis visit will be used; if 
two values are equidistant from the scheduled study day, then the later value will be used. In case 
of multiple non-missing values on the same date, the one with the earliest time will be used if the 
time of assessment/collection is available (eg, lab and ECG); if the time is unavailable, the one 
with the earliest visit number will be used; if the visit numbers are also the same, the worst of the 
multiple non-missing values will be used.
For non-visit-based analyses (eg, lab marked abnormalities), all data, including any multiple 
values within the same analysis visit window, will be used.


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5.4.
Analysis Populations
5.4.1.
Intent-to-treat Population
The intent-to-treat (ITT) population will include all subjects who are randomized and receive at 
least 1 dose of IP. The analysis of placebo-controlled (Weeks 0-24) efficacy and PD data in this 
study will be based on the ITT population unless otherwise specified and subjects will be 
included in the randomized treatment group. 
5.4.2.
Safety Population
The safety population will include all subjects who are randomized and receive at least 1 dose of 
IP. The analysis of placebo-controlled safety data in this study will be based on the safety 
population and subjects will be included in the treatment group corresponding to the IP they 
actually received.
5.4.3.
Per-protocol Population
The per-protocol (PP) population will include all subjects in the ITT population who have no 
protocol deviations that may substantially affect the efficacy results. These protocol deviations 
could include, but are not limited to, not meeting key inclusion/exclusion criteria, gross IP non-
compliance, receiving incorrect IP, treatment unblinding by the investigator, concomitant use of 
protocol-prohibited medications that are potentially effective for SLE for an unrelated comorbid 
condition, not having the required assessment at the designated time point without experiencing a 
treatment failure, or discontinuing due to lack of efficacy or a drug-related AE prior to the time 
point. The final determination of protocol deviations and thereby the composition of the PP
population will be made prior to the DBL for the Week 24 analysis and will be separately 
documented. A supportive analysis of the primary endpoint will be based on the PP population 
and subjects will be included in the randomized treatment group.
 
5.4.5.
CC-220 Subjects as Randomized Population 
The efficacy analysis in Weeks 0-52 will be based on the CC-220 subjects as randomized 
population, which will include all subjects who are either initially randomized (at Week 0) or re-
randomized (at Week 24) to a CC-220 treatment group, and receive at least one dose of CC-220 
after (re-)randomization. Subjects will be included in the (re-)randomized CC-220 treatment
group.
5.4.6.
CC-220 Subjects as Treated Population 
The safety analysis for the Weeks 0-52 and Weeks 0-104 CC-220-exposure periods will be based 
on the CC-220 subjects as treated population, which will include all subjects who are either 
initially randomized (at Week 0) or re-randomized (at Week 24) to a CC-220 treatment group, 


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and receive at least one dose of CC-220 after (re-)randomization. Subjects will be included in the 
CC-220 treatment group corresponding to the CC-220 dose they actually received.
5.4.7.
Extension Phase Population 
The efficacy and safety analysis in the extension phase (Weeks 52-104) will be based on the 
extension phase population, which will include subjects who receive at least one dose of CC-220 
after Week 52. Subjects will be included in the (re-)randomized CC-220 treatment group.
5.5.
Missing Data
Binary efficacy endpoints
Missing data for binary efficacy endpoints will be handled by nonresponder imputation (NRI), 
by which a subject will be considered a nonresponder at a given time point if the subject 1) does 
not have sufficient data (including the baseline data for the endpoints assessing the change from 
baseline) assessed within the analysis visit window for response determination, or 2) has had an 
event of treatment failure (Section 5.6) before the date of assessment (or the date of the last 
assessment in the case of a composite endpoint involving multiple criteria that may be assessed 
on different dates) for the time point.
Continuous efficacy and PD endpoints through Week 52 when assessed by the mean change
or percent change from baseline
Missing data for continuous efficacy and PD endpoints through Week 52 when they are assessed 
by the mean change or percent change from baseline will be handled by an adaptive approach 
(Mehrotra, 2012) that uses either a longitudinal data analysis (LDA) model (Liu, 2009) (in the 
absence of severe departures from normality) or multiple imputation in conjunction with a robust 
regression model that uses M-estimation (in the presence of severe departures from normality).
Unless otherwise specified, data after the date of treatment failure will be considered missing for 
the efficacy analysis.
The LDA model assumes a common mean across treatment groups at baseline and a different 
mean for each treatment group at each of the post-baseline time points. In this model, the 
response vector consists of the baseline and post-baseline values for the analysis of a change 
from baseline, or the baseline value and the post-baseline percent changes from baseline for the 
analysis of a percent change from baseline. Time is treated as a categorical variable so that no 
restriction is imposed on the trajectory of the means over time. Where specified, the model will 
also adjust for the randomization stratification factors (baseline corticosteroid dose [≥ 10 mg/d 
and < 10 mg/d], screening SLEDAI 2K score [≥ 10 points and < 10 points]) and their 
interactions with time. An unstructured covariance matrix will be used to model the correlation 
among repeated measurements. The Kenward-Roger adjustment will be used with restricted 
maximum likelihood to make proper statistical inference. If the model with an unstructured 
covariance fails to converge with the default Newton-Raphson algorithm, the Fisher scoring 
algorithm or other appropriate methods can be used to provide initial values of the covariance 
parameters. In the rare event that none of the above methods yields convergence, a structured 
covariance such as the heterogeneous Toeplitz or Toeplitz structures will be used to model the 
correlation among repeated measurements. In this case, the empirical option will be used because 


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the sandwich variance estimator is asymptotically unbiased while the model-based variance 
estimator can grossly overestimate or underestimate the true variance.
The LDA model assumes the vector of the model-based residuals follows a multivariate normal 
distribution. Under severe departures from normality, the LDA model can be inefficient or 
potentially misleading. Accordingly, the vector of the residuals from the LDA model, scaled by 
the inverse Cholesky root of the estimated variance-covariance matrix, will be subjected to a test 
for normality. If normality is not rejected at the significance level of 0.001, then the LDA model 
will be used for the analysis. However, if normality is rejected, then the analysis will be 
conducted using multiple imputation in conjunction with a robust regression model that uses M-
estimation. Of note, the significance level of 0.001 for the normality test is chosen so that the 
LDA is abandoned only under a clear departure from normality.
Continuous efficacy 
 through Week 52 when assessed by the median
change or percent change from baseline
Missing data for continuous efficacy and PD endpoints through Week 52 when they are assessed 
by the median change or percent change from baseline will be handled by multiple imputation in 
conjunction with a quantile regression model (using PROC QUANTREG). Unless otherwise 
specified, data after the date of treatment failure will be considered missing for the efficacy 
analysis.
Continuous efficacy data after Week 52
Continuous efficacy data after Week 52 will be summarized based on observed cases and 
missing data will not be imputed. Efficacy data after the date of treatment failure will be 
considered missing for the efficacy analysis.
Safety data
Safety data will be summarized based on observed cases and missing data will generally not be 
imputed. However, lab values of the form of “< x” or “> x” will be imputed by “x” in the 
calculation of descriptive statistics but displayed as “< x” or “> x” in the listings.
Joint counts
Joints not assessed (eg, recorded as “NA”) at baseline will be imputed by the corresponding joint 
assessments at screening, if assessed; otherwise, these joints will be excluded from joint count 
for any analysis and reporting. Joints not assessed (eg, recorded as “NA”) at post-baseline visits 
will be imputed using the last observation (baseline or post-baseline) carried forward (LOCF) 
method. If no assessment is performed for any joint at a given visit, LOCF will not apply and 
joint count at that visit will be missing.
BILAG 2004
Letter scoring (A, B, C, D, or E) of the 9 BILAG 2004 organ systems will be performed by the 
vendors in the raw data with the following rules:

An item indicated as not due to SLE activity will be considered normal (ie, ignored in 
the scoring), regardless of the value recorded.

For a given organ system,


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o
If any (but not all) of the items within the organ system has a missing value 
(eg, an item that should be evaluated but is not evaluated [ie, marked as NOT 
DONE], or a missing lab test value due to any reasons), it will be imputed by 
the last non-missing value within the last 70 days of the date of the current 
BILAG 2004 assessment (ie, up to the last 2 visits or 56 days from the current 
assessment plus additional 14 days to allow for variations of visit scheduling, 
and to be consistent with the defined analysis visit windows [Appendix A]). 
For the items in the renal organ system that involve a comparison with the 
previous visit, a missing value at the previous visit will be imputed by the last 
non-missing value within the last 98 days of the date of the current BILAG 
2004 assessment (ie, the same 70-day window described above applies to the 
previous visit, which itself is 28 days from the current assessment). In the 
event that any item still has a missing value after imputation, the organ system 
will be scorable only if a score can be determined based on the available items 
and all items involved in the evaluation of the higher score(s) are present such 
that the higher score(s) can be precluded definitively; otherwise, the organ 
system will not be scorable and will have a missing letter score. See the 
additional exceptions below for the renal and hematological organ systems.
o
If all items within the organ system have missing values, then no imputation 
will be performed, and the organ system will not be scorable and will have a 
missing letter score.

Scores D and E will be differentiated. If an organ system is scorable and has no A, B, 
or C at the current visit, and has no A, B, C, or D at all previous visits including 
baseline, the score at the current visit will be E. If an organ system is scorable and has 
no A, B, or C at the current visit, but has A, B, C, or D at any of the previous visits 
including baseline, the score at the current visit will be D.

For the renal organ system, 
o
Renal biopsy is not mandatory in this study. Accordingly, if the item “active 
nephritis” (item 89 in Appendix C of the protocol; the corresponding scoring 
rule is “histological evidence of active nephritis within last 3 months”) has a
missing value (eg, marked as NOT DONE), it will be ignored in the scoring. 
However, a non-missing value (eg, a value of Yes) of this item will still be 
included in the scoring.
o
24-hour urine protein and urine albumin-creatinine ratio are not done in this 
study and therefore ignored in the scoring.
o
The reference visit for assessing the change at the current visit is the previous 
visit (or an unscheduled visit, if applicable, between the current visit and the 
previous visit).
o
Urine dipstick protein will be ignored in the scoring as long as urine protein-
creatinine ratio is available (subject to the aforementioned imputation) at both 
the current visit and the reference visit. Otherwise, urine dipstick protein, if 
available (subject to the aforementioned imputation) at both the current visit 
and the reference visit, will be used as the substitute.


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
For the hematological organ system,
o
The Coombs’ test is not required in this study. Accordingly, if the item 
“Coombs’ test positive (isolated)” (item 97 in Appendix C of the protocol; the 
corresponding scoring rule is “isolated Coombs’ test positive”) has a missing 
value (eg, marked as NOT DONE), it will be ignored in the scoring. However, 
a non-missing value (eg, a value of Yes) of this item will still be included in 
the scoring.
Partially missing items within other efficacy measures
For SLEDAI 2K (total score, clinical score, and organ system scores), CLASI activity and 
damage scores, and SLICC/ACR SLE damage index, if any (but not all) of the items of the score 
has a missing value, it will be imputed by the last non-missing value within the last 70 days of 
the date of the current assessment (ie, up to the last 2 visits or 56 days from the current 
assessment plus additional 14 days to allow for variations of visit scheduling, and to be 
consistent with the defined analysis visit windows [Appendix A]). If a non-missing value cannot 
be found within the aforementioned time limit, then the score will be missing. If all items of the 
score have missing values, then no imputation will be performed and the score will be missing.
For the derivation of SF-36, FACIT-Fatigue, LupusPRO, and HAQ-DI, partially missing items 
will be handled according to the respective official scoring algorithm.
Missing dates
The handling of partial or completely missing dates for certain data is given in Appendix B.
5.6.
Treatment Failures
Treatment failure is defined as protocol-prohibited initiation or dose increase of concomitant 
medications indicated for SLE. Treatment failures will be identified, separately for Weeks 0-52 
and Weeks 52-104, by medical review of medications with the medical history of SLE as the 
primary reason or an additional indication (according to the prior and concomitant medications 
eCRF and the SLE medical history eCRF). Medications that can be used for SLE but are 
indicated for non-SLE uses, systemic or topical, will not be included in this medical review to 
identify treatment failures; as such, uses of such concomitant medications will not lead to 
treatment failures. The treatment failure rules in the efficacy and PD analyses, ie, data after the 
date of treatment failure will be considered missing, and a subject will be considered a 
nonresponder after the date of treatment failure, apply only to the treatment failures within the 
corresponding period (Weeks 0-52 or Weeks 52-104). In other words, treatment failures in 
Weeks 0-52 will have no effect in the analysis of Weeks 52-104.


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6.
SUBJECT DISPOSITION
The number of subjects screened, the number and percentage of subjects discontinuing the 
screening phase and the reasons for discontinuation (as collected in the screening phase 
disposition eCRF), and the number and percentage of the inclusion/exclusion criteria failed will 
be summarized for all screened subjects.
The number and percentage of subjects included in each analysis population will be summarized
by treatment group and overall for all randomized subjects. A listing of subjects excluded from 
the PP population and the reason for exclusion will be provided.
The number and percentage of subjects who enter, complete, and discontinue the placebo-
controlled phase, active-treatment phase, extension phase, and follow-up phase, respectively, and 
the reasons for discontinuation (as collected in the respective phase disposition eCRF) will be 
summarized by treatment group and overall for the ITT population. Overall summaries of 
completion and discontinuation (including the reasons) through the active-treatment phase and 
through the extension phase, respectively, will also be provided by randomized treatment group 
and overall for the ITT population. A listing of discontinued subjects including the phase 
discontinued and the reason for discontinuation will be provided.
The number and percentage of subjects in each region, each country, and each site will be 
summarized by treatment group and overall for the ITT population.


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7.
PROTOCOL DEVIATIONS
Protocol deviations will be classified as protocol deviations (PD) or important protocol 
deviations (IPD) according to Celgene or Contract Research Organization (CRO)’s standard 
procedure. The identification and classification of PD/IPD will be finalized and documented 
prior to the DBL for each applicable planned analysis (Section 2).
A summary of IPD by treatment group and overall will be provided for the screening phase and 
placebo-controlled phase, respectively, for the ITT population, and for the active-treatment phase 
and extension phase for subjects who receive at least one dose of CC-220 after Week 24 and 
Week 52, respectively.
A listing of IPD will be provided for the ITT population.


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8.
DEMOGRAPHIC AND BASELINE CHARACTERISTICS
8.1.
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized descriptively by treatment group 
and overall for the ITT population. The comparability of the treatment groups for each relevant 
characteristic will be assessed descriptively; no statistical hypothesis tests will be performed on 
these characteristics.
Listings of demographic and baseline characteristics will be provided for the ITT population.
Demographic and baseline characteristic variables include:

Age (years)

Age (< 40, 40 to 50, > 50 to < 65, ≥ 65 years)

Sex (male, female)

Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not Collected or Reported, Other)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown)

Region (North America, Europe, South America [including Mexico], Russia)

Weight (kg)

Weight (< 55, 55 to < 70, 70 to < 85, 85 to < 100, ≥ 100 kg)

Body mass index (BMI; kg/m2)

BMI (< 18.5, 18.5 to < 25, 25 to < 30, 30 to < 35, 35 to < 40, ≥ 40 kg/m2)
Baseline disease characteristics include:

Duration of SLE (years)

Duration of SLE (≤ 1, > 1 to 2, > 2 to 5, > 5 to 10, > 10 years)

Joint involvement (yes, no, unknown)

Skin involvement (yes, no, unknown)

Baseline cutaneous lupus subtype (acute, subacute, chronic)

Screening SLEDAI 2K score per clinical database (≥10, < 10)

Screening SLEDAI 2K score as randomized (≥10, < 10)

Screening SLEDAI 2K score

Baseline SLEDAI 2K score

Screening clinical SLEDAI 2K score

Baseline clinical SLEDAI 2K score

BILAG 2004 global score


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
BILAG 2004 1 A or 2 B scores (yes, no)

BILAG 2004 mucocutaneous organ system score of A, B, or C (yes, no)

BILAG 2004 renal organ system score of A, B, or C (yes, no)

BILAG 2004 hematological organ system score of A, B, or C (yes, no)

PGA score

CLASI activity score 

CLASI activity score (≥10, < 10; ≥8, < 8)

CLASI damage score

Swollen joint count ≥ 6 and tender joint count ≥ 6 (yes, no)

Swollen joint count ≥ 2 and tender joint count ≥ 2 (yes, no)

Swollen joint count (≥2, ≤ 1)

Tender joint count (≥2, ≤ 1)

Swollen joint count

Tender joint count

Non-zero swollen joint count

Non-zero tender joint count

SLICC/ACR SLE damage index score

Antinuclear antibodies ≥1:40 (yes, no)

Antinuclear antibodies ≥1:80 (yes, no)

anti-DNA antibodies (normal, high)

Smith antibody (normal, abnormal)

Sjogrens SS-A antibody (normal, abnormal)

Sjogrens SS-B antibody (normal, abnormal)

Sjogrens SS-A antibody abnormal and/or Sjogrens SS-B antibody abnormal (yes, no)

Lupus anticoagulant (normal, high as determined by high in dilute Russell’s viper 
venom time ratio)

Cardiolipin antibody (any of IgG, IgM) (normal, high/abnormal)

Beta-2 glycoprotein 1 antibody (any of IgG, IgM, IgA) (normal, high)

High/abnormal in all of lupus anticoagulant, cardiolipin antibody (any of IgG, IgM), 
and Beta-2 glycoprotein 1 antibody (any of IgG, IgM, IgA) (yes, no)

Ribonucleoprotein antibody (normal, abnormal)


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
Baseline oral corticosteroids (OCS) (yes [alone, with antimalarials, with 
immuosuppressants], no)

Baseline OCS dose (mg/d)

Baseline OCS dose per clinical database (≥ 10 mg/d, < 10 mg/d)

Baseline OCS dose as randomized (≥ 10 mg/d, < 10 mg/d)

Baseline antimalarials (yes [hydroxychloroquine, quinacrine, chloroquine, alone, with
immuosuppressants], no)

Baseline immunosuppressants (yes [methotrexate, azathioprine, mycophenolic 
compounds, 6-mercaptopurine, leflunomide, sulfasalazine, oral tacrolimus, oral 
cyclosporine], no)
For categorical variables, a “missing” category will be added, where applicable, to account for
subjects in the ITT population who have a missing value for the variable.
Unless otherwise indicated (eg, screening SLEDAI 2K score per clinical database), the above  
demographic and characteristic variables refer to the baseline values; see Section 5.3.1 for the 
screen value and baseline value definitions. In particular, baseline cutaneous lupus subtype 
(collected at the screening and baseline visits) is defined as the last value on or before the date of 
the first dose of IP (ie, the value at the screening visit will be used as the baseline value if the 
value at the baseline visit is not available). The derivations of age and disease duration are given 
in Appendix B. Joint involvement and skin involvement will be determined according to the SLE 
medical history eCRF.
Baseline SLE medications are defined as all medications with the medical history of 
“SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)”, “JOINT INVOLVEMENT ARTHRITIS”, 
or “SKIN INVOLVEMENT” as the primary reason or an additional indication (according to the 
prior and concomitant medications eCRF and the SLE medical history eCRF) with an intake on 
the date of the first dose of IP (ie, start date on or before the date of the first dose of IP, and end 
date on or after the date of the first dose of IP or ongoing). The handling of partial or completely 
missing dates of medications is given in Appendix B. Specific SLE medications are identified as 
follows, together with the medical history of “SYSTEMIC LUPUS ERYTHEMATOSUS 
(SLE)”, “JOINT INVOLVEMENT ARTHRITIS”, or “SKIN INVOLVEMENT” being the 
primary reason or an additional indication:

OCS: ATC2 level = H02 according to the Anatomical Therapeutic Chemical (ATC) 
coding scheme of the World Health Organization Drug Dictionary (WHODD) and 
oral route of administration

Hydroxychloroquine: Preferred names containing HYDROXYCHLOROQUINE

Quinacrine: Preferred names containing MEPACRINE

Chloroquine: Preferred names containing CHLOROQUINE

Methotrexate: Preferred names containing METHOTREXATE

Azathioprine: Preferred names containing AZATHIOPRINE


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
Mycophenolic compounds: Preferred names containing MYCOPHENOLIC ACID or 
MYCOPHENOLATE MOFETIL

6-mercaptopurine: Preferred names containing MERCAPTOPURINE

Leflunomide: Preferred names containing LEFLUNOMIDE

Sulfasalazine: Preferred names containing SULFASALAZINE

Oral tacrolimus: Preferred names containing TACROLIMUS and oral route of 
administration

Oral cyclosporine: Preferred names containing CICLOSPORIN and oral route of 
administration
The baseline OCS (prednisone-equivalent) dose is defined as the daily OCS dose on the date of 
the first dose of IP. The calculation of daily OCS doses is detailed in Appendix C.
8.2.
Medical History
Medical history will be coded according to the MedDRA, and summarized by treatment group
(and overall), system organ class (SOC), and preferred term (PT) for the ITT population. A 
separate summary of ongoing medical history will be provided similarly. A listing of medical 
history will be provided for the ITT population.
8.3.
Prior and Concomitant Medications
Prior medications are defined as medications with a start date before the date of the first dose of 
IP (whether or not the end date is before the date of the first dose of IP). Concomitant 
medications during a safety analysis period defined in Section 5.2 are defined as medications 
taken at any time during the safety analysis period (ie, the start date is before the start date of the 
analysis period and the end date is on or after the start date of the analysis period or ongoing, or 
the start date is in the analysis period). The handling of partial or completely missing dates of 
medications is given in Appendix B.
Prior and concomitant medications will be coded using the ATC coding scheme of the WHODD. 
Prior medications will be summarized by treatment group (and overall), ATC2 level, and 
preferred name for the ITT population. Concomitant medications will be summarized by 
treatment group, ATC2 level, and preferred name for the placebo-controlled phase for the safety 
population, and for the CC-220-exposure periods for the CC-220 subjects as treated population.
A listing of prior and concomitant medications will be provided for the ITT population.
8.4.
Prior and concomitant Procedures
Prior procedures are defined as procedures with a start date before the date of the first dose of IP.
Concomitant procedures during a safety analysis period defined in Section 5.2 are defined as 
procedures performed at any time during the safety analysis period (ie, the start date is in the 


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analysis period). The handling of partial or completely missing dates of medications is given in 
Appendix B.
Prior and concomitant procedures will be coded according to the MedDRA. Prior medications 
will be summarized by treatment group (and overall), SOC, and PT for the ITT population. 
Concomitant procedures will be summarized by treatment group, SOC, and PT for the placebo-
controlled phase for the safety population, and for the CC-220-exposure periods for the CC-220 
subjects as treated population.
A listing of prior and concomitant procedures will be provided for the ITT population.


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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
9.1.
Treatment Duration
Treatment duration in days in a safety analysis period defined in Section 5.2 will be calculated as 
date of the last dose of IP in the analysis period – date of the first dose of IP in the analysis 
period + 1. Treatment duration in weeks is treatment duration in days divided by 7. The total 
person-years of treatment duration is the sum of treatment duration in days among all subjects 
divided by 365.25. For subjects who receive at least one dose of CC-220 after Week 24, the date 
of the last dose of IP in the placebo-controlled phase is defined as the date before the first Week 
24 dose of CC-220. Similarly, for subjects who receive at least one dose of CC-220 after Week 
52, the date of the last dose of IP in the Weeks 0-52 CC-220-exposure period is defined as the 
date before the first Week 52 dose of CC-220.
Descriptive statistics of treatment duration in weeks, a frequency summary of treatment duration 
categories, and the total person-years of treatment duration will be provided by treatment group 
for the placebo-controlled phase for the safety population, and for the CC-220-exposure periods 
for the CC-220 subjects as treated population. The treatment duration categories are the 
following:

Placebo-controlled phase: ≤8, > 8 to 16, > 16 to 24, > 24 weeks

Weeks 0-52 CC-220-exposure period: ≤8, > 8 to 16, > 16 to 24, > 24 to 38, > 38 to 52, 
> 52 weeks

Weeks 0-104 CC-220-exposure period: ≤8, > 8 to 16, > 16 to 24, > 24 to 38, > 38 to 52, 
> 52 to 65, > 65 to 78, > 78 to 91, > 91 to 104, > 104 weeks
A listing of study drug exposure records will be provided. 
9.2.
Overdose 
A listing of overdose records will be provided.
9.3.
Treatment Compliance 
Treatment compliance will be assessed using the drug accountability records. The compliance 
rate (%) in a period will be calculated as 100 times the total number of capsules taken over the 
period (the total number of dispensed capsules in the period minus the total number of returned 
capsules with the IP kit numbers matching those dispensed) divided by the intended total number 
of capsules that should have been taken over the same period. The total number of dispensed 
capsules in a period will be calculated from the following dispensing records:

Placebo-controlled phase: The dispensing records at the scheduled visits before Week 24 
and any unscheduled visits with a dispensing date before the dispensing date at Week 24 
for subjects who receive at least one dose of CC-220 after Week 24, or all dispensing 
records for subjects who do not receive at least one dose of CC-220 after Week 24

Active-treatment phase: The dispensing records at the scheduled visits between Week 24 
and Week 52 (inclusive of Week 24 and exclusive of Week 52) and any unscheduled 


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visits with a dispensing date on or after the dispensing date at Week 24 and before the 
dispensing date at Week 52 for subjects who receive at least one dose of CC-220 after 
Week 52, or the dispensing records at the scheduled visits at or after Week 24 and any 
unscheduled visits with a dispensing date on or after the dispensing date at Week 24 for 
subjects who do not receive at least one dose of CC-220 after Week 52

Extension phase: The dispensing records at the scheduled visits at or after Week 52 and 
any unscheduled visits with a dispensing date on or after the dispensing date at Week 52
The intended total number of capsules that should have been taken over a period will be 
calculated as 2 × (date of the last dose of IP in the period – date of the first dose of IP in the 
period + 1). For subjects who receive at least one dose of CC-220 after Week 24, the date of the 
last dose of IP in the placebo-controlled phase is defined as the date before the first Week 24 
dose of CC-220. Similarly, for subjects who receive at least one dose of CC-220 after Week 52, 
the date of the last dose of IP in the active-treatment phase is defined as the date before the first 
Week 52 dose of CC-220.
Descriptive statistics of treatment compliance rate and a frequency summary of treatment 
compliance rate categories (< 75%, 75% – 120%, and > 120%) will be provided by treatment 
group for the placebo-controlled phase for the ITT population, and for the active-treatment phase 
and extension phase for subjects who receive at least one dose of CC-220 after Week 24 and 
Week 52, respectively.
A listing of drug accountability records will be provided.


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10.
EFFICACY ANALYSIS
Unless otherwise specified, the efficacy analysis in Weeks 0-24 (placebo-controlled phase), 
Weeks 0-52 (placebo-controlled phase through active-treatment phase), and Weeks 52-104
(extension phase) will be based on the ITT population (Section 5.4.1), CC-220 subjects as 
randomized population (Section 5.4.5), and extension phase population (Section 5.4.7), 
respectively. Unless otherwise specified, the efficacy analysis tables will be presented by the 
following treatment groups:

Weeks 0-24 (placebo-controlled phase): placebo, 0.15 mg QD, 0.3 mg QD, and 0.45 
mg QD

Weeks 0-52 (placebo-controlled phase through active-treatment phase): placebo/0.3 
mg QD, placebo/0.45 mg QD, 0.15 mg QD, 0.3 mg QD, and 0.45 mg QD

Weeks 52-104 (extension phase): placebo/0.3 mg QD, placebo/0.45 mg QD, 0.15 mg 
QD, 0.3 mg QD, 0.45 mg QD, 0.3 mg QD combined, 0.45 mg QD combined
For the efficacy endpoints defined over Weeks 0-104 (as opposed to by time point in Weeks 
0-104), ie, standardized total OCS dose in weeks 0-104, annualized (severe) flare rate in Weeks 
0-104, time to the first (severe) flare in Weeks 0-104, and percentage of subjects who achieve 
SRI(4) at all of Week 24, Week 52, and Week 104, and at ≥ 70% of the visits between Week 24 
and Week 104 in subjects who achieve SRI(4) at Week 24, the analysis will be based on the CC-
220 subjects as randomized population and presented by placebo/0.3 mg QD, placebo/0.45 mg 
QD, 0.15 mg QD, 0.3 mg QD, and 0.45 mg QD.
For all endpoints, data based on observed cases will be summarized and presented in the same 
tables of the corresponding analysis results (where applicable). For continuous endpoints, 
descriptive statistics of the absolute value for subjects with a value at the post-baseline time 
point, the corresponding baseline value and change from baseline (also percent change from 
baseline only if it is analyzed as an endpoint) for subjects with a baseline value and a value at the 
post-baseline time point will be provided by time point, and data after the date of treatment 
failure will be considered missing for the efficacy analysis (ie, excluded from observed cases).
For binary endpoints, a frequency summary will be provided by time point, and subjects who 
have sufficient data (ie, observed cases) but have had an event of treatment failure before the 
date of assessment for the time point, while included in the analysis, will be nonresponders.
Planned figures will be provided only where explicitly specified.
10.1.
Multiplicity
The statistical tests comparing 0.3 mg QD with placebo and 0.45 mg QD with placebo with 
respect to the primary endpoint will be conducted at a 2-sided significance level of 0.1, with the 
multiplicity adjusted by the Hochberg procedure as follows. If the larger of the 2 p-values 
associated with the 2 tests is ≤ 0.1, then statistical significance will be declared for both tests; 
otherwise, statistical significance will not be declared for the test associated with the larger p-
value and the smaller p-value will be compared with 0.05. If the smaller p-value is ≤ 0.05, then 
statistical significance will be declared for the test associated with the smaller p-value; otherwise, 
no statistical significance will be declared for both tests.


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No multiplicity adjustments will be made for other comparisons. P-values from the tests not 
considered to be statistically significant due to the aforementioned multiplicity adjustment and 
from the tests not subject to multiplicity adjustment will be considered nominal.
10.2.
Primary Endpoint
The primary endpoint, the percentage of subjects who achieve SRI(4) at Week 24, will be 
analyzed by the Cochran-Mantel-Haenszel (CMH) test stratified by the following randomization 
stratification factors:

Baseline OCS dose (≥ 10 mg/d and < 10 mg/d)

Screening SLEDAI 2K score (≥ 10 points and < 10 points)
For each treatment comparison between a CC-220 dose and placebo, the unstratified difference 
in percentages, the stratified difference in percentages and the 2-sided 95% stratified Newcombe 
CI (Yan, 2010) for the difference using the CMH weights, and the 2-sided p-value from the 
CMH test will be provided. The validity of the chi-square approximation for the distribution of 
the CMH statistic will be assessed by the Mantel-Fleiss criterion, using the CMH 
(MANTELFLEISS) option in PROC FREQ. If the Mantel-Fleiss criterion is >= 5, the CMH test 
based on the chi-square distribution will be used; otherwise, an exact test that the common odds 
ratio across strata equals one, using the COMOR option in the EXACT statement and the “Sum 
<= Point” definition of the 2-sided p-value, will be used.
If one and only one of the 2 treatment groups being compared has no subject in a stratum, the 
stratified treatment comparison will not be performed, and the 2-sided 95% unstratified 
Newcombe CI for the difference and the p-value from the chi-square test will be provided; if 
both treatment groups being compared have no subject in a stratum, the stratified treatment 
comparison will stratify by the remaining strata. When used, the validity of the chi-square test 
will be assessed by the rule implemented in PROC FREQ, using the CHISQ (WARN=OUTPUT) 
option that adds a warning indicator variable to the output dataset when more than 20% of the 
table cells have expected frequencies < 5, in which case the 2-sided Barnard’s unconditional 
exact test, using the BARNARD option in the EXACT statement, will be used.
The following sensitivity analyses will be performed for the primary endpoint. All sensitivity 
analyses, except the tipping point analysis, will be presented in the same table as the primary 
analysis.
Sensitivity analysis with a tipping point analysis
To assess the impact of nonresponder imputation due to insufficient data for the Week 24 SRI(4) 
response determination (mainly due to early discontinuation before Week 24) (Section 5.5), a 
tipping point analysis, which varies the assumptions on the responses among subjects with 
insufficient data, will be performed as follows:

The percentage of subjects who achieve SRI(4) at Week 24 will be analyzed by the 
chi-square test, instead of the CMH test, since each step of the tipping point analysis 
involves changing a non-specific subject with insufficient data from not achieving 
SRI(4) to achieving SRI(4) and thus the randomization strata cannot be determined 
and used for the CMH test.


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
For the subset of subjects who do not have sufficient data (including the necessary 
baseline data) assessed within the analysis visit window for the Week 24 SRI(4) 
response determination and have not had an event of treatment failure (Section 5.6)
before the date of the last SRI assessment (ie, SLEDAI 2K, BILAG 2004, or PGA, if 
they are assessed on different dates) at Week 24 if such a date exists, or before the 
date of completion or discontinuation in the placebo-controlled phase (as collected in 
the placebo-controlled phase disposition eCRF), the Week 24 SRI(4) response status 
will change from not achieving SRI(4) (as in the primary analysis) to achieving 
SRI(4) in an iterative manner. The SRI(4) response at Week 24 for subjects that are 
not in the aforementioned subset will be the same as that in the primary analysis.

At each step of the tipping point analysis, one of the subjects from the 
aforementioned subset is changed from not achieving SRI(4) to achieving SRI(4), and 
the chi-square test is re-run. The test results in terms of statistical significance at the 
2-sided significance level of 0.1 will be presented in a grid where the x-axis and y-
axis represent the number of subjects assumed to achieve SRI(4) in the placebo group 
and the given CC-220 treatment group, respectively. The grid is limited from the top 
by the expected number of subjects from the aforementioned subset in the CC-220 
treatment group that could have achieved SRI(4) had they had sufficient data 
(calculated as the number of subjects from the aforementioned subset in the CC-220 
treatment group multiplied by the percentage of subjects achieving SRI(4) at Week 24 
among subjects in the CC-220 treatment group who have sufficient data for the Week 
24 SRI(4) response determination), and limited from the right by the number of 
subjects from the aforementioned subset in the placebo group. 

The grid will be divided into 3 regions:
o
Likely: This region’s right limit is the expected number of subjects from the 
aforementioned subset in the placebo group that could have achieved SRI(4) 
had they had sufficient data (calculated as the number of subjects from the 
aforementioned subset in the placebo group multiplied by the percentage of 
subjects achieving SRI(4) at Week 24 among subjects in the placebo group 
who have sufficient data for the Week 24 SRI(4) response determination)
o
Uncertain: This region’s right limit is the expected number of subjects from 
the aforementioned subset in the placebo group that could have achieved 
SRI(4) had they had sufficient data (calculated as the number of subjects from 
the aforementioned subset in the placebo group multiplied by the percentage
of subjects achieving SRI(4) at Week 24 among subjects in the CC-220 
treatment group who have sufficient data for the Week 24 SRI(4) response 
determination)
o
Unlikely: This is the region to the right of the uncertain region
Sensitivity analysis with multiple imputation
To assess the impact of nonresponder imputation due to insufficient data for the Week 24 SRI(4) 
response determination (mainly due to early discontinuation before Week 24) (Section 5.5), a 
sensitivity analysis using multiple imputation will be performed as follows:


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
For the subset of subjects who do not have sufficient data (including the necessary
baseline data) assessed within the analysis visit window for the Week 24 SRI(4) 
response determination and have not had an event of treatment failure (Section 5.6) 
before the date of the last SRI assessment (ie, SLEDAI 2K, BILAG 2004, or PGA, if 
they are assessed on different dates) at Week 24 if such a date exists, or before the 
date of completion or discontinuation in the placebo-controlled phase (as collected in 
the placebo-controlled phase disposition eCRF), missing values of the SRI 
assessments (SLEDAI-2k, BILAG 2004, or PGA) will be imputed separately, and the 
SRI(4) response at Week 24 will then be determined based on the imputed values of 
the SRI assessments. The SRI(4) response at Week 24 for subjects that are not in the 
aforementioned subset will be the same as that in the primary analysis. Missing 
values of the SRI assessments will be imputed as follows:
o
SLEDAI 2K: Missing SLEDAI 2K total scores at baseline, Weeks 4, 8, 12, 
16, 20, and 24 will be imputed as a continuous variable. Enough missing 
values will first be imputed, by treatment group and randomization 
stratification factors, with PROC MI using the MCMC 
IMPUTE=MONOTONE specification and a VAR statement specifying the 
variables of SLEDAI 2K scores at baseline, Weeks 4, 8, 12, 16, 20, and 24 in 
order of analysis visit to result in monotone missing data patterns. Then 
monotone missing values will be imputed, by treatment group, with PROC MI 
using the regression method and a VAR statement specifying first the 
randomization stratification factors and then the variables of SLEDAI 2K 
scores at baseline, Weeks 4, 8, 12, 16, 20, and 24 in order of analysis visit.
MINIMUM=0 and MAXIMUM=105 will be specified to ensure imputed 
values are within the range of SLEDAI 2K scores.
o
BILAG 2004: Missing BILAG 2004 binary responses, ie, whether or not the 
criterion of “no new BILAG 2004 A score or more than one new BILAG 2004 
B score compared to baseline” is met, at Weeks 4, 8, 12, 16, 20, and 24 will 
be imputed as a binary variable, by treatment group, with PROC MI using the 
FCS LOGISTIC specification, a VAR statement specifying first the 
randomization stratification factors, baseline BILAG 2004 global score, and 
then the variables of BILAG 2004 binary response at Weeks 4, 8, 12, 16, 20, 
and 24 in order of analysis visit (all VAR variables except for the baseline 
BILAG 2004 global score will also be specified in the CLASS statement).
o
PGA: Missing PGA scores will be imputed in the same way as the SLEDAI 
2K total scores. MINIMUM=0 and MAXIMUM=3 will be specified to ensure 
imputed values are within the range of PGA scores.

100 imputed datasets will be generated, and the results will be combined as follows:
o
The combined estimates of the percentage within each treatment group, and 
the unstratified and stratified differences in percentages will be calculated as 
the average of the corresponding estimates over all imputed datasets.
o
To calculate the combined 95% CIs for the stratified difference in 
percentages, the point estimate (calculated only for the purpose of calculating 


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the combined 95% CI) and associated standard error will be obtained from an 
adjusted Wald 95% CI (following the idea in Agresti, 1998) as follows for 
each imputed dataset and then combined using PROC MIANALYZE. The 
95% CI produced by PROC MIANALYZE will be reported as the combined 
95% CI. Let 
 = 	
/
 denote the estimated proportion in treatment group 
 and stratum ,  denote the CMH weight for stratum , and . denote the 
97.5th percentile of the standard normal distribution. The point estimate is 
∑

(
 −
 ) and the standard error is ∑


(
 !"
 #$% !"
 &
'!"

+
 !"
 )$% !"
 *
'!"

), 
where 
 = 
 + .

and 
 = (	
 + .

/2)/
.
o
The CMH test will be conducted for each imputed dataset. The value of the 
CMH general association test statistic will be transformed using the Wilson-
Hilferty transformation to create a more normally distributed statistic: z =
-./0/1%/
(/)0/2
, which is approximately normally distributed with a mean of 0 and 
a standard deviation of 1. The resulting transformed values from the 100 
imputed datasets will be combined using PROC MIANALYZE and the 
combined p-value for the CMH test will be obtained as the upper-tailed p-
value from the test produced by PROC MIANALYZE.
Sensitivity analysis with an observed case analysis
A sensitivity analysis with an observed case analysis will be performed based on the subset of 
subjects who have sufficient data (including necessary the baseline data) assessed within the 
analysis visit window for the Week 24 SRI(4) response determination, whether or not having had 
an event of treatment failure (Section 5.6) before the date of the last SRI assessment (ie, SLEDAI 
2K, BILAG 2004, or PGA, if they are assessed on different dates) at Week 24 (subjects with an 
event of treatment failure before the date of the last SRI assessment at Week 24, while included 
in this analysis, will be nonresponders). The same analysis methods described for the primary 
analysis will then be applied to this subset.
Sensitivity analysis with a per-protocol analysis
A sensitivity analysis using the per-protocol population will be performed, with the same 
analysis methods described for the primary analysis applied to the per-protocol population.
Dose-response modeling
Dose-response modeling with different assumed dose-response shapes may be explored.
10.3.
Secondary Endpoints
10.3.1.
SLEDAI 2K
The secondary endpoint evaluating SLEDAI 2K is the percentage of subjects with an 
improvement of ≥ 4 from baseline in the SLEDAI 2K score at Week 24. The analysis methods 
described for the primary analysis of the primary endpoint (simply referred to as the analysis of 
the primary endpoint hereafter) in Section 10.2 will be used. The results will be presented in the 


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table of the longitudinal presentation of the results by time point in Weeks 0-24 rather than in a
standalone table.
10.3.2.
CLASI
The secondary endpoint evaluating CLASI is the percentage of subjects with an improvement of 
≥ 50% from baseline in the CLASI activity score at Week 24, in subjects with baseline CLASI 
activity score ≥ 10. The analysis methods described for the analysis of the primary endpoint in 
Section 10.2 will be used. The results will be presented in the table of the longitudinal 
presentation of the results by time point in Weeks 0-24 rather than in a standalone table.
10.3.3.
BILAG 2004
The secondary endpoint evaluating BILAG 2004 is the percentage of subjects with no new 
BILAG 2004 A score or more than one new BILAG 2004 B score compared to baseline at Week 
24. The analysis methods described for the analysis of the primary endpoint in Section 10.2 will 
be used. The results will be presented in the table of the longitudinal presentation of the results 
by time point in Weeks 0-24 rather than in a standalone table.
10.3.4.
PGA
Percentage of subjects with no worsening from baseline (defined as change of < 0.30 from 
baseline) in the PGA score at Week 24
The analysis methods described for the analysis of the primary endpoint in Section 10.2 will be 
used. The results will be presented in the table of the longitudinal presentation of the results by 
time point in Weeks 0-24 rather than in a standalone table.
Change from baseline in the PGA score at Week 24
The change from baseline in the PGA score at Week 24 will be analyzed by the adaptive 
approach that uses either a LDA model (in the absence of severe departures from normality) or 
multiple imputation in conjunction with a robust regression model that uses M-estimation (in the 
presence of severe departures from normality).
The LDA model assumes a common mean across treatment groups at baseline and a different 
mean for each treatment group at each of the post-baseline time points. The response vector 
consists of the baseline value and the post-baseline values at Weeks 4, 8, 12, 16, 20, and 24. 
Time is treated as a categorical variable so that no restriction is imposed on the trajectory of the 
means over time. The model will also adjust for the randomization stratification factors (baseline 
OCS dose [≥ 10 mg/d and < 10 mg/d], screening SLEDAI 2K score [≥ 10 points and < 10 
points]), and their interactions with time. An unstructured covariance matrix will be used to 
model the correlation among repeated measurements. The Kenward-Roger adjustment will be 
used with restricted maximum likelihood to make proper statistical inference. If the model with 
an unstructured covariance fails to converge with the default Newton-Raphson algorithm, the 
Fisher scoring algorithm or other appropriate methods can be used to provide initial values of the 
covariance parameters. In the rare event that none of the above methods yields convergence, a 
structured covariance such as the heterogeneous Toeplitz or Toeplitz structures will be used to 
model the correlation among repeated measurements. In this case, the empirical option will be 
used because the sandwich variance estimator is asymptotically unbiased while the model-based 


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variance estimator can grossly overestimate or underestimate the true variance. Adjusted within-
group means and the associated SEs, adjusted treatment differences in means between CC-220 
doses and placebo and the associated SEs and 2-sided 95% CIs and 2-sided p-values will be 
derived from the LDA model.
The LDA model assumes the vector of the model-based residuals follows a multivariate normal 
distribution. Under severe departures from normality, the LDA model can be inefficient or 
potentially misleading. Accordingly, the vector of the residuals from the LDA model, scaled by 
the inverse Cholesky root of the estimated variance-covariance matrix, will be subjected to a test 
for normality. If normality is not rejected at the significance level of 0.001, then the LDA model 
will be used for the analysis. However, if normality is rejected, then the analysis will be 
conducted using multiple imputation in conjunction with a robust regression model that uses M-
estimation. Of note, the significance level of 0.001 for the normality test is chosen so that the 
LDA is abandoned only under a clear departure from normality. Multiple imputation will be 
performed in the same way as described for the sensitivity analysis of the primary endpoint with 
multiple imputation (Section 10.2). A robust regression model that uses M-estimation will be run 
for each imputed dataset by using PROC ROBUSTREG, with the change from baseline at a 
given post-baseline time point (Weeks 4, 8, 12, 16, 20, or 24) as the response variable and 
adjusting for treatment group, the baseline value, and the randomization stratification factors 
(baseline corticosteroid dose [≥ 10 mg/d and < 10 mg/d] and screening SLEDAI 2K score [≥ 10 
points and < 10 points]). The COVOUT option will be specified in the PROC ROBUSTREG 
statement to output the estimated covariance matrix of the parameter estimates to the OUTEST= 
dataset. Adjusted within-group means are not provided directly by PROC ROBUSTREG and 
will be calculated as (assuming the placebo group is coded as the last level of the treatment term 
and therefore the reference treatment group)
for the placebo group, where β
4, β5678 9
: , β<
4, β7= , β>
4 are the parameter estimates for the intercept, 
CC-220 dose  ( = 0.15 mg QD, 0.3 mg QD, 0.45 mg QD), baseline corticosteroid dose, 
screening SLEDAI 2K score, and the baseline value, respectively, from the OUTEST= dataset, 
and baseline mean is the overall mean of the baseline values across the treatment groups in the 
intended analysis population (ITT population in this case). The SEs for the adjusted within-group 
means will be calculated as √G′ΣG, where Σ is the estimated 7-dimentional covariance matrix of 
the parameter estimates from the OUTEST= dataset and G is the 7-dementional vector of 
coefficients in the aforementioned calculation of adjusted within-group means, ie, GJ =
(1, 1, 0, 0, 0.5, 0.5, @ABCDC ECA), GJ = (1, 0, 1, 0, 0.5, 0.5, @ABCDC ECA), GJ =
(1, 0, 0, 1, 0.5, 0.5, @ABCDC ECA), and GJ = (1, 0, 0, 0, 0.5, 0.5, @ABCDC ECA) for the CC-
220 treatment and placebo groups, respectively. Adjusted treatment differences in means 
between CC-220 doses and placebo and the associated SEs are simply the parameter estimates 
β5678 9
: and the associated SEs provided in the ODS table ParameterEstimates. The above results 
from each imputed dataset will be combined using PROC MIANALYZE, from which adjusted 
within-group means and the associated SEs, adjusted treatment differences in means between 


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CC-220 doses and placebo and the associated SEs and 2-sided 95% CIs and 2-sided p-values will 
be provided.
The results at each post-baseline time point (Weeks 4, 8, 12, 16, 20, and 24) will be presented.
Line plots of adjusted means with SEs (also showing the number of subjects and the adjusted 
mean) by time point will be provided.
10.3.5.
Joint Counts
The secondary endpoints evaluating joint counts are the mean change from baseline in swollen 
joint count at Week 24 in subjects with ≥2 swollen joints at baseline and the mean change from
baseline in tender joint count at Week 24 in subjects with ≥2 tender joints at baseline. The 
analysis methods described for the mean change from baseline in the PGA score in Section 
10.3.4 will be used. Line plots of adjusted means with SEs (also showing the number of subjects 
and the adjusted mean) by time point will be provided.
10.3.6.
Fatigue
The secondary endpoint evaluating fatigue is the mean change from baseline in the 
FACIT-Fatigue score at Week 24. The analysis methods described for the mean change from 
baseline in the PGA score in Section 10.3.4 will be used, with the appropriate post-baseline time 
points. Line plots of adjusted means with SEs (also showing the number of subjects and the 
adjusted mean) by time point will be provided.
10.3.7.
Corticosteroid Reduction
Percentage of subjects with oral corticosteroid (OCS) dose reduced to ≤ 7.5 mg/day by 
Week 16 and maintained through Week 24 with no flares between Week 16 and Week 24, 
in subjects with baseline OCS dose ≥10 mg/day
The analysis methods described for the analysis of the primary endpoint in Section 10.2 will be 
used, except that the randomization stratification factors in the stratified analysis will be reduced 
to only screening SLEDAI 2K score (≥ 10 points and < 10 points).
Percentage of subjects with OCS dose reduced to < 10 mg/day by Week 16 and maintained 
through Week 24 with no flares between Week 16 and Week 24, in subjects with baseline 
OCS dose ≥ 10 mg/day
The analysis methods described for the above endpoint will be used. The analysis of this 
endpoint will be presented in the same table as the one above.
Percent change from baseline in OCS dose at Week 24 in subjects with the baseline OCS 
dose ≥10 mg/day
The results of the mean percent change and median percent change from baseline will be 
presented in one table.
To assess the mean percent change, the analysis methods described for the mean change from 
baseline in the PGA score in Section 10.3.4 will be used. The randomization stratification factors 
in the stratified analysis will be reduced to only screening SLEDAI 2K score (≥ 10 points and 
< 10 points). The response vector in the LDA model consists of the baseline value and the post-
baseline percent changes from baseline, whereas the response variable in the robust regression 


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model is the percent change from baseline at a given post-baseline time point. As many zero 
changes from baseline in OCS dose are expected, model fitting issues may arise due to these 
excessive zeros, particularly with the robust regression model. In the event of unresolvable 
modeling fitting issues, the corresponding modeling results will not be provided at the time 
points impacted.
To assess the median percent change, multiple imputation in conjunction with a quantile 
regression model will be used. Multiple imputation will be performed in the same way as 
described for the sensitivity analysis of the primary endpoint with multiple imputation (Section 
10.2). A quantile regression model will be run for each imputed dataset by using PROC 
QUANTREG, with the percent change from baseline at a given post-baseline time point (Weeks 
4, 8, 12, 16, 20, or 24) as the response variable and adjusting for treatment group, the baseline 
value, and the randomization stratification factor (screening SLEDAI 2K score [≥ 10 points and 
< 10 points]). The CI=RESAMPLING option will be specified in the PROC QUANTREG 
statement and the QUANTILE=0.5 option will be specified in the MODEL statement. Adjusted 
within-group medians and the associated SEs will be estimated by using the ESTIMATE 
statement (eg, ESTIMATE ‘0.15 mg QD median’ INTERCEPT 1 TREATMENT 1 0 0 0 
BLOCS baseline mean, where the treatment term is coded in the order of 0.15 mg QD, 0.3 mg
QD, 0.45 mg QD, placebo, BLOCS is the variable for baseline OCS dose, and the overall 
baseline mean OCS dose across the treatment groups in the intended analysis population [ITT 
population with the baseline OCS dose ≥ 10 mg/day in this case] is used as the coefficient for 
BLOCS) and the results are provided in the ODS table Estimates. Adjusted treatment differences 
in medians between CC-220 doses and placebo and the associated SEs are simply the parameter 
estimates and the associated SEs for the treatment term (coded in the order of 0.15 mg QD, 0.3 
mg QD, 0.45 mg QD, placebo) provided in the ODS table ParameterEstimates. The above results 
from each imputed dataset will be combined using PROC MIANALYZE, from which adjusted 
within-group medians and the associated SEs, adjusted treatment differences in medians between 
CC-220 doses and placebo and the associated SEs and 2-sided 95% CIs and 2-sided p-values will 
be provided. Other quantiles (other than 50% or median) of the percent change from baseline 
may be explored in the same manner if no treatment effects are demonstrated for the median 
percent change from baseline. The results at each post-baseline time point (Weeks 4, 8, 12, 16, 
20, and 24) will be presented in one table.
Standardized total OCS dose in Weeks 0-24
The analysis methods described for the mean change from baseline in the PGA score in Section 
10.3.4 will be used. The response vector in the LDA model consists of the baseline OCS dose 
and the calculated post-baseline standardized total OCS dose, whereas the response variable in 
the robust regression model is the calculated post-baseline standardized total OCS dose (the 
baseline OCS dose still as a covariate). By construction of this endpoint, missing data is not 
possible, so multiple imputation will not be applicable if the robust regression model is used 
under a clear departure from normality.
The adjusted average daily OCS dose will be calculated as the adjusted mean standardized total 
OCS dose divided by the normalizing duration of 168 days.
























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10.5.
Subgroup Analysis
To assess whether the treatment effect is consistent across various subgroups, treatment 
differences in percentages and nominal 2-sided 95% CIs for the primary endpoint (percentage of 
subjects who achieve SRI(4) at Week 24) will be provided within each category of the following 
classification variables:

Age (< 40, 40 to < 65, ≥ 65 years)

Sex (male, female)

Race (Black or African American, White, others)

Ethnicity (Hispanic or Latino, others)

Region (North America, Europe, South America [including Mexico], Russia)

Baseline weight (< 70, ≥ 70 kg)

Duration of SLE (≤2, > 2 to 5, > 5 years)


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
Baseline cutaneous lupus subtype (acute, subacute, chronic, any of acute, subacute, or 
chronic, any of subacute or chronic)

Screening SLEDAI 2K score per clinical database (≥10, < 10)

Baseline BILAG 2004 1 A or 2 B scores (yes, no)

Baseline CLASI activity score (≥8, < 8)

Baseline CLASI activity score (≥10, < 10)

Baseline swollen joint count ≥6 and tender joint count ≥6 (yes, no)

Baseline antinuclear antibodies ≥1:40 (yes, no)

Baseline OCS dose per clinical database (≥ 10 mg/d, < 10 mg/d)

Baseline antimalarials (yes, no)

Baseline immuosuppressants (yes, no)
If the value of a classification variable cannot be determined, the subject will be excluded from 
the corresponding subgroup analysis.
In addition to the individual treatment groups, the 0.3 mg QD and 0.45 mg QD treatment groups 
will be combined to form an additional CC-220 treatment group in the subgroup analysis. The 
unstratified percentage within each treatment group will be provided. For each treatment 
comparison between a CC-220 group and the placebo group, the unstratified difference in 
percentages, the stratified difference in percentages and the 2-sided 95% stratified Newcombe CI 
(Yan, 2010) for the difference using the CMH weights will be provided by category of the 
classification variables listed above.
For the subgroup analysis of each of the 2 randomization stratification factors (baseline OCS 
dose and screening SLEDAI 2K score), the stratified analysis will only stratify by the other 
factor. If one and only one of the 2 treatment groups being compared has no subject in a stratum, 
the stratified treatment comparison will not be performed (the stratified difference in percentages 
and the 2-sided 95% stratified Newcombe CI for the difference using the CMH weights will not 
be provided) and the 2-sided 95% unstratified Newcombe CI for the difference will be provided; 
if both treatment groups being compared have no subject in a stratum, the stratified treatment 
comparison will stratify by the remaining strata.
Forest plots for the treatment differences in percentages by subgroup will be provided.


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11.
SAFETY ANALYSIS
The safety analysis for the placebo-controlled phase, the Weeks 0-52 and Weeks 0-104 CC-220-
exposure periods, and the extension phase (Section 5.2) will be based on the safety population 
(Section 5.4.2), the CC-220 subjects as treated population (Section 5.4.6), and the extension 
phase population (Section 5.4.7), respectively. The safety analysis tables will be presented by the 
following treatment groups:

Placebo-controlled phase: placebo, 0.15 mg QD, 0.3 mg QD, 0.45 mg QD, and CC-
220 total

CC-220-exposure periods and extension phase: 0.15 mg QD, 0.3 mg QD, 0.45 mg 
QD, and CC-220 total
Unless otherwise specified, all safety summaries will be provided separately for the placebo-
controlled phase, the Weeks 0-52 CC-220-exposure period, and the Weeks 0-104 CC-220-
exposure period. All AE summaries will also be provided for the extension phase, unless 
otherwise specified.
11.1.
Adverse Events
Unless otherwise specified, all frequency summaries of AEs will provide the EAIR and be 
presented by system organ class (SOC) and preferred term (PT), with SOCs sorted in the 
standard international order and PTs within each SOC in descending order of percentage (and
then alphabetically if needed). A subject with multiple occurrences will be counted only once for 
each applicable category (eg, any TEAE, or a given SOC or PT).
Overall summaries of subjects with at least one TEAE in the following categories will be 
provided:

Any TEAE

Any drug-related TEAE

Any severe TEAE 

Any serious TEAE

Any TEAE leading to drug interruption

Any TEAE leading to drug withdrawal

Any TEAE leading to death
Subjects with at least one TEAE will be summarized for the following categories:

Any TEAE

Any TEAE ≥5% in any treatment group, including CC-220 total (not provided for 
the extension phase)

Any TEAE by time interval (not provided for the Weeks 0-104 CC-220-exposure 
period and the extension phase)

Any drug-related TEAE


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
Any TEAE by maximum severity (EAIR will not be provided for this summary)

Any serious TEAE

Any TEAE leading to drug withdrawal

Any TEAE leading to death
Listings of all AEs (TEAEs and non-TEAEs), serious AEs (TEAEs and non-TEAEs), TEAEs
leading to drug withdrawal, and all deaths will be provided.
11.2.
Clinical Laboratory Tests
For the protocol-specified laboratory analytes of hematology, serum chemistry, immunology, 
and urinalysis, descriptive statistics of the baseline value, the absolute value and the change from 
baseline by time point (including the follow-up visit), and tables of shifts from baseline by time 
point (including each post-baseline time point, the maximum value [or the worst value for non-
numeric urinalysis analytes], the minimum value [not applicable for non-numeric urinalysis 
analytes], and the last value in the safety analysis period [Section 5.2]) in abnormality category 
(low/normal/high, or normal/abnormal where applicable, eg, for some urinalysis parameters) 
according to the reference range will be provided. As noted in Section 5.2, these summaries will 
include testosterone, FSH, and LH that are collected at the 12-week follow-up visit for males 
only, irrespective of their timing relative to the end of the respective period.
A frequency summary of subjects with laboratory marked abnormalities (Appendix D) by time 
point and at least once in the safety analysis period (Section 5.2) will be provided.
A shift table of neutrophil (“Neutrophils, segmented and band form”), lymphocyte, and 
hemoglobin shifts from baseline by time point (including each post-baseline time point, the 
minimum value, and the last value in the safety analysis period [Section 5.2]) in CTCAE grade 
for overall subjects and by baseline use of methotrexate (yes, no), azathioprine (yes, no), 
mycophenolic compounds (yes, no), oral tacrolimus or oral cyclosporine (yes, no) will be 
provided.
For the time to the first neutropenia (“Neutrophils, segmented and band form”) of CTCAE grade 
3 or above, the numbers of subjects who have an event (neutropenia of CTCAE grade 3 or 
above) and who are censored will be summarized. The KM estimates of the 25th, median, and 
75th percentile of the time to the first event and the 2-sided 95% CIs will be provided. The 
cumulative number of events, the number of subjects at risk, and the KM estimate of the event 
rate (ie, failure probability instead of survival probability) and SE will be provided by time point 
(Weeks 4, 8, 12, etc.). The KM plot of failure curves (instead of survival curves) with the 
number of subjects at risk at each time point will be presented.
A listing of all values of the applicable laboratory analytes will be provided for subjects with any 
laboratory marked abnormalities. A listing of all laboratory data will also be provided.
11.3.
Vital Signs and Weight
Descriptive statistics of the baseline value, the absolute value and the change from baseline in 
vital signs and weight by time point (including the follow-up visit), and tables of shifts from 
baseline by time point (including each post-baseline time point, the maximum value, the 


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minimum value, and the last value in the safety analysis period [Section 5.2]) in abnormality 
category (low/normal/high) according to the reference range for the applicable vital signs will be 
provided.
A frequency summary of subjects with vital signs marked abnormalities (Appendix E) by time 
point and at least once in the safety analysis period (Section 5.2) will be provided.
A listing of all values of the applicable vital signs will be provided for subjects with any marked 
abnormalities. A listing of all vital signs and weight will also be provided.
11.4.
ECG
Descriptive statistics of the baseline value, the absolute value and the change from baseline in 
ECG variables by time point (including the follow-up visit), and tables of shifts from baseline by 
time point (including each post-baseline time point, the worst result, and the last result in the
safety analysis period [Section 5.2]) in abnormality category (normal/abnormal, not clinically 
significant/abnormal, clinically significant ECG interpretation results) will be provided.
A frequency summary of subjects with ECG potentially clinically significant values/changes 
from baseline (Appendix F) by time point and at least once in the safety analysis period (Section 
5.2) will be provided.
A listing of all values of the applicable ECG variables will be provided for subjects with any 
potentially clinically significant values/changes from baseline. A listing of all ECG interpretation 
results will be provided for subjects with any clinically significantly abnormal interpretation 
result. A listing of all ECG variables and interpretation results will also be provided.








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13.
INTERIM ANALYSIS
One unblinded interim analysis is planned. The purpose of the interim analysis is to ensure that 
the study is conducted with an acceptable benefit/risk ratio by reviewing the safety and efficacy 
data, including the efficacy data in subgroups defined by baseline mRNA and DNA. The interim 
analysis will be conducted after approximately 50% of the subjects (approximately 140 subjects) 
have completed or discontinued prior to Week 24. An independent external Data Monitoring 
Committee (DMC) will review the interim analysis results and make recommendations, 
including discontinuing any CC-220 treatment group or the study. The operational details are 
documented in the DMC charter.


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14.
CHANGES TO THE STATISTICAL SECTION OF THE 
PROTOCOL
The following changes have been made to the statistical section of the protocol:

Changes have been made to the exploratory efficacy endpoints as a result of expert 
input received after the finalization of the protocol version on which this SAP is 
based.

The protocol states that no multiplicity adjustment will be conducted for this Phase 2 
study. In this SAP, multiplicity adjustment using the Hochberg procedure will be 
applied to the statistical tests comparing 0.3 mg QD with placebo and 0.45 mg QD 
with placebo with respect to the primary endpoint.


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16.
APPENDICES


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APPENDIX A. ANALYSIS VISIT WINDOWS
Table 3:
Analysis Visit Windows
Analysis Visit
Scheduled Study Day
a
Analysis Visit Windowa
SLEDAI 2K, SLEDAI Flare Index, BILAG 2004, PGA, Swollen and Tender Joint Counts, ds-DNA, Complement Panel, 
Urine Protein/Creatinine, Chemistry, Urinalysis, eGFR, Vital Signs
Baseline
≤ 1
≤ 1
Week 4
29
2 – 42
Week 8
57
43 – 70
Week 12
85
71 – 98
Week 16
113
99 – 126
Week 20
141
127 – 154
Week 24
169

Except for the safety analysis in the CC-220-exposure period for 
subjects who switch from placebo to CC-220 at Week 24:
155 – Date of the first Week 24 dose of CC-220 (or date of CC-
220 dispensing at Week 24 as a substitute
b
) for subjects who 
receive at least one dose of CC-220 after Week 24, or
≥155 for subjects who do not receive at least one dose of CC-
220 after Week 24

For the safety analysis in the CC-220-exposure period for 
subjects who switch from placebo to CC-220 at Week 24: 155 –
182
Week 28
197

Except for the safety analysis in the CC-220-exposure period for 
subjects who switch from placebo to CC-220 at Week 24: Date 
after the first Week 24 dose of CC-220 – 210

For the safety analysis in the CC-220-exposure period for 
subjects who switch from placebo to CC-220 at Week 24: 183 –
210
Week 32
225
211 – 238
Week 36
253
239 – 266
Week 40
281
267 – 294
Week 44
309
295 – 322
Week 48
337
323 – 350
Week 52
365
351 – 406
Week 64
449
407 – 490
Week 76
533
491 – 574
Week 88
617
575 – 672
Week 104
729
≥ 673
CLASI Activity
Baseline
≤ 1
≤ 1
Week 4
29
2 – 42
Week 8
57
43 – 70
Week 12
85
71 – 98


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Analysis Visit
Scheduled Study Day
a
Analysis Visit Windowa
Week 16
113
99 – 126
Week 20
141
127 – 154
Week 24
169
155 – Date of the first Week 24 dose of CC-220 (or date of CC-220 
dispensing at Week 24 as a substituteb) for subjects who receive at least 
one dose of CC-220 after Week 24, or
≥155 for subjects who do not receive at least one dose of CC-220 after 
Week 24
Week 40
281
Date after the first Week 24 dose of CC-220 – 322
Week 52
365
323 – 406
Week 64
449
407 – 490
Week 76
533
491 – 574
Week 88
617
575 – 672
Week 104
729
≥ 673
CLASI Damage, HAQ-DI, Lupus Autoantibody Panel
Baseline
≤ 1
≤ 1
Week 24
169
2 – Date of the first Week 24 dose of CC-220 (or date of CC-220 
dispensing at Week 24 as a substituteb) for subjects who receive at least 
one dose of CC-220 after Week 24, or
≥2 for subjects who do not receive at least one dose of CC-220 after Week 
24
Week 52
365
Date after the first Week 24 dose of CC-220 – 546
Week 104
729
≥ 547
FACIT Fatigue
Baseline
≤ 1
≤ 1
Week 12
85
2 – 126
Week 24
169
127 – Date of the first Week 24 dose of CC-220 (or date of CC-220 
dispensing at Week 24 as a substituteb) for subjects who receive at least 
one dose of CC-220 after Week 24, or
≥ 127 for subjects who do not receive at least one dose of CC-220 after 
Week 24
Week 36
253
Date after the first Week 24 dose of CC-220 – 308
Week 52
365
309 – 448
Week 76
533
449 – 630
Week 104
729
≥ 631
SF-36
Baseline
≤ 1
≤ 1
Week 12
85
2 – 126


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Analysis Visit
Scheduled Study Day
a
Analysis Visit Windowa
Week 24
169
127 – Date of the first Week 24 dose of CC-220 (or date of CC-220 
dispensing at Week 24 as a substituteb) for subjects who receive at least 
one dose of CC-220 after Week 24, or
≥ 127 for subjects who do not receive at least one dose of CC-220 after 
Week 24
Week 52
365
Date after the first Week 24 dose of CC-220 – 448
Week 76
533
449 – 630
Week 104
729
≥ 631
LupusPRO
Baseline
≤ 1
≤ 1
Week 24
169
2 – Date of the first Week 24 dose of CC-220 (or date of CC-220 
dispensing at Week 24 as a substituteb) for subjects who receive at least 
one dose of CC-220 after Week 24, or
≥2 for subjects who do not receive at least one dose of CC-220 after Week 
24
Week 52
365
Date after the first Week 24 dose of CC-220 – 406
Week 64
449
407 – 490
Week 76
533
491 – 574
Week 88
617
575 – 672
Week 104
729
≥ 673
SLICC/ACR SLE Damage Index
Baseline
≤ 1
≤ 1
Week 52
365
2 – 546
Week 104
729
≥ 547
Hematology
Baseline
≤ 1
≤ 1
Week 4
29
2 – 42
Week 8
57
43 – 70
Week 12
85
71 – 98
Week 16
113
99 – 126
Week 20
141
127 – 154
Week 24
169

Except for the data in the CC-220-exposure period for subjects 
who switch from placebo to CC-220 at Week 24:
155 – Date of the first Week 24 dose of CC-220 (or date of CC-
220 dispensing at Week 24 as a substituteb) for subjects who 
receive at least one dose of CC-220 after Week 24, or
≥155 for subjects who do not receive at least one dose of CC-
220 after Week 24

For the data in the CC-220-exposure period for subjects who 
switch from placebo to CC-220 at Week 24: 155 – 182


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Analysis Visit
Scheduled Study Day
a
Analysis Visit Windowa
Week 28
197

Except for the data in the CC-220-exposure period for subjects 
who switch from placebo to CC-220 at Week 24: Date after the 
first Week 24 dose of CC-220 – 210

For the data in the CC-220-exposure period for subjects who 
switch from placebo to CC-220 at Week 24: 183 – 210
Week 32
225
211 – 238
Week 36
253
239 – 266
Week 40
281
267 – 294
Week 44
309
295 – 322
Week 48
337
323 – 350
Week 52
365
351 – 378
Week 56
393
379 – 406
Week 60
421
407 – 434
Week 64
449
435 – 462
Week 68
477
463 – 490
Week 72
505
491 – 518
Week 76
533
519 – 546
Week 80
561
547 – 574
Week 84
589
575 – 602
Week 88
617
603 – 630
Week 92
645
631 – 658
Week 96
673
659 – 686
Week 100
701
687 – 714
Week 104
729
≥ 715
ECG
Baseline
≤ 1
≤ 1
Week 4
29
2 – 98
Week 24
169

Except for the data in the CC-220-exposure period for subjects 
who switch from placebo to CC-220 at Week 24:
99 - Date of the first Week 24 dose of CC-220 (or date of CC-220 
dispensing at Week 24 as a substituteb) for subjects who receive 
at least one dose of CC-220 after Week 24, or
≥99 for subjects who do not receive at least one dose of CC-220 
after Week 24

For the data in the CC-220-exposure period for subjects who 
switch from placebo to CC-220 at Week 24: 99 – 182
Week 28
197

Except for the data in the CC-220-exposure period for subjects 
who switch from placebo to CC-220 at Week 24: Date after the 
first Week 24 dose of CC-220 – 280

For the data in the CC-220-exposure period for subjects who 
switch from placebo to CC-220 at Week 24: 183 – 280


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Analysis Visit
Scheduled Study Day
a
Analysis Visit Windowa
Week 52
365
281 – 546
Week 104
729
≥ 547
IgA, IgM, IgG, Testosterone, FSH, LH
Baseline
≤ 1
≤ 1
Week 24
169

Except for the data in the CC-220-exposure period for subjects 
who switch from placebo to CC-220 at Week 24:
2 – Date of the first Week 24 dose of CC-220 (or date of CC-220 
dispensing at Week 24 as a substituteb) for subjects who receive 
at least one dose of CC-220 after Week 24, or
≥2 for subjects who do not receive at least one dose of CC-220 
after Week 24

For the data in the CC-220-exposure period for subjects who 
switch from placebo to CC-220 at Week 24: 2 – 266
Week 52
365

Except for the data in the CC-220-exposure period for subjects 
who switch from placebo to CC-220 at Week 24: Date after the 
first Week 24 dose of CC-220 – 448

For the data in the CC-220-exposure period for subjects who 
switch from placebo to CC-220 at Week 24: 267 – 448
Week 76
533
449 – 630
Week 104
729
≥ 631
ESR, hsCRP
Baseline
≤ 1
≤ 1
Week 12
85
2 – 126
Week 24
169

Except for the data in the CC-220-exposure period for subjects 
who switch from placebo to CC-220 at Week 24:
127 – Date of the first Week 24 dose of CC-220 (or date of CC-
220 dispensing at Week 24 as a substituteb) for subjects who 
receive at least one dose of CC-220 after Week 24, or
≥ 127 for subjects who do not receive at least one dose of CC-
220 after Week 24

For the data in the CC-220-exposure period for subjects who 
switch from placebo to CC-220 at Week 24: 127 – 210
Week 36
253

Except for the data in the CC-220-exposure period for subjects 
who switch from placebo to CC-220 at Week 24: Date after the 
first Week 24 dose of CC-220 – 308

For the data in the CC-220-exposure period for subjects who 
switch from placebo to CC-220 at Week 24: 211 – 308
Week 52
365
≥ 309
Lupus Anti-Phospholipid Profile
Baseline
≤ 1
≤ 1
Week 12
85
2 – 126


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Analysis Visit
Scheduled Study Day
a
Analysis Visit Windowa
Week 24
169
127 – Date of the first Week 24 dose of CC-220 (or date of CC-220 
dispensing at Week 24 as a substituteb) for subjects who receive at least 
one dose of CC-220 after Week 24, or
≥ 127 for subjects who do not receive at least one dose of CC-220 after 
Week 24
Week 36
253
Date after the first Week 24 dose of CC-220 – 308
Week 52
365
309 – 406
Week 64
449
407 – 490
Week 76
533
491 – 574
Week 88
617
575 – 672
Week 104
729
≥ 673
a Unless otherwise specified, study day is defined as date of assessment/collection – date of the first dose of IP + 1 if the date of 
assessment/collection is on or after the date of the first dose of IP, or date of assessment/collection – date of the first dose of IP 
if the date of assessment/collection is before the date of the first dose of IP. For visit-based safety data (ie, labs, vital signs, and 
ECG) in the CC-220-exposure period for subjects who switch from placebo to CC-220 at Week 24, study day is defined as date 
of assessment/collection – date of the first dose of CC-220 + 1.
b At the time of the interim analysis or the Week 24 analysis, if the date of the first Week 24 dose of CC-220 (derived from the 
Study Drug Exposure eCRF which may not be entered by sites until the next visit after Week 24) is not yet available for 
subjects with CC-220 dispensed at Week 24 and on or before the (possibly derived) date of the last dose of IP as of the time of 
analysis (ie, no evidence that the subject has discontinued without receiving at least one dose of CD-220 after Week 24), the 
date of CC-220 dispensing at Week 24 will replace the date of the first Week 24 dose of CC-220 in the above definition for 
these subjects.


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APPENDIX B. HANDLING OF PARTIAL OR COMPLETELY MISSING 
DATES
Age
Age (in years) will be calculated as the integer part of (date of informed consent – date of birth + 
1) / 365.25 when the complete date of birth is collected; otherwise, the age recorded will be used.
Disease Duration
Disease duration (in years) will be calculated as (date of informed consent – date of diagnosis + 
1) / 365.25. In case of a partial date of diagnosis, July 1 of the year will be used if only year is 
present, or the 16th of the month will be used if both year and month are present. Disease 
duration will be missing if the date of diagnosis is completely missing.
Date of the Last Dose of IP (as of the Time of Analysis)
The date of the last dose of IP as of the time of analysis will be determined from the last dose of 
study treatment eCRF or derived as follows:

If a complete date exists in the last dose of study treatment eCRF, the date of the last dose 
of IP will be set to that date.

If a partial date exists in the last dose of study treatment eCRF, the date of the last dose of 
IP will be set to the maximum of the following:
o
The earliest possible date given the non-missing field(s) of the partial date (ie, 
January 1 of the year will be used if only year is present, or the first date of the 
month will be used if both year and month are present), or
o
The minimum of the latest possible date given the non-missing field(s) of the 
partial date (ie, December 31 of the year will be used if only year is present, or the 
last date of the month will be used if both year and month are present), the date of 
the last follow-up, the date of the Week 104 visit, or the date of the early 
termination visit.

If the date is completely missing in the last dose of study treatment eCRF, the date of the 
last dose of IP will be set to the minimum of the date of the last follow-up, the date of the 
Week 104 visit, or the date of the early termination visit.
Medical History
Partial or completely missing dates of medical history will not be imputed other than the 
handling described above in the derivation of disease duration.
Prior and Concomitant Medications/Procedures
Completely missing dates of medications/procedures will not be imputed. Medications with a 
completely missing start date will be considered prior and/or concomitant according to the
response to the question of “did the medication start before the first dose of study treatment” in 
the prior and concomitant medications eCRF, and the (possibly imputed) end date or the ongoing 
indication. In case the response to the question is also missing, the medication will be considered 
prior (and concomitant if indicated by the [possibly imputed] end date or as ongoing).
Procedures with a completely missing start date will be considered prior.


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Partial start dates of medications/procedures and partial end dates of medications will be 
imputed. For medications, if the imputed start date is after the (possibly imputed) end date, then 
the start date will be imputed by the end date.
Partial start dates of medications/procedures will be imputed by the earliest possible date given 
the non-missing field(s) of the partial date, ie, January 1 of the year will be used if only year is 
present, or the first date of the month will be used if both year and month are present. For 
medications, however, if the imputed start date is before the date of the first dose of IP whereas 
the response to the question of “did the medication start before the first dose of study treatment” 
in the prior and concomitant medications eCRF is “no”, then the start date will be imputed by the 
date of the first dose of IP.
Partial end dates of medications will be imputed by the latest possible date given the non-missing 
field(s) of the partial date, ie, December 31 of the year will be used if only year is present, or the 
last date of the month will be used if both year and month are present.
Adverse Events
Partial or completely missing start dates of AEs will be imputed. Partial end dates of AEs will 
also be imputed to ensure that the imputed start date is not after the imputed end date, whereas 
completely missing end dates of AEs will not be imputed. If the imputed start date is after the 
(possibly imputed) end date, then the start date will be imputed by the end date.
The imputation rules for partial or completely missing start dates of AEs are given in Table 4. 
The principle of the imputation rules is to treat the AE as treatment-emergent, ie, starting on or 
after the date of the first dose of IP, if possible.
Table 4:
Imputation Rules for Partial or Completely Missing Start Dates of Adverse 
Events
Scenario
Imputation Rule
1. Partial start date with only year present
a. YEvent < YIP
31/12/YEvent
b. Otherwise, ie, YEvent ≥ YIP
Max (date of the first dose of IP, 1/1/YEvent)
2. Partial start date with both year and month present
a. YEvent < YIP, or (YEvent = YIP and MEvent < MIP)
Last date of MEvent/YEvent
b. Otherwise, ie, YEvent > YIP, or (YEvent = YIP and MEvent ≥ MIP)
Max (date of the first dose of IP, 1/MEvent/YEvent)
3. Completely missing start date
Date of the first dose of IP
DEvent/MEvent/YEvent represents the AE start date. DIP/MIP/YIP represents the date of the first dose of IP.
Partial end dates of AEs will be imputed by the latest possible date given the non-missing field(s) 
of the partial date, ie, December 31 of the year will be used if only year is present, or the last date 
of the month will be used if both year and month are present.


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APPENDIX C. DERIVATIOIN OF DAILY ORAL CORTICOSTEROID 
DOSES
Daily oral corticosteroid (OCS) (prednisone-equivalent) doses will be calculated for the records 
in the prior and concomitant medications eCRF satisfying all the following:

ATC2 level = H02

The medical history of “SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)”, “JOINT 
INVOLVEMENT ARTHRITIS”, or “SKIN INVOLVEMENT” as the primary reason or 
an additional indication (according to the prior and concomitant medications eCRF and 
the SLE medical history eCRF)

Oral route of administration
For the records with a dosing frequency of less frequent than daily, the recorded dose will be
divided equally according to the dosing frequency to calculate the daily dose (eg, for the dosing 
frequency of 1 time per week, the daily dose will be the recorded dose divided by 7). The 
“effective” end date corresponding to the daily dose for such records will be derived by start date 
+ number of administrations × dosing frequency – 1, where the number of administrations will 
be determined as (end date – start date + 1) / dosing frequency, rounded up to the next integer. 
For example, if the start and end dates are July 1 and July 15, respectively, and the dosing 
frequency is 1 time per week, the number of administrations is (July 15 – July 1 + 1) / 7 = 3, and 
the “effective” end date corresponding to the daily dose is July 1 + 3 × 7 – 1 = July 21.
Corticosteroids administered PRN will not be considered in the calculation of the daily dose.
If more than one record contributes doses to a given date (due to, for example, doses from 
different records with overlapping start/end dates, or doses allocated from records with a dosing 
frequency of less frequent than daily), the daily dose on that date will be the sum of these doses.
Daily OCS doses will be expressed as prednisone-equivalent doses. Conversions to prednisone-
equivalent doses are given in Table 5.
Table 5:
Conversions to Prednisone-equivalent Doses
Corticosteroid (Preferred Term)
Equivalent Dose
Prednisone
10 mg
Betamethasone
1.2 mg
Cortisone
50 mg
Deflazacort
12 mg
Dexamethasone
1.5 mg
Hydrocortisone
40 mg
Methylprednisolone
8 mg
Prednisolone
10 mg
Triamcinolone
8 mg


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APPENDIX D. LABORATORY MARKED ABNORMALITY CRITERIA
Table 6:
Laboratory Marked Abnormality Criteria
Category/Analyte
SI Unit
Criteria
Chemistry
  Alanine Aminotransferase (SGPT)
U/L
> 3 x ULN
  Albumin
Kg/m3
< 25
  Alkaline Phosphatase
U/L
> 2 x ULN  
  Aspartate Aminotransferase (SGOT)
U/L
> 3 x ULN  
  Total Bilirubin
µmol/L
> 2 x ULN  
  Blood Urea Nitrogen
mmol/L
> 15
  Calcium
mmol/L
< 1.8
> 3.0
  Creatinine 
µmol/L 
> 2 x ULN 
  Glucose
mmol/L
< 2.8
> 13.9
  Lactate Dehydrogenase
U/L
> 3 x ULN
  Magnesium
mmol/L
> 1.2
  Phosphate
mmol/L
< 0.64
> 1.60
  Potassium
mmol/L
< 3.0
> 5.5
  Sodium
mmol/L
< 130
> 150
  Urine Protein Creatinine Ratio
g/mol
> 226
Increase > 56.5 from baseline
  
Hematology
  Hemoglobin
g/L
< 80
Male: > 185, Female: > 170
  Leukocytes
10^9/L 
< 1.5
  Lymphocytes
10^9/L
< 0.5
  Neutrophils
10^9/L
< 1.0
  Platelets
10^9/L
< 75
> 600
  Eosinophils
10^9/L
> 1.0


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APPENDIX E. VITAL SIGNS MARKED ABNORMALITY CRITERIA
Table 7:
Vital Signs Marked Abnormality Criteria
Vital Sign
Unit
Criteria
Diastolic Blood Pressure
mmHg
Increase from baseline > 5 but ≤10
Increase from baseline > 10 but ≤ 15
Increase from baseline > 15 
Systolic Blood Pressure
mmHg
Increase from baseline > 10 but ≤ 15
Increase from baseline > 15 but ≤ 20
Increase from baseline > 20


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APPENDIX F.
ECG POTENTIALLY CLINICALLY SIGNIFICANT 
VALUES/CHANGES FROM BASELINE
Table 8:
ECG Potentially Clinically Significant Values/Changes from Baseline
ECG Variable
Unit
Criteria
QTcB - Bazett's correction formula
msec
Male: ≥450, Female: ≥470
Increase from baseline > 0 but ≤30
Increase from baseline > 30 but < 60
Increase from baseline ≥60
QTcF - Fridericia's correction formula
msec
Male: ≥450, Female: ≥470
Increase from baseline > 0 but ≤30
Increase from baseline > 30 but < 60
Increase from baseline ≥60
Summary (mean) QT duration
msec
> 500