Conditions: Systemic Lupus Erythematosus
Keywords: Lupus, Systemic Lupus, SLE
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 42
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether CC-220 is effective for the treatment of skin, joint and serological manifestations of systemic lupus erythematosus.

Detailed description:
The study consists of 2 parts. Part 1 is a randomized, double-blind, placebo controlled, ascending dose study to evaluate the safety and tolerability of CC-220 in SLE subjects.

Subject participation in Part 1 consists of 3 phases:

* Pre-treatment Screening Phase: up to 28 days prior to the first dose of the investigational product (IP)
* Treatment Phase: up to 84 days
* Observation Phase: 84 day post-treatment A total of approximately 40 subjects will be randomized into 4 dose groups with a 4:1 ratio of CC-220 (0.3 mg every other day \[QOD\], 0.3 mg everyday \[QD\], 0.6 mg and 0.3 mg on alternating days, and 0.6 mg QD) or matching placebo. In each dosing arm, 8 subjects will receive active drug and 2 subjects will receive placebo. The Treatment Phase will be up to 84 days in duration for all dose groups. Subjects who discontinue IP early and all subjects who complete the 84 day treatment phase will enter into the Observational Follow-up Phase for an 84 day period. A subject will be permitted to reduce their dose one time during Part 1 of the study.

Part 2 is the Active Treatment Extension Phase (ATEP) which is an extension to evaluate the long-term efficacy and safety/tolerability of CC-220 in SLE subjects who completed Part 1 of the study. Subjects who complete the Treatment Phase of Part 1 of the study will be eligible to receive CC-220 in the ATEP for up to 2 years. All subjects who participate in the ATEP will receive either 0.3 mg QD or 0.6 mg and 0.3 mg QD on alternating days. Subjects who terminate the Treatment Phase of Part 1 early will not be eligible for entry into the ATEP.

Subject participation consists of two phases:

* Active Treatment Extension Phase: Up to 2 years
* Observational Follow-up Phase: One month

Arms:
arm 1: Part 1: CC-220 0.3mg capsules by mouth every other day (QOD) arm 2: * Part 1: CC-220 0.3mg capsules by mouth every day (QD)
* ATEP: CC-220 0.3 mg capsules by mouth every day (QD) arm 3: * Part 1: CC-220 0.6 mg and 0.3mg capsules PO on alternating days
* ATEP:CC-220 0.6 mg and 0.3 mg capsules PO on alternating days arm 4: Part 1: CC-220 0.6mg capsules by mouth QD arm 5: Part 1: Identically matching placebo capsules PO QD

Interventions: intervention 1: CC-220 intervention 2: CC-220 intervention 3: CC-220 intervention 4: CC-220 intervention 5: Placebo
Intervention descriptions: intervention 1: 0.3 mg oral capsules once every other day with or without food intervention 2: Subjects will receive 0.3 mg oral capsules every day with or without food intervention 3: CC-220 oral capsules 0.6 mg and 0.3 mg on alternating days with or without food intervention 4: CC-220 oral capsule 0.6 mg QD with or without food intervention 5: Matching oral placebo daily

Protocol document:
SAP_002.pdf: 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PILOT, PHASE 2, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, 
STUDY TO EVALUATE EFFICACY, SAFETY, TOLERABILITY, PHARMACOKINETICS, 
PHARMACODYNAMICS AND PHARMACOGENETICS OF CC-220 IN SUBJECTS WITH 
SYSTEMIC LUPUS ERYTHEMATOSUS
STUDY DRUG:
CC-220
PROTOCOL NUMBER:
CC-220-SLE-001 – ATEP
DATE FINAL:
31OCT2018
Prepared by:
On behalf of
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
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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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ............................................................................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................8
2.
INTRODUCTION..................................................................................................10
3.
STUDY OBJECTIVES...........................................................................................11
3.1.
Primary Objective...................................................................................................11
3.2.
Secondary 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 ..............................................................................................15
4.3.
Stratification, Randomization, and Blinding............................................................22
4.4.
Sample Size Determination.....................................................................................22
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................23
5.1.
Reporting Conventions ...........................................................................................23
5.2.
Baseline Definition.................................................................................................23
5.3.
Time Points ............................................................................................................23
5.4.
Analysis Populations ..............................................................................................24
5.4.1.
ATEP Population....................................................................................................24
6.
SUBJECT DISPOSITION......................................................................................25
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................26
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................27
8.1.
Demographics.........................................................................................................27
8.2.
Baseline Characteristics..........................................................................................27
8.3.
Medical History......................................................................................................28
8.4.
Prior and Concomitant Medications........................................................................28
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
3
8.4.1.
Prior Medications ...................................................................................................28
8.4.2.
Concomitant Medications .......................................................................................28
8.5.
Prior and Concomitant Procedures..........................................................................29
8.5.1.
Prior Procedures .....................................................................................................29
8.5.2.
Concomitant Procedures.........................................................................................29
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................30
9.1.
Treatment Duration.................................................................................................30
9.2.
Treatment Compliance............................................................................................30
10.
EFFICACY ANALYSIS ........................................................................................31
10.1.
Multiplicity.............................................................................................................31
10.2.
Analysis of Efficacy Endpoints...............................................................................31
10.3.
Subgroup Analysis..................................................................................................31
10.4.
Assessing Study Center Effect and Treatment-by-Center Interaction.......................31
11.
SAFETY ANALYSIS ............................................................................................32
11.1.
Adverse Events.......................................................................................................32
11.1.1.
All Treatment-emergent Adverse Events.................................................................33
11.1.2.
Drug-related Treatment-emergent Adverse Events..................................................33
11.1.3.
Treatment-emergent Adverse Events by Maximum Severity...................................33
11.1.4.
Serious Treatment-emergent Adverse Events..........................................................33
11.1.5.
Treatment-emergent Adverse Events Leading to Drug Interruption and 
Leading to Drug Withdrawal ..................................................................................33
11.1.6.
Treatment-emergent Adverse Events Leading to Deaths .........................................34
11.2.
Clinical Laboratory Evaluations..............................................................................34
11.3.
Vital Sign Measurements........................................................................................35
11.4.
Electrocardiograms.................................................................................................35
11.5.
Ophthalmological Examination...............................................................................35
11.6.
Physical Examination .............................................................................................35
11.7.
Tetanus Toxoid, Pneumococcal and Influenza Titers ..............................................35
13.
PHARMACOKINETIC 
 ANALYSIS ...................37
14.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................38
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
4
15.
REFERENCES.......................................................................................................39
16.
APPENDICES........................................................................................................40
16.1.
Handling of Dates...................................................................................................40
16.1.1.
Calculations Using Dates........................................................................................40
16.2.
Date Imputation Guideline......................................................................................42
16.2.1.
Adverse Events.......................................................................................................42
16.2.2.
Prior/Concomitant Medications/Procedures ............................................................42
16.2.3.
Medical History......................................................................................................43
16.3.
Marked Abnormalities Criteria ...............................................................................43
16.4.
Schedule of Events .................................................................................................45
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................8
Table 2:
Imputation Rules for Partially Missing Adverse Event Start Date ...........................42
Table 3:
Imputation Rules for Partially Missing Prior/Concomitant 
Medication/Procedure Start Dates...........................................................................43
Table 4:
Imputation Rules for Partially Missing Prior/Concomitant Medication Stop 
Dates ......................................................................................................................43
Table 5:
Imputation Rules for Partially Missing Medical History Start Dates........................43
Table 6:
Laboratory Marked Abnormality Criteria................................................................43
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
8
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation
Description
ACR
American College of Rheumatology
ADaM
Analysis Dataset Model
AE
Adverse event
ALT
Alanine aminotransferase/ serum glutamic-pyruvic transaminase (SGPT)
AST
Aspartate aminotransferase/ serum glutamic-oxaloacetic transaminase (SGOT)
ATC
Anatomical Therapeutical Chemical
BMI
Body mass index
CLASI
Cutaneous Lupus Area and Severity Index
CRP
C-reactive protein
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
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IP
Investigational product
LDH
Lactate dehydrogenase
MDRD
Modification of Diet in Renal Disease formula
MedDRA
Medical Dictionary for Regulatory Activities
NSAID
Nonsteroidal anti-inflammatory drug
PGA
Physician’s global assessment
PRN
As needed
PT
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DRA
NSAID
NSAID


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
9
Abbreviation
Description
PT
Preferred term
QD
Once daily
QOD
Once every other day
RBC
Red blood cells
SAP
Statistical analysis plan
SD
Standard deviation
SE
Standard error 
SLE
Systemic lupus erythematosus
SLEDAI
Systemic lupus erythematosus Disease Activity Index
SLICC
Systemic Lupus International Collaborating Clinics
SOC
System organ class
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
US
United States
VA
Visual acuity
WBC
White blood cells
WHODD
World Health Organization Drug Dictionary
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
10
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-220-SLE-001 “A Pilot, Phase 2, Randomized, Placebo-Controlled, Double-Blind 
Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and 
Pharmacogenetics of CC-220 in Subjects with Systemic Lupus Erythematosus (SLE).” This SAP 
pertains to Active Treatment Extension Phase (ATEP) of the study design only. Analyses of Part 
1 of the study design are presented in a separate document. This SAP contains definitions of 
analysis populations, derived variables, and statistical methods for the analysis of efficacy and 
safety parameters.
This SAP provides a more technical and detailed elaboration of the statistical analyses, as 
outlined and/or specified in the CC-220-SLE-001 study protocol amendment dated 18Jun2018. 
The SAP will be finalized and approved prior to the database lock. All statistical analyses 
detailed in this SAP will be conducted using SAS® Version 9.2 or higher.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
11
3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective of ATEP
!
To evaluate the long-term safety and tolerability of CC-220 in subjects with SLE who 
completed Part 1 of the core study
3.2.
Secondary Objectives
The secondary objective of ATEP
!
To evaluate the long-term efficacy of CC-220 in subjects with SLE who completed 
Part 1 of the core study
 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
12
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
The Active Treatment Extension Phase (ATEP) is an extension of the core CC-220-SLE-001 
study to evaluate the long-term efficacy and safety/tolerability of CC-220 in SLE subjects who 
completed Part 1 of the core study. 
Subjects who complete the Treatment Phase of Part 1 of the core study will be eligible to enter 
this phase of the study and should be enrolled immediately to avoid dose interruption. In the 
event the ATEP has not been implemented by a subject’s study center at the time they have 
completed the Treatment Phase, subjects will enter the Observation Phase of the core study and 
be eligible to enroll in the ATEP upon implementation of the protocol amendment #5. There are 
no time restrictions on how long subjects can be off CC-220 prior to entering the ATEP as long 
as they completed treatment in Part 1 of the core study. Subjects who terminate the Treatment 
Phase of Part 1 early will not be eligible for entry into the ATEP. All subjects who participate in 
the ATEP will receive the same active treatment they received during their participation in Part 1 
with the exception of those on placebo or 0.3 mg QOD or 0.6 mg QD (see below for information 
on dosing for these subjects).
Subject participation consists of two phases:
!
Active Treatment Extension Phase: Up to 2 years
!
Observational Follow-up Phase: 28 days
Subjects receiving CC-220 0.3 mg QOD or CC-220 0.3 mg QD during their participation in the 
core study will be assigned to receive CC-220 0.3 mg QD during the ATEP. Subjects receiving 
CC-220 0.6 mg/0.3 mg on alternating days during their participation in the core study will 
remain on the same assigned dose during the ATEP. Subjects receiving CC-220 0.6 mg QD 
during their participation in the core study were originally permitted to enter the ATEP on the 
same dose. However, based on data that has become available for Part 1 (Protocol Section 4.2.3), 
any subject originally enrolled in the ATEP on the 0.6 mg QD dose should be dose reduced to 
the 0.6 mg/0.3 mg on alternating days dose upon implementation of Protocol Amendment 5.
Subjects receiving placebo during their participation in the core study (Part 1) will receive the 
CC-220 dose given to those on active drug in their respective cohort. For example, if a subject 
was taking placebo in Dose Group 3 of Part 1, he or she would receive CC-220 0.6 mg/0.3 mg on 
alternating days during the ATEP.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
13
Subjects will remain on their assigned treatment for up to 2 years. In the event a subject 
experiences clinically significant investigational product (IP) related adverse events (AE), a dose 
interruption for up to 14 days will be permitted (Protocol Section 12.1). If a subject is unable to 
remain on their assigned dose, he/she may reduce their dose to the next lowest dosing regimen. 
Dose reductions will occur as follows:
!
Subjects on 0.6 mg QD will reduce their dose to 0.6 mg/0.3 mg on alternating days
!
Subjects on 0.6 mg/0.3 mg on alternating days will reduce their dose to 0.3 mg QD
!
Subjects on 0.3 mg QD will be terminated from the study
A subject will only be permitted to reduce their dose one time during the study (subjects who 
originally came into the ATEP on 0.6 mg QD and dose reduce to 0.6/0.3 mg QD on alternating 
days upon implementation of Protocol Amendment 5 will be eligible for one additional dose 
reduction in the ATEP). The decision to modify IP dosing will be based on the rules provided in
Protocol section 8.2.1. The sponsor should be notified of the intent to dose reduce prior to a 
change in dosing.
All subjects will be allowed to remain on stable doses of hydroxychloroquine, chloroquine, 
and/or quinacrine for ≥ 4 weeks prior to their baseline visit and throughout the study. Subjects on 
antimalarials will be permitted to modify or stop their treatment at any time during the ATEP. 
Methotrexate (7.5 mg – 25 mg per week), leflunomide (maintenance dosing must not exceed 20 
mg daily) or sulfasalazine (dosing not to exceed 3 g daily) will be permitted, although no other 
additional systemic immunosuppressives will be permitted. In addition, PRN treatment with 
systemic anti-pruritics and/or systemic analgesics will be permitted. However, subjects must stop 
using all systemic anti-pruritics 48 hours prior to all study visits and systemic analgesics 12 
hours prior to all study visits. Oral NSAIDs may be used PRN, but must be stopped 12 hours 
prior to all study visits. Use of oral corticosteroids will be permitted only at doses of 10 mg or 
less per day and must be maintained at a stable dose during study participation. Inhaled 
corticosteroids for use in a disease other than lupus, eg, asthma, will be allowed. No IV or IM 
corticosteroids will be permitted during the study. No other topical (with the exception of 
potency class 6 and 7 topicals only), local or systemic treatments for dermatological 
manifestations of SLE will be permitted.
Subjects will have regularly scheduled visits to assess IP activity and safety. Required
assessments will be completed as depicted in the table of section 16.4.
Upon completion of, or discontinuation from the ATEP, all subjects (including premature 
discontinuations) will enter a 28 day Observational Follow-up Phase.
4.2.
Study Endpoints
Safety and Efficacy endpoints are listed in Sections 4.2.1 through 4.2.3. .
4.2.1.
Primary Endpoint
The primary endpoints will assess safety.
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4.2


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
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The following safety parameters will be evaluated throughout the duration of the study:
!
Adverse events
∀
Type, frequency, severity and relationship of AEs to IP
∀
Number of subjects who discontinue IP due to any AE
!
Laboratory evaluations for hematology, serum chemistry, and urinalysis will be 
collected. 
∀
Laboratory parameters for hematology will include: red blood cells (RBC), 
hemoglobin (HgB), hematocrit, white blood cells (WBC) and differential 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils [percent and 
absolute]), and platelet count.
∀
Laboratory parameters for serum chemistry will include: total protein, albumin, 
calcium, phosphorus, glucose, uric acid, total bilirubin, alkaline phosphatase, 
aspartate aminotransferase (AST; serum glutamic-oxaloacetic transaminase 
[SGOT]), alanine aminotransferase (ALT; serum glutamic pyruvic transaminase 
[SGPT]), lipase, sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, lactate dehydrogenase (LDH), and magnesium. Additionally, the 
central lab will calculate and report the estimated glomerular filtration rate 
(eGFR) in mL/min using the Modification of Diet in Renal Disease formula 
(MDRD eGFR).
∀
Laboratory parameters for urinalysis dipstick include: microscopic and 
quantitative protein.
∀
Laboratory parameters for micronutrients include: apolipoproteins, total 
cholesterol, and lipid-soluble vitamins A,D,E,K) 
∀
Laboratory parameters for inflammation panel include: high sensitivity C-reactive 
protein (hs-CRP), erythrocyte sedimentation rate (ESR), fibrinogen, and serum 
amyloid A.
∀
Laboratory parameters for assessment of immunoglobulins include:
immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A 
(IgA).
∀
Laboratory parameters for assessment of blood clotting include: prothrombin 
time, internationalized normalized ratio, and partial thromboplastin time.
!
Laboratory endpoints include:
∀
Number and percentage of subjects with marked abnormalities (see Section 16.3)
∀
Observed value and change from Baseline over time 
∀
Shift from Baseline to postbaseline time points and to the worst postbaseline 
value in terms of normal/abnormal (low or high) in hematology and serum 
chemistry laboratory parameters
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
15
!
Vital signs and weight endpoints include:
∀
Change from Baseline over time in vital sign parameters (temperature, pulse, 
weight and seated blood pressure) 
∀
Shift from Baseline to postbaseline time-points and to worst postbaseline value in 
terms of normal/abnormal (see Section 11.3) in blood pressure and pulse
!
Electrocardiogram (ECG, 12-lead) recordings will be obtained throughout the study 
and assessed by a central (cardiologist) reader. The cardiologist will interpret all 
ECGs with relevance to PR interval, QRS duration, heart rate and R-R interval, QT 
and QTc. The ECG endpoints include:
∀
Change from Baseline over time in ECG parameters 
∀
Shift from Baseline to postbaseline time points and to worst postbaseline value in 
terms of normal/abnormal in ECG findings
!
Physical examination will include skin, nasal cavities, eyes, ears, respiratory, 
cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal system 
evaluations. Results of the physical examinations will be recorded only in the source 
documents, however clinically significant changes in physical examination findings
will be captured as AEs.
!
Ophthalmological examinations will include visual acuity (VA) and slit lamp exams 
with fluorescein staining following papillary dilation. Ophthalmological endpoints 
include:
∀
Number and percentage of subjects with clinically significant ophthalmological 
findings
!
Change from Baseline in tetanus toxoid, pneumococcal and influenza titer at Week 1, 
Week 52, and Week 96.
4.2.2.
Secondary Endpoints
The secondary endpoints will assess the efficacy of CC-220.
4.2.2.1.
Cutaneous Lupus Area and Severity Index (CLASI)
!
The CLASI Activity Score (Protocol Appendix A) 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 
nonscarring 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.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
16
!
Change from Baseline and percent change from Baseline in the CLASI Activity score 
at Week 1, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, 
Week 84, Week 96, and Week 100. 
!
The CLASI Damage Score (Protocol Appendix A) 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.
!
Change from Baseline and percent change from Baseline in the CLASI Damage score 
at Week 1, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, 
Week 84, Week 96, and Week 100.
4.2.2.2.
Swollen and Tender Joint Count
!
Using this tool, joint tenderness and swelling will be noted as “present” or “absent,” 
with no quantitation of severity (Protocol Appendix B). 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.
!
Change from Baseline and percent change from Baseline in swollen and tender joint 
count at Week 1, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 
72, Week 84, Week 96, and Week 100. 
4.2.2.3.
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) SELENA 
Modification
!
The hybrid SELENA SLEDAI (Protocol Appendix E) measures disease activity 
through assessment of 24 lupus manifestations using a weighted score of 1 to 8 
points. A decrease of 4 or greater points in the Hybrid SELENA SLEDAI is 
considered clinically meaningful. A manifestation is recorded if it is present over the 
previous 10 days regardless of severity or whether it has improved or worsened. What 
differentiates the hybrid SELENA SELEDAI from the SELENA SLEDAI is the 
definition of proteinuria. The Hybrid SELENA SLEDAI defines proteinuria as > 0.5 
gm/24 hours – ‘new onset or recent increase of more than 0.5 gm/24 hours’ has been 
removed from the definition.
!
Change from Baseline and percent change from Baseline in Hybrid SELENA SLE 
Disease Activity Index (SLEDAI) at Week 1, Week 4, Week 12, Week 24, Week 36, 
Week 48, Week 60, Week 72, Week 84, Week 96, and Week 100. 
!
Proportion of subjects who achieve ≥ 4 point reduction from Baseline in Hybrid 
SELENA SLEDAI score at Week 1, Week 4, Week 12, Week 24, Week 36, Week 48, 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
17
Week 60, Week 72, Week 84, Week 96, and Week 100, in subjects with Baseline 
Hybrid SELENA SLEDAI score ≥ 4.
4.2.2.4.
Pericardial/Pleuritic Numerical Pain Scale
!
Each scale (Protocol Appendix G) is scored using numerical values of 1 through 10 
with 1 representing ‘no pain’ and 10 representing ‘worst possible pain’. Both pain 
scales will be self-administered by the subject and gauge the severity of their SLE 
pain related to pericardial and pleuritic discomfort. Any indication from subjects or 
study assessments, aside from pain, which indicate clinically significant pericardial or 
pleuritic manifestations of SLE must be thoroughly investigated. If clinically 
significant SLE related complications are found, the subject should be discontinued 
from the study into the Observational Follow-up Period and treated appropriately.
!
Change from Baseline and percent change from Baseline in Pericardial/Pleuritic Pain 
Scale score at Week 1, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, 
Week 72, Week 84, Week 96, and Week 100. 
4.2.2.5.
Physician’s Global Assessment (PGA)
!
The PGA (Protocol Appendix C) 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
This is a physician administered instrument used to gauge a subject’s overall state of
health. A 10% increase (0.3 points) is considered a clinically relevant worsening of 
disease.
!
Change from Baseline and percent change from Baseline in the PGA score at Week 1, 
Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 
96, and Week 100. 
4.2.2.6.
Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Damage Index (SLICC/ACR)
!
The SLICC/ACR Damage Index (Protocol Appendix O) 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.
!
Change from Baseline and percent change from Baseline in the Systemic Lupus 
International Collaborating Clinics/American College of Rheumatology 
(SLICC/ACR) Damage Index score at Week 1, Week 4, Week 12, Week 24, Week 
36, Week 48, Week 60, Week 72, Week 84, Week 96, and Week 100. 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
18
4.2.2.7.
British Isles Lupus Assessment Group 2004 (BILAG)
!
The BILAG 2004 (Protocol Appendix P) 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). Disease activity is categorized into five levels, Grades A-E.
!
The BILAG-2004 global score is calculated by summing up the numerical score 
equivalents across the organ systems, with the numerical score equivalents given as: 
A = 12, B = 8, C = 1, D = 0, E = 0.
!
Change from Baseline and percent change from Baseline in the British Isles Lupus 
Assessment Group 2004 global score as well as in each organ system at Week 1, 
Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 
96, and Week 100.
4.2.2.8.
Fatigue Visual Analog Scale (VAS)
!
The Fatigue VAS (Protocol Appendix H) will evaluate SLE related fatigue using a 0-
100 mm VAS scale. A Fatigue VAS will allow the subject to indicate the degree of 
SLE related fatigue they experienced over the previous week.
!
Change from Baseline and percent change from Baseline in the Fatigue Visual 
Analog Scale score at Week 1, Week 4, Week 12, Week 24, Week 36, Week 48, 
Week 60, Week 72, Week 84, and Week 96.
 
 
 
 
 
 
 
 
 
 
 
 
 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
22
!
 
 
 
 
 
 
 
4.3.
Stratification, Randomization, and Blinding
As an extension of core CC-220-SLE-001, Active Treatment Extension Phase will be made up of 
subjects completing Part 1 and completed the screening and consent process. Subjects will 
continue their active treatment or be assigned doses as described in section 4.1.
4.4.
Sample Size Determination
Subjects who completed Part 1 are eligible to participate in ATEP, no formal sample size or 
power calculation was performed.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
23
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
Summary statistics for continuous variables include sample size (n), mean, standard deviation 
(SD), median, minimum, and maximum. All mean and median values will be formatted to one 
more decimal place than the measured value. Standard deviation values will be formatted to two 
more decimal places than the measured value. Minimum and maximum values will be presented 
to the same number of decimal places as the measured value. The frequency summary for 
categorical variables includes number and percentage. All percentages will be rounded to one 
decimal place. Number and percentage values will be presented as xx (xx.x). All analysis and 
summary tables will have the population sample size for each treatment group in the column 
heading. All laboratory data will be reported using standard international units.
In data derivations requiring the date of the first dose of IP dispensed at a specific visit, in the 
absence of a definitive record of this date, the study drug dispense date (from the study drug 
accountability records) associated with that visit, or if this date is also missing, then the visit 
date, will be used to estimate the date of the first dose of IP in question. In the absence of a 
definitive record of the date of the last dose of IP for subjects who have completed the study or 
have discontinued early, the date of the Week 96 visit or the discontinuation visit will be used to 
estimate the last dose date for subjects who have completed the study or have discontinued early 
and have the discontinuation visit; for subjects who have discontinued but do not have the 
discontinuation visit, the last “follow-up” date (ie, the maximum date among the subject’s 
records of study visits, study drug records, AEs [start and end dates], concomitant 
medications/procedures, laboratory, vital signs, and ECG) will be used to estimate the last dose 
date.
All tables and listings will be presented by the 0.3 mg QD and 0.3/0.6 mg QD alternating groups, 
and the tables will additionally present a total group combing the above 2 groups. Subjects 
originally assigned to 0.3 mg QD and 0.3/0.6 mg QD alternating at the entry into the ATEP will 
be included in the respective treatment groups, irrespective of the possible dose reduction during 
the ATEP. Subjects originally assigned to 0.6 mg QD will be included in the 0.3/0.6 mg QD 
alternating group, regardless of whether or not dose reduction to 0.3/0.6 mg QD alternating per 
Protocol Amendment 5 has occurred before early discontinuation.
5.2.
Baseline Definition
The baseline is defined as the last value measured on or before the day of the first dose of IP
during ATEP.
5.3.
Time Points
Time points (including the scheduled study weeks per protocol, the end of treatment, and the 
observational follow-up visit) in all analyses are based on the visits/study weeks as recorded in 
the database. 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
24
Appropriate dates (eg, date of measurement or date of specimen collection) will first be used to 
ensure only data (including data from scheduled, unscheduled, discontinuation, and 
observational follow-up visits) measured or collected within the specific analysis period are 
included, and then the visits/study weeks as recorded in the database will be used to assign one 
value (possibly missing) to each time point at the subject level according to the following rules:
!
If a value is available at a scheduled visit (eg, Week 2/Visit 3), then that value will be 
used for the study week, regardless of whether a value is available from an 
unscheduled visit in the corresponding visit window. If the value at a scheduled visit 
is missing, but an unscheduled visit is available in the corresponding visit window,  
the value from the nearest earlier unscheduled visit will be used for the study week. 
!
If the value at a scheduled visit is missing and there is no value available from an 
unscheduled visit in the corresponding visit window, the value at the study week will 
be missing.
!
A value from the discontinuation visit (for a discontinued subject) will be mapped to 
the next scheduled visit after the last visit the subject has completed.
!
The end of treatment is defined as the last postbaseline visit among all the scheduled 
and unscheduled visits and, if applicable, the discontinuation visit; the observational 
follow-up visit is not included in the derivation of the end of treatment value.
5.4.
Analysis Populations
5.4.1.
ATEP Population
The ATEP Population will include all subjects who are enrolled into ATEP and received at least 
one dose of IP. All statistical analyses for ATEP data will be based on the ATEP Population. 
Subjects will be included in the treatment groups as described in Section 5.1.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
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6.
SUBJECT DISPOSITION
The number of subjects screened and the eligibility criteria failed will be summarized. The failed 
inclusion/exclusion criteria of subjects who were screened and not enrolled will be included in 
the summary. The above percentages will be based on the number of subjects screened.
The number and percentage of subjects included in each analysis population will be summarized 
by treatment group. The percentages will be based on the number of subjects enrolled. A listing 
of subjects excluded from the analysis populations, with the reasons for exclusions, will be 
provided.
The number and percentage of subjects who entered, completed, and discontinued each study 
phase (Treatment Phase and Observational Follow-up Phase), and the number and percentage of 
primary reasons for discontinuation for subjects who early discontinued will be summarized. The 
percentages will be based on the number of subjects enrolled. 
The primary reason for discontinuation is collected in the study disposition electronic case report 
form (eCRF) and will be summarized with the following categories:
!
Death
!
Adverse event
!
Withdrawal by subject
!
Lost to follow-up
!
Protocol violation
!
Lack of Efficacy
!
Other
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7.
PROTOCOL DEVIATIONS/VIOLATIONS
The protocol deviations will be summarized by treatment group for the ATEP Population. A by-
subject listing of subjects with protocol deviations will be provided. 
&(/*(1(35235,(7$5<,1)250$7,21


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Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
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27
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
The demographics and baseline characteristics will be summarized descriptively by treatment 
group for the ATEP Population. Individual subject listings will be provided to support the 
summary tables. The demographic data that were collected during part 1 and unchanged (eg, sex, 
race) will be populated from part 1 and included in the ATEP summary.
8.1.
Demographics
Demographic variables include:
!
Age (years)
!
Age category (< 40, 40 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, Other)
!
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
!
Weight (kg)
!
Weight category (< 70, ≥ 70 to < 85, ≥ 85 to < 100, ≥ 100 kg)
!
Height (cm) at Screening
!
Body mass index (BMI; kg/m2)
!
BMI category (< 25, ≥ 25 to < 30, ≥ 30 to < 35, ≥ 35 to < 40, ≥ 40 kg/m2) 
!
Alcohol use (never, current, former user)
!
Tobacco use (never, current, former user)
!
Caffeine use (never, current, former user)
8.2.
Baseline Characteristics
Baseline characteristics include:
!
Duration of SLE (years)
!
Baseline CLASI activity score 
!
Baseline CLASI damage score 
!
Baseline PGA score
!
Baseline non-zero swollen joint counts
!
Baseline non-zero tender joint counts
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Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
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!
Baseline Hybrid SELENA SLEDAI score
!
Baseline SLICC/ ACR Damage Index
!
Baseline of BILAG 2004 global score
!
Baseline of Pericardial/Pleuritic Pain Scale
!
Baseline of Fatigue VAS score
8.3.
Medical History
Only medical events that occurred prior to the first dose in part 1 are included as medical history.  
Medical events that occurred after the first dose of part 1 and before the first dose of ATEP, are 
included in the AE results of the part 1 analyses. Medical history will be coded according to the 
Medical Dictionary for Regulatory Activities (MedDRA; Version 17.0 or higher). A frequency 
summary of medical history will be presented by treatment group, system organ class (SOC), and 
preferred term (PT) for the ATEP Population. A data listing including the verbatim and coded 
terms will be presented.
A frequency summary of SLE medical history will also be presented by treatment group for the 
ATEP Population.
8.4.
Prior and Concomitant Medications
Medications that were initiated prior to the start of study treatment and continued after the start 
of study treatment in ATEP will be counted as both prior and concomitant medications. The 
Anatomical Therapeutical Chemical (ATC) coding scheme of the World Health Organization 
Drug Dictionary (WHODD; Version March 2016 or higher) will be used to group medications 
into relevant categories. A data listing including the verbatim and coded terms will be presented.  
Medication use during part 1 or prior to the first dose in ATEP are considered as prior 
medications for ATEP.
8.4.1.
Prior Medications
Prior medications are defined as medications that were started before the start of study treatment
in ATEP and either ended before the start of study treatment or continued after study treatment.
A frequency summary of prior medications will be provided by treatment group, ATC1 level, 
and standardized medication name for the ATEP Population.
8.4.2.
Concomitant Medications
Concomitant medications are defined as medications that were initiated before the first dose of 
IP in ATEP and continued during the study treatment, or initiated on/after the date of the first 
dose of IP and on/before the date of treatment discontinuation. A frequency summary of 
concomitant medications will be provided by treatment group, ATC1 level and standardized 
medication name for the ATEP Population.
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dose of IP 
concom
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di


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Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
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8.5.
Prior and Concomitant Procedures
Procedures will be coded according to MedDRA, Version 19.0 or higher. Medical procedures 
during part 1 or prior to the first dose in ATEP are considered as prior procedures for ATEP.
8.5.1.
Prior Procedures
Prior procedures are defined as procedures or surgeries that occurred before the first dose of IP
of ATEP. A frequency summary of prior procedures will be presented by treatment group, SOC, 
and PT for the ATEP Population.
8.5.2.
Concomitant Procedures
Concomitant procedures will be identified similar to the criteria in Section 8.4.2. A frequency 
summary of concomitant procedures will be provided by treatment group, SOC, and PT for the 
ATEP Population.
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frequency
frequency
and PT
nd PT fo
for


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Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
9.1.
Treatment Duration
Treatment duration (in weeks) is calculated as (the date of the last dose of IP in ATEP – the date 
of the first dose of IP in ATEP + 1) / 7 and rounded to one decimal place. 
Treatment duration will be summarized by treatment group for the ATEP Population. 
Frequency summaries of treatment duration will also be presented for the following categories: 
≤12, >12 – 24, >24 – 36, >36 – 48, >48 – 60, >60 – 72, >72 – 84, > 84 weeks.
A subject data listing of study drug records will be provided.
9.2.
Treatment Compliance 
As part of the routine recording of the amount of IP taken by each subject, the number of tablets 
dispensed and returned will be recorded at each visit after Visit 1. These records will be used to 
calculate cumulative treatment compliance. A subject data listing of drug accountability records 
will be provided.
The compliance rate (%) for each subject for a period will be computed as 100 times the total 
number of tablets taken (the total number of tablets dispensed minus the total number of tablets 
returned) over the duration of treatment divided by the intended total number of tablets that 
should have been taken. 
The intended total number of tablets is calculated as follows. First chronologically order the first 
dose date, the second dispense date, the third dispense date, etc., up to the last dose date. The 
first and last dose dates are defined in the same way as those defined for treatment duration 
calculations (see Section 9.1). The intended number of tablets between any two consecutive 
dates is calculated as 2 × n, where n denotes the number of days between the 2 consecutive dates 
(ie, the second date minus the first date for all pairs of consecutive dates, and the second date 
minus the first date plus 1 for the last pair). Then the intended total number of tablets is the sum 
of all intended numbers of tablets as calculated above from the first dose date through the last 
dose date. Of note, compliance rate will not be calculated for subjects (if existent) who have only 
the dispense record at Day 1/Visit 2 and no other drug accountability records.
Treatment compliance will be summarized by treatment group for the ATEP Population. 
Frequency summaries of compliance rate will also be presented with the following categories: 
< 75%, ≥75% to ≤ 120%, and > 120%.
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75%
5% toto ≤ 12
≤ 12


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Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
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10.
EFFICACY ANALYSIS
All efficacy evaluations will be conducted using the ATEP Population. Missing data will not be 
imputed, and only observed results will be summarized. For categorical endpoints, only subjects 
with sufficient data for response determination at the visit of interest will be included in the 
denominator at that time point. No p-values will be provided.
10.1.
Multiplicity
No multiplicity adjustment will be conducted.
10.2.
Analysis of Efficacy Endpoints
Summary statistics by visit will be provided for all endpoints.
10.3.
Subgroup Analysis
No subgroup analyses will be conducted.
10.4.
Assessing Study Center Effect and Treatment-by-Center Interaction
This is not assessed in the ATEP.
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atment
atment-by
b


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Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
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11.
SAFETY ANALYSIS
The purpose of this section is to define the safety parameters for the study. All summaries of 
safety data will be performed for the ATEP Population.
For the analyses of TEAEs and marked abnormalities, subject incidence will be provided, unless 
otherwise specified. Subject incidence (ie, percentage [%] used in a frequency summary) is 
defined as 100 times the number of subjects with the specific event divided by the number of 
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.
Summaries of safety parameters over time (eg, summary statistics over time and shifts from 
Baseline to postbaseline time points in terms of normal/abnormal) will include data collected at 
scheduled, unscheduled, and discontinuation visits up to 28 days after the last dose of study drug 
in the study and data collected at observational follow-up visits. Summaries of marked 
abnormalities and shifts from Baseline to worst postbaseline value will include all data up to 28 
days after the last dose of study drug in the study, irrespective of the visits from which these data 
are collected. The “worst” lab results will be defined using the worst of all post-baseline 
reference range indicators and grouped into “LOW” or “HIGH” or “Both L and H” or 
“NORMAL”.
In summaries of continuous variables with summary statistics by time point, values for Baseline, 
time point, and change from Baseline will be summarized at each time point for subjects who 
have both values at Baseline and at the time point. Similarly, in frequency summaries of shifts 
from Baseline, only subjects who have both values at Baseline and at the time point will be 
included in the summaries of shifts to the scheduled study days per protocol and only subjects 
who have a Baseline value and at least one postbaseline value will be included in the summaries 
of shifts to the end of period and to the worst postbaseline value.
11.1.
Adverse Events
Adverse events will be analyzed in terms of treatment-emergent adverse events (TEAE) which 
are defined as any AEs that begin or worsen on or after the start of study drug in ATEP through 
28 days after the last dose of study drug or study treatment discontinuation date, whichever is 
later. All AEs will be coded using MedDRA Version 17.0 or higher. A subject data listing of all 
AEs, including the verbatim and coded terms, will be presented.
Unless otherwise specified, AEs will be summarized by SOC and PT, with SOCs presented in 
the standard international order and PTs within each SOC in descending order of subject 
incidence (and then alphabetically if needed).
An overall summary of the following AE categories will be provided:
!
Any TEAE
!
Any drug-related TEAE
!
Any severe TEAE
!
Any serious TEAE
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overall sum
!


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
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!
Any serious drug-related TEAE
!
Any TEAE leading to drug interruption
!
Any TEAE leading to drug withdrawal
!
Any TEAE leading to death
Specific TEAEs under each of the above categories will be summarized.
A drug-related TEAE is defined as a TEAE which is considered to be of suspected relationship 
to study drug. Adverse events with missing relationship to study drug will be assessed as drug-
related.
11.1.1.
All Treatment-emergent Adverse Events
All TEAEs will be summarized by SOC and PT as well as by PT only (in descending order of 
subject incidence). 
All TEAEs will be summarized by age category (< 40, ≥ 40 years) and sex (Male, Female).
All TEAEs occurring after the date of the last dose of IP and up to 28 days after the last dose 
of IP will also be summarized by SOC and PT for subjects who enter the observational follow-up 
phase during the ATEP.
11.1.2.
Drug-related Treatment-emergent Adverse Events
Drug-related TEAEs will be summarized.
11.1.3.
Treatment-emergent Adverse Events by Maximum Severity
All TEAEs will be summarized by maximum severity (mild, moderate, severe, and, if needed, 
missing). If a subject reports multiple occurrences of a specific event within a specific analysis 
period, the subject will be counted only once by the maximum severity. If the severity is missing 
for one or more of the occurrences, the maximum severity of the remaining occurrences will be 
used. If the severity is missing for all of the occurrences, the subject will be counted only once in 
the “missing” category of severity.
11.1.4.
Serious Treatment-emergent Adverse Events
Serious TEAEs will be summarized by SOC and PT as well as by PT only (in descending order 
of subject incidence).
Serious drug-related TEAEs will be summarized.
A subject data listing of all serious AEs (both TEAEs and non-TEAEs) will be provided.
11.1.5.
Treatment-emergent Adverse Events Leading to Drug Interruption and Leading 
to Drug Withdrawal
Treatment-emergent AEs leading to drug interruption will be summarized. 
Treatment-emergent AEs leading to drug withdrawal will also be summarized. A subject data 
listing of TEAEs leading to drug withdrawal will be provided.
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11.1.6.
Treatment-emergent Adverse Events Leading to Deaths
Treatment-emergent AEs leading to death will be summarized. A subject data listing of all 
deaths will be provided.
11.2.
Clinical Laboratory Evaluations
Summary statistics of observed values and changes from Baseline in hematology and serum 
chemistry laboratory parameters will be provided over time. Frequency summaries (shift tables) 
of shifts from Baseline to postbaseline time points and to the worst postbaseline value in terms of 
normal/abnormal will be provided for hematology and serum chemistry. The urinalysis results 
will be provided only in a listing.
Laboratory marked abnormalities (see Table 6 in Section16.3) will be summarized; subject 
incidence for each abnormality will be calculated based on subjects with a baseline value and at 
least one postbaseline value for criteria requiring baseline or subjects with at least one 
postbaseline value for criteria not requiring baseline. A subject data listing of laboratory marked 
abnormalities will be provided.
CCI
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Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
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A subject data listing of all laboratory data will be provided.
11.3.
Vital Sign Measurements
Summary statistics of observed values and changes from Baseline in vital signs will be provided 
over time. Frequency summaries (shift tables) of shifts from Baseline to postbaseline time points 
and to the worst postbaseline value in terms of normal/abnormal will be provided for pulse and 
blood pressure. The normal ranges are defined as: 60 to 100 beats/minute for pulse, 90 to 
140 mm Hg for systolic blood pressure, and 60 to 90 mm Hg for diastolic blood pressure.
A subject data listing of all vital signs and weight data will be provided.
11.4.
Electrocardiograms
Summary statistics of observed values and changes from Baseline in ECG findings will be 
provided over time. For each parameter, triplicate ECG readings will be averaged and this 
average used as the result in summary statistics. The overall ECG interpretation will be 
summarized by presenting the number and percentage of subjects with ‘Normal’ and 
‘Abnormal’ by treatment. The shift from Baseline to worst during the treatment in the overall 
ECG interpretation will be displayed for each treatment.
11.5.
Ophthalmological Examination
The overall interpretation will be summarized by presenting the number and percentage of 
subjects with ‘Normal’, ‘Abnormal, not clinically significant’, and ‘Abnormal, clinically 
significant’ by treatment. The shift from Baseline to Week 24, Week 48, Week 72, and Week 96
in the overall interpretation will be displayed for each treatment.
11.6.
Physical Examination
No summary of physical examination findings will be provided. Clinically significant changes in 
physical examination findings will be captured as AEs.
11.7.
Tetanus Toxoid, Pneumococcal and Influenza Titers
Summary statistics of observed values and change from Baseline will be provided over time.
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f observed


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
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CCI
&(/*(1(35235,(7$5<,1)250$7,21


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Celgene Corporation
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13.
PHARMACOKINETIC 
 ANALYSIS
The ATEP does not collect Pharmacokinetic
 data. 
CCI
CCI


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14.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
No changes to the statistical analyses section of the protocol are made in this SAP.
&(/*(1(35235,(7$5<,1)250$7,21


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15.
REFERENCES
CCI
&(/*(1(35235,(7$5<,1)250$7,21


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Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
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16.
APPENDICES
16.1.
Handling of Dates
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie, the Date9. datetime format in SAS). Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedure are 
performed. They include the dates of laboratory testing, physical examinations, tumor 
scans, etc. They should be present whenever data for a protocol-specified procedure 
are present and should only be missing when a procedure is marked as NOT DONE 
in the database. Procedure dates will not be imputed.
!
Log Dates are dates recorded in CRF data logs. Specifically, they are the start and 
end dates for AEs and concomitant medications/procedures. They should not be 
missing unless an event or medication is marked as ongoing in the database. 
Otherwise, incomplete log dates will be imputed according to the rules in Appendix 
16.2 (eg, for duration or cycle assignment, etc.). However, in listings, log dates will 
be shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study drug termination date, study closure date, etc. They should not be 
missing if the milestone occurs for a subject. They will not be imputed.
!
Special Dates cannot be classified in any of the above categories and they include the 
date of birth. They may be subject to variable-specific censoring and imputation rules. 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
16.1.1.
Calculations Using Dates
Calculations using dates (eg, subject’s age or relative day after the first dose of study drug) will 
adhere to the following conventions: 
16.1.1.1.
Study Day
Study days after the start day of study drug (first dose date) will be calculated as follows:
!
For dates of interest on or after the first dose date: The study days will be 
calculated as the difference between the date of interest and the first dose date of 
study medication plus 1 day.
     STUDY DAY= (TARGET DATE – DSTART) + 1;
     where DSTART = the first dose date. 
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calc
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Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
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!
For dates of interest prior to the first dose date: The study days will be calculated 
as the difference between the date of interest and the first dose date of study 
medication only.
STUDY DAY= TARGET DATE – DSTART; 
where DSTART = the first dose date. 
!
Study Day 1 is the first day of treatment of study drug. Negative study days are 
reflective of observations obtained during the baseline/screening period. 
!
Partial dates for the first study drug are not imputed in general. All effort should be 
made to avoid incomplete study drug start dates. Some analyses may exclude subjects 
without study drug start date. The SAP may be amended on a case-by-case basis, 
including guideline and suggestion such as imputing Day 1 by consent date of treated 
patient.
16.1.1.2.
Age
Age (expressed in years) is calculated as the difference between the date of birth and the 
informed consent date plus 1 day. Age will be transformed to years by dividing the difference by 
365.25 days, then truncating.     
AGE at part 1 = Integer portion of (DATE of CONSENT at part 1 – DATE of BIRTH + 1) 
/365.25
AGE at ATEP = Integer portion of (DATE of CONSENT at ATEP– DATE of BIRTH + 1) 
/365.25
!
Preference is for using calculated age from clinical database. When not available, 
calculated age from CRF or IVRS may be used
!
Partial birth date: impute missing day as 15th of the month; impute missing month as 
July; set missing age for missing year
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
     WEEKS = DAYS /7
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
     MONTHS = DAYS /30.4167
16.1.1.3.
Duration of Systemic Lupus Erythema
Duration of SLE (expressed in years) is calculated as the difference between the date of 
diagnosis of SLE and the informed consent date plus 1 day divided by 365.25 days, then rounded
to 1 decimal.
     Duration of SLE = (DATE of CONSENT – DATE of SLE DIAGNOSIS + 1) /365.25
Partially missing SLE diagnosis dates will be imputed as specified in Section 16.2.3.
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ur


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
42
16.2.
Date Imputation Guideline
16.2.1.
Adverse Events
Partially missing AE start dates will be imputed in the analysis dataset model (ADaM) dataset 
for AEs, but partially missing AE end dates will not be imputed in the same dataset. If the AE 
end date is complete with no missing year, month, or day, and the partially missing start date 
imputed by the rules below is after the AE end date, then the start date will be imputed by the AE 
end date.
The principle of the imputation rules is to treat the AE as treatment-emergent, ie, occurring on or 
after the date of the first dose of IP, if possible.
Let an AE start date be represented as “DEvent/MEvent/YEvent”, and the date of the first dose of IP in 
ATEP as “DIP/MIP/YIP”. The imputation rules for partially missing AE start dates are stated in 
Table 2.
Table 2:
Imputation Rules for Partially Missing Adverse Event Start Date
Scenario
Condition
Imputation Rule
A. Partially missing date includes year only (both month and day are missing)
1
YEvent < YIP
31/12/YEvent
2
Otherwise, ie, YIP ≤ YEvent
Max (date of first dose of IP, 
01/01/YEvent)
B. Partially missing date includes both year and month (only day is missing)
1
YEvent < YIP, or 
(YEvent = YIP and MEvent < MIP)
Last date of MEvent/YEvent
2
Otherwise, ie, YIP < YEvent, or 
(YIP = YEvent and MIP ≤ MEvent) 
Max (date of first dose of IP,
01/MEvent/YEvent)
16.2.2.
Prior/Concomitant Medications/Procedures
Partially missing start/stop dates for prior/concomitant medications and partially missing start 
dates for prior/concomitant procedures will be imputed in the ADaM dataset. For 
prior/concomitant medications, if the stop date is complete with no missing year, month, or day, 
and the partially missing start date imputed by the rule below is after the stop date, then the start 
date will be imputed by the stop date.
Partially missing prior/concomitant medication/procedure start dates will be imputed by the 
earliest possible date given the non-missing field(s) of the date.
Partially missing prior/concomitant medication stop dates will be imputed by the latest possible 
date given the non-missing field(s) of the date.
Let a prior/concomitant medication/procedure start/stop date be represented as 
“DEvent/MEvent/YEvent”. The imputation rules for partially missing prior/concomitant medication 
start dates are stated in Table 3. The imputation rules for partially missing prior/concomitant 
medication stop dates are stated in Table 4.
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et a p
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
43
Table 3:
Imputation Rules for Partially Missing Prior/Concomitant 
Medication/Procedure Start Dates
Scenario
Condition
Imputation Rule
1
Partially missing date includes year only (both 
month and day are missing)
01/01/YEvent
2
Partially missing date includes both year and month 
(only day is missing)
01/MEvent/YEvent
Table 4:
Imputation Rules for Partially Missing Prior/Concomitant Medication Stop 
Dates
Scenario
Condition
Imputation Rule
1
Partially missing date includes year only (both 
month and day are missing)
31/12/YEvent
2
Partially missing date includes both year and month 
(only day is missing)
Last date of MEvent/YEvent
16.2.3.
Medical History
Partially missing medical history start dates will be imputed in the ADaM dataset for medical 
history (for the purposes of calculating duration of SLE). The 16th of the month will be used to 
impute a partially missing start date that has only the day missing, and July 1st will be used to 
impute a partially missing start date that has both the month and day missing.
Let a medical history start date be represented as “DEvent/MEvent/YEvent”. The imputation rules for 
partially missing medical history start dates are stated in Table 5 . 
Table 5:
Imputation Rules for Partially Missing Medical History Start Dates
Scenario
Condition
Imputation Rule
1
Partially missing date includes year only (both 
month and day are missing)
01/07/YEvent
2
Partially missing date includes both year and month 
(only day is missing)
16/MEvent/YEvent
16.3.
Marked Abnormalities Criteria
The laboratory marked abnormality criteria is presented in Table 6.
Table 6:
Laboratory Marked Abnormality Criteria
Category / Analyte
SI Units 
Criteria 
Chemistry
   Alanine Aminotransferase (SGPT)
U/L
> 3 xULN  
   Albumin
Kg/m3
< 25
   Alkaline Phosphatase
U/L
> 400  
   Aspartate Aminotransferase (SGOT)
U/L
> 3 x ULN  
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
44
Category / Analyte
SI Units 
Criteria 
   Total Bilirubin
μmol/L
> 1.8 x ULN  
   Blood Urea Nitrogen
mmol/L
> 15
   Calcium 
mmol/L
< 1.8
> 3.0
   Creatinine 
μmol/L 
> 1.7 x ULN 
   Glucose
mmol/L
< 2.8
> 13.9
   Hemoglobin A1C
%
> 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
   Triglycerides
mmol/L
> 3.4
   Urate
umol/L
Male: > 590; Female: > 480
   Alanine Aminotransferase (SGPT)
   Aspartate Aminotransferase (SGOT)
   Total Bilirubin
U/L
U/L
μmol/L
(ALT > 3xULN or 
AST > 3xULN) and 
Total Bilirubin > 1.5x ULN
Hematology
   Hemoglobin
g/L
Male: < 105, Female: < 85 
Male: > 185, Female: > 170
  Leukocytes
10^9/L
< 1.5
  Lymphocytes
10^9/L
< 0.8
  Neutrophils
10^9/L
< 1.0
  Platelets
10^9/L
< 75
> 600
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35


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
45
16.4.
Schedule of Events
&(/*(1(35235,(7$5<,1)250$7,21


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
46
CCI
(7$5<,1)250$7,21
&(/*(1


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – ATEP
Celgene Corporation
Confidential and Proprietary
47
HCG = beta human chorionic gonadotropin; ECG = electrocardiogram; IgG = immunoglobulin G; IgM = immunoglobulin M; 
IgA = immunoglobulin A; IP = investigational
product; PK = pharmacokinetics; VAS = visual analog scale; PPRMP= Pregnancy Prevention Risk Management Plans; 
PT=prothrombin time; INR=internationalized normalized
ratio; PTT=partial thromboplastin time; HBsAg=Hepatitis B surface antigen; CLASI=Cutaneous Lupus Area and Severity Index; 
PGA=physician global assessment; SLEDAI=
Systemic Lupus Erythematosus Disease Activity Index; 
 
; FSH=follicle-stimulating hormone; LH=luteinizing hormone; 
IRB=institutional review board.
a FCBP are required to have 2 negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting IP. The first 
pregnancy test must be performed within 10 to
14 days prior to the start of IP and the second test must be performed within 24 hours of starting IP. The subject may not 
receive IP until the Investigator has verified that
the results of these pregnancy tests are negative. FCBP with 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 Day 113 and Day 169 following IP discontinuation (if urine pregnancy test is 
positive on Day 113, a serum pregnancy test
must be conducted to confirm result). If menstrual cycles are irregular or do not occur, the pregnancy testing must occur weekly 
for the first 28 days and then every 14 days
while on study, at treatment discontinuation and at 14 and 28 days following treatment discontinuation.
b 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 and within 28 days of discontinuing investigational product.
c Collection of these analytes must occur at the same time of day (± 1 hour) at the Baseline (Visit 2) and Day 85 (End of 
Treatment or Early Termination Visit) for males only.
For example, if collected at the Baseline Visit at 9 AM, the Final Treatment/Early Termination Visit sample must be collected
between 8 and 10 AM.
d On Day 1 and Day 29 PK blood samples will be collected at pre-dose (Time=0 hours), 1, 2, 3, 4, between 6 and 8 hours and 24 
hours (±5 hours) after administration of IP.
e Subjects who discontinue treatment early should enter into the Observational Follow-up Phase. Subjects who elect to enter the 
ATEP (at sites which have IRB approval for the
ATEP) will not enter the Observational Follow-Up Phase and directly enter the ATEP. Those subjects who conclude their 
treatment at a site which does not have IRB approval
for the ATEP must enter the Observational Follow-Up Phase. Subjects who would like to enter ATEP, but whose site does not 
have IRB approval may enter the Observational
Follow-Up Phase and then enter the ATEP once the site’s IRB approves the amendment containing the ATEP.
f If a subject is planning to receive a primary booster dose of pneumococcal vaccine at any time during the study, a prevaccination 
blood sample should be obtained to measure the prevaccination titer.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
1
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
TITLE PAGE
A PILOT, PHASE 2, RANDOMIZED, PLACEBO-
CONTROLLED, DOUBLE-BLIND, STUDY TO 
EVALUATE EFFICACY, SAFETY, TOLERABILITY,
PHARMACOKINETICS, PHARMACODYNAMICS AND 
PHARMACOGENETICS OF CC-220 IN SUBJECTS 
WITH SYSTEMIC LUPUS ERYTHEMATOSUS
INVESTIGATIONAL PRODUCT (IP):
CC-220
PROTOCOL NUMBER:
CC-220-SLE-001
DATE FINAL:
22 Apr 2014
AMENDMENT 1:
24 Jul 2014
AMENDMENT 2:
19 Sep 2014
AMENDMENT 3:
11 Jun 2015
AMENDMENT 4:
05 Jan 2016
AMENDMENT 5:
17 Mar 2017
AMENDMENT 6:
18 Jun 2018
EudraCT NUMBER:
NA
IND NUMBER:
116088
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
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.
&&,
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ul 2014
ul 20
19 Sep 201
9 Sep 20
11 J
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05 5
RESS:
RESS:
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&(


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
2
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name: 
Title:
Address:
Phone:
(Office)
E-mail:
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.
Back-up 24 Hour Global Emergency Contact Call Center: 
&&,
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
3
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, ICH Good Clinical Practices 
Guidelines, and local regulations governing the conduct of clinical studies.
&&,
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
5
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
6
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
PROTOCOL SUMMARY
Study Title
A Pilot, Phase 2, Randomized, Placebo-Controlled, Double-Blind Study to Evaluate Efficacy, 
Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of CC-220 in
Subjects with Systemic Lupus Erythematosus 
Indication
Systemic Lupus Erythematosus (SLE) 
Objectives
Part 1
!
Primary:
∀
To evaluate the safety and tolerability of CC-220 for subjects with SLE
!
Secondary:
∀
To describe the pharmacokinetics (PK) of CC-220 for subjects with SLE
!
 
 
 
 
Active Treatment Extension Phase
!
Primary:
∀
To evaluate the long-term safety and tolerability of CC-220 in subjects with SLE 
who completed Part 1 of the core study
!
Secondary:
∀
To evaluate the long-term efficacy of CC-220 in subjects with SLE who 
completed Part 1 of the core study
!
 
 
Study Design
This is a pilot, Phase 2, randomized, placebo-controlled, double-blind, multicenter study to 
evaluate the preliminary efficacy, safety, tolerability, pharmacokinetics, pharmacodynamics and 
pharmacogenetics of CC-220 in SLE subjects with skin involvement.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
7
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
This study will be conducted in two parts.
Part 1
Part 1 is a randomized, double-blind, placebo-controlled, ascending dose study to evaluate the 
safety and tolerability of CC-220 in SLE subjects. 
Subject participation in Part 1 will consist of 3 phases:
!
Pre-treatment Screening Phase: up to 42 days prior to the first dose of the 
investigational product (IP) 
!
Treatment Phase: up to 84 days
!
Observational Follow-up Phase: 84 day post-treatment (subjects who consent and 
qualify for the Active Treatment Extension Phase [ATEP] will NOT enter the 
Observational Follow-up Phase and will directly enter the ATEP)
A total of approximately 40 subjects will be randomized into 4 dose groups with a 4:1 ratio of 
CC-220 (0.3 mg every other day [QOD], 0.3 mg everyday [QD], 0.6 mg and 0.3 mg on 
alternating days and 0.6 mg QD) or matching placebo (8 subjects in the CC-220 arm and 2 
subjects in the placebo arm for each dose group) using an Interactive Voice Response System 
(IVRS). Subjects will be randomized into the first two dose groups of 0.3 mg QOD and 0.3 mg 
QD in parallel. Following confirmation of safety of the first two dose groups, remaining subjects 
will then be randomized into the 0.6 mg and 0.3 mg on alternating days and 0.6 mg QD dose 
groups in a sequential, dose-ascending manner (first the 0.6 mg and 0.3 mg on alternating days 
dose group followed by the 0.6 mg QD dose group). The Treatment Phase will be up to 84 days 
in duration for all dose groups. Subjects who discontinue IP early and all subjects who complete 
the 84-day Treatment Phase (who do not consent to enroll into the ATEP) will enter into the 
Observational Follow-up Phase for an 84-day period. In all cases of early termination from the 
study, subjects will be encouraged to complete an Early Termination Visit. See Figure 1 for 
graphical representation of the Part 1 dosing administration schedule.
All subjects will be allowed to remain on stable doses of hydroxychloroquine, chloroquine, 
and/or quinacrine for ≥ 4 weeks prior to their baseline visit and throughout the study. No 
additional systemic immunosuppressives will be permitted.  In addition, as needed (PRN) 
treatment with systemic anti-pruritics and/or systemic analgesics will be permitted; subjects must 
stop using all systemic anti-pruritics 48 hours prior to all study visits and systemic analgesics 12
hours prior to all study visits. Oral non-steroidal anti-inflammatory drugs (NSAIDs) may be 
used, but must be stopped 12 hours prior to all study visits. Use of oral corticosteroids will be 
permitted only at doses of 10 mg or less per day and must be maintained at a stable dose during 
study participation. Inhaled corticosteroids for use in a disease other than lupus, eg, asthma, will 
be allowed. No IV (intravenous) or IM (intramuscular) corticosteroids will be permitted during 
the study. No other topical (with the exception of potency class 6 and 7 topicals only), local or 
systemic treatments for dermatological manifestations of SLE will be permitted. 
Following completion of the first 28 days of the treatment phase by at least 8 subjects in Dose 
Group 1 (0.3 mg QOD) and 8 subjects in Dose Group 2 (0.3 QD), an assessment of safety and 
tolerability will be conducted. If Dose Groups 1 and 2 are deemed to have acceptable safety and 
tolerability, subjects will continue to receive investigational product for up to 84 days and 
enrollment of subjects into Dose Group 3 (0.6 mg and 0.3 mg on alternating days) will be 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
8
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
initiated. Following completion of the first 28 days of the treatment phase by at least 8 subjects 
in Dose Group 3 (0.6 mg and 0.3 mg on alternating days), an assessment of safety and 
tolerability will be conducted. If Dose Group 3 is deemed to have acceptable safety and 
tolerability, subjects will continue to receive investigational product for up to 84 days and 
enrollment of subjects into Dose Group 4 (0.6 mg QD) will be initiated. Following completion of 
the first 28 days of the treatment phase by at least 8 subjects in Dose Group 4 (0.6 mg QD), an 
assessment of safety and tolerability will be conducted. If Dose Group 4 is deemed to have 
acceptable safety and tolerability, subjects will continue to receive investigational product for up 
to 84 days. 
Subjects will remain on their assigned treatment for up to 84 days. In the event a subject 
experiences clinically significant IP-related adverse events (AEs), a dose interruption for up to 
14 days will be permitted (see Section 12.1). If a subject is unable to remain on their assigned 
dose, he/she may reduce their dose to the next lowest dosing regimen. Dose reductions will occur 
as follows:
!
Subjects on 0.6 mg QD will reduce their dose to 0.6 mg/0.3 mg on alternating days
!
Subjects on 0.6 mg/0.3 mg on alternating days will reduce their dose to 0.3 mg QD
!
Subjects on 0.3 mg QD will reduce their dose to 0.3 mg QOD
!
Subjects on 0.3 mg QOD will reduce their dose to placebo 
A subject will only be permitted to reduce their dose one time during the study. The decision to 
modify IP dosing will be based on the rules provided in Section 12.1. The sponsor should be 
notified of the intent to dose reduce prior to a change in dosing.
Subjects who discontinue from the study prior to completing 28 days of treatment may be 
replaced (for up to a total of 10 subjects for Part 1) at the discretion of the sponsor. 
Active Treatment Extension Phase
The ATEP is an extension of the core CC-220-SLE-001 study to evaluate the long-term efficacy 
and safety/tolerability of CC-220 in SLE subjects who completed Part 1 of the core study. 
Subjects who complete the Treatment Phase of Part 1 of the core study will be eligible to receive 
CC-220 in the ATEP for up to 2 years. All subjects who participate in the ATEP will receive the 
same active treatment they received during their participation in Part 1 with the exception of 
those on placebo or 0.3 mg QOD (see below for information on dosing for these subjects).  
Subjects who complete the Treatment Phase of Part 1 of the core study will be eligible to enter 
this phase of the study and should be enrolled immediately to avoid dose interruption. In the 
event the ATEP has not been implemented by a subject’s study center at the time they have 
completed the Treatment Phase, subjects will enter the Observation Phase of the core study and 
be eligible to enroll in the ATEP upon implementation of this amendment. There are no time 
restrictions on how long subjects can be off CC-220 prior to entering the ATEP as long as they 
completed treatment in Part 1 of the core study, but with the implementation of Protocol 
Amendment 5, enrollment into the ATEP is now closed. Subjects who terminate the Treatment 
Phase of Part 1 early will not be eligible for entry into the ATEP. 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
9
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Subject participation consists of two phases:
!
Active Treatment Extension Phase: Up to 2 years
!
Observational Follow-up Phase: 28 days
Subjects receiving CC-220 0.3 mg QOD or CC-220 0.3 mg QD during their participation in the 
core study will be assigned to receive CC-220 0.3 mg QD during the ATEP. Subjects receiving 
CC-220 0.6 mg/0.3 mg on alternating days during their participation in the core study will 
remain on the same assigned dose during the ATEP. Subjects receiving CC-220 0.6 mg QD 
during their participation in the core study were originally permitted to enter the ATEP on the 
same dose. However, based on data that has become available for Part 1 (see Section 4.2.3), any 
subject originally enrolled in the ATEP on the 0.6 mg QD dose should be dose reduced to the 0.6 
mg/0.3 mg on alternating days dose upon implementation of Protocol Amendment 5. 
Subjects receiving placebo during their participation in the core study (Part 1) will receive the 
CC-220 dose given to those on active drug in their respective cohort. For example, if a subject 
was taking placebo in Dose Group 3 of Part 1, he or she would receive CC-220 0.6 mg/0.3 mg on 
alternating days during the ATEP. However, based on data that has become available for Part 1 
(see Section 4.2.3), any subject who was on placebo in the 0.6 mg QD cohort for Part 1 and 
originally entered the ATEP on 0.6 mg QD should be dose reduced to 0.6/0.3 mg QD on 
alternating days upon implementation of Protocol Amendment 5.
For subjects who are eligible to roll directly into the ATEP, Week 12 (Visit 10) of Part 1
may be on the same day as Visit 1 of the ATEP. All Visit 10 (Part 1) and Visit 1 (ATEP) 
procedures must be conducted as outlined in Table 1 and Table 2. Please note that subjects 
rolling directly into the ATEP who have both Week 12 (Visit 10) of Part 1 and Visit 1 of the 
ATEP on the same day, will only undergo a subset of assessments for Visit 1 of the ATEP 
(indicated in Table 2). If the subject remains eligible for entry into the ATEP following Visit 1 
assessments, drug will be dispensed and the subject will begin the ATEP. Subjects entering the 
ATEP who cannot hold their Week 12 (Visit 10) of Part 1 and Visit 1 of the ATEP on the same 
day, can hold their Visit 1 of the ATEP at any time after their sites has received IRB approval.
However, once 14 days have elapsed since a subject has had their Part 1 Week 12 (Visit 10),
they must undergo the ATEP Screening Visit and all assessments listed for Visit 1 of the 
ATEP in Table 2 if they wish to enter the ATEP. As long as a subject comes in for their 
Visit 1 ATEP within 14 days after their Part 1 Week 12 (Visit 10) they will only need to 
complete the subset of assessments identified under footnote b of Table 2.
All subjects will be allowed to remain on stable doses of hydroxychloroquine, chloroquine, 
and/or quinacrine for ≥ 4 weeks prior to their baseline visit and throughout the study. Subjects on 
antimalarials will be permitted to modify or stop their treatment at any time during the ATEP. 
Methotrexate (7.5 mg – 25 mg per week), leflunomide (maintenance dosing must not exceed 20 
mg daily) or sulfasalazine (dosing not to exceed 3g daily) will be permitted, although no other 
additional systemic immunosuppressives will be permitted. In addition, PRN treatment with 
systemic anti-pruritics and/or systemic analgesics will be permitted. However, subjects must stop 
using all systemic anti-pruritics 48 hours prior to all study visits and systemic analgesics 12 
hours prior to all study visits. Oral NSAIDs may be used, but must be stopped 12 hours prior to 
all study visits. Use of oral corticosteroids will be permitted at doses of 10 mg or less per day and 
ideally should be maintained at a stable dose during study participation. Inhaled corticosteroids 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
10
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
for use in a disease other than lupus, eg, asthma, will be allowed. No IV or IM corticosteroids 
will be permitted during the study.  No other topical (with the exception of potency class 6 and 7 
topicals only), local or systemic treatments for dermatological manifestations of SLE will be 
permitted.
Thromboprophylaxis with low dose aspirin, low molecular weight heparin or other equivalent 
antithrombotic or anticoagulant is required unless the investigator determines that, based on the 
totality of the subjects’ risk factors for thrombosis, thromboprophylaxis is not required or is 
contraindicated.
If any additional prophylaxis is needed, it should be based on the local standard of care and the 
investigator’s best judgement after careful consideration of the benefit versus the potential risk 
for the individual subject.
Subjects will remain on their assigned treatment for up to 2 years. In the event a subject 
experiences clinically significant IP-related AEs, a dose interruption for up to 14 days will be 
permitted (see Section 12.1). If a subject is unable to remain on their assigned dose, he/she may 
reduce their dose to the next lowest dosing regimen. Dose reductions will occur as follows:
!
Subjects on CC-220 0.6 mg QD will reduce their dose to CC-220 0.6 mg/0.3 mg on 
alternating days
!
Subjects on CC-220 0.6 mg/0.3 mg on alternating days will reduce their dose to CC-
220 0.3 mg QD
!
Subjects on CC-220 0.3 mg QD will be terminated from the study
A subject will only be permitted to reduce their dose one time during the study (subjects who 
originally came into the ATEP on 0.6 mg QD and dose reduce to 0.6/0.3 mg QD on alternating 
days upon implementation of Protocol Amendment 5 will be eligible for one additional dose 
reduction in the ATEP). The decision to modify IP dosing will be based on the rules provided in 
Section 12.1. The sponsor should be notified of the intent to dose reduce prior to a change in 
dosing.
Subjects will have regularly scheduled visits to assess IP activity and safety. Required 
assessments will be completed as depicted in Table 2.
Upon completion of, or discontinuation from the ATEP, all subjects (including premature 
discontinuations) will enter a 28 day Observational Follow-up Phase. Subjects who discontinue 
IP early should complete an Early Termination Visit.
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
applicable regulatory requirements.
Study Population
The study population consists of male and female subjects 18 years of age and older at the time 
of signing the informed consent document (ICD).
Subjects in Part 1 are required to have:
An established diagnosis of SLE as defined by the 1997 Update of the 1982 American College of 
Rheumatology (ACR) Revised Criteria for Classification of SLE at Screening (Appendix D) and 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
11
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
a minimum Hybrid SELENA Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)
score of ≥ 4 points.
Subjects in the Active Treatment Extension Phase are required to have:
!
Completed the CC-220-SLE-001 core study (Part 1).
Length of Study
The length of study participation for each subject in Part 1 is 210 days (Up to a 42-day Screening 
Phase, 84-day Treatment Phase and an 84-day Observational Follow-Up Phase). The length of 
study participation for each subject in the ATEP is up to 2 years and 1 month (up to a 2-year 
ATEP and a 28-day post-treatment Observational Follow-Up Phase). Subjects who participate in 
both Part 1 and the ATEP will participate in the study for a total of approximately 2 years and 6 
months.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary and/or exploratory analyses, as pre-specified in the protocol and/or the 
Statistical Analysis Plan, whichever is the later date. 
Study Treatments
CC-220 will be provided as 0.3 mg capsules.  Standard matching placebo capsules will also be 
provided.  Capsules will be taken by mouth (PO) with or without food.
Subjects will be randomized to one of the 4 following dose groups for Part 1. The ATEP will 
allow for subjects to continue on the dose they were administered during their involvement in the 
core study (with the exception of subjects on CC-220 0.3 mg QOD or placebo who will be re-
assigned as described in the Study Design above). Subjects receiving CC-220 0.6 mg QD during 
their participation in the core study were originally permitted to enter the ATEP on the same 
dose. However, based on data that has become available for Part 1 (see Section 4.2.3), any 
subject originally enrolled in the ATEP on the 0.6 mg QD dose should be dose reduced to the 0.6 
mg/0.3 mg on alternating days dose upon implementation of Protocol Amendment 5. 
Investigational product will be administered PO as described below:
CC-220 
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0.3 mg QOD (Part 1 only)
Subjects will receive 0.3 mg once every other day
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0.3 mg QD
Subjects will receive 0.3 mg every day 
!
0.6 mg and 0.3 mg on alternating days
Subjects will receive 0.6 mg and 0.3 mg on alternating days. 
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Subjects will receive 0.6 mg every day 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
12
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Placebo (Part 1 only)
Subjects assigned to the placebo group will receive matching placebo capsule(s) daily.
In the event a subject experiences clinically significant IP-related AEs, a dose interruption for up 
to 14 days will be permitted (see Section 12.1). If a subject is unable to remain on their 
treatment, the subject will either be dose reduced or discontinue IP early and enter into an 84-day 
Observational Follow-up Phase. In the case of a dose reduction, subjects on placebo will be 
reduced to placebo to maintain the blind. In all cases of early termination from the study, 
subjects will be encouraged to complete an Early Termination Visit. The decision to modify IP 
dosing will be based on the rules provided in Section 12.1. The sponsor should be notified of the 
intent to dose reduce prior to a change in dosing.
In the event that a subject experiences a flare during the Observational Follow-up Period, the 
Investigator may treat the subject with the standard of care in order to allow the subject to remain 
in the Observational Follow-up Period and continue with the scheduled visits and assessments 
indicated by the schedule of assessments.
There will be no placebo in the ATEP.
The safety assessments may be conducted by a physician, physician assistant, nurse practitioner, 
or study nurse. Ideally, the safety assessor should be the same individual throughout the course 
of each subject’s participation at a site. The efficacy assessments must be conducted by a 
physician, physician assistant, or qualified nurse practitioner. The trained investigator/sub-
investigator conducting efficacy assessments should remain the same throughout the study.  
Overview of Safety Assessments
!
Adverse events
!
Vital signs, including height, weight, pulse, temperature and blood pressure
!
Hematology, chemistry, urinalysis
!
Inflammation panel
!
Serum beta-human chorionic gonadotropin (HCG) and urine pregnancy tests (for
females of childbearing potential [FCBP])
!
Tetanus toxoid vaccine, pneumococcal antigen and influenza titers
!
Centralized 12-lead electrocardiograms (ECGs)
!
Physical examinations, including height and weight
!
Concomitant medications and procedures
!
Ophthalmological examinations will be conducted by a qualified ophthalmologist. 
Testing will include visual acuity and slit lamp exams with fluorescein staining 
following pupillary dilation, focusing on the anterior chamber, iris and anterior 
vitreous (unless use of fluorescein is contraindicated, eg, due to hypersensitivity).
!
Hepatitis screening
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Testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH) for 
males only
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
13
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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Amylase and lipase
Overview of Pharmacokinetic Assessments
Blood samples for quantification of CC-220 in plasma will be taken at specified timepoints
(Table 1) during the course of the study.
Approximately 4 subjects in each of the 4 treatment groups in Part 1 (a targeted total of 32 
subjects) will be identified for participation in the Intensive PK sub-study. The IVRS will be 
used to identify for inclusion approximately 4 intensive PK participants per dose group. 
Noncompartmental PK parameters of CC-220 will be estimated from these subjects.
All other subjects who do not participate in the Intensive PK sub-study will have sparse PK 
samples collected.
No PK will be assessed during the ATEP.
 
 
 
 
Overview of Efficacy Assessments
!
Cutaneous Lupus Area and Severity Index (CLASI) (Appendix A)
!
Hybrid SELENA Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)
(Appendix E)
!
Physician’s Global Assessment (PGA) (Appendix C)
!
Swollen and Tender Joint Counts (Appendix B)
!
Pericardial/Pleuritic Pain Numerical Rating Scale (Appendix G)
!
Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Systemic Lupus Erythematosus (SLICC/ACR SLE) Damage Index 
(Appendix O)
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British Isles Lupus Assessment Group 2004 (BILAG) (Appendix P)
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
14
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
15
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................22
2.
STUDY OBJECTIVES...........................................................................................27
2.1.
Part 1......................................................................................................................27
2.1.1.
Primary...................................................................................................................27
2.1.2.
Secondary...............................................................................................................27
2.2.
Active Treatment Extension Phase..........................................................................27
2.2.1.
Primary...................................................................................................................27
2.2.2.
Secondary...............................................................................................................27
3.
STUDY ENDPOINTS............................................................................................28
3.1.
Part 1......................................................................................................................28
3.1.1.
Primary...................................................................................................................28
3.1.2.
Secondary...............................................................................................................28
3.2.
Active Treatment Extension Phase..........................................................................29
3.2.1.
Primary...................................................................................................................29
3.2.2.
Secondary...............................................................................................................29
4.
OVERALL STUDY DESIGN ................................................................................31
4.1.
Study Design ..........................................................................................................31
4.2.
Study Design Rationale ..........................................................................................35
4.2.1.
Duration of Treatment ............................................................................................35
4.2.2.
Study Population ....................................................................................................35
4.2.3.
Dose and Dose Interval...........................................................................................35
4.2.4.
Blinding..................................................................................................................36
4.2.5.
Concomitant Medications .......................................................................................36
4.2.6.
Efficacy..................................................................................................................37
4.2.7.
Safety.....................................................................................................................37
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EDMS Doc. Number:
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4.2.7.1.
Internal Celgene Monitoring at the Study Level......................................................39
4.2.7.2.
Internal Celgene Safety Monitoring of CC-220 at the Compound Level –
Role of the Safety Management Team ....................................................................39
4.2.8.
Pharmacokinetic
 Markers ...................................................39
4.3.
Study Duration .......................................................................................................41
4.4.
End of Trial ............................................................................................................41
5.
TABLE OF EVENTS.............................................................................................42
6.
PROCEDURES......................................................................................................50
7.
STUDY POPULATION.........................................................................................59
7.1.
Number of Subjects and Sites .................................................................................59
7.2.
Inclusion Criteria....................................................................................................59
7.2.1.
Part 1......................................................................................................................59
7.2.2.
Active Treatment Extension Phase..........................................................................61
7.3.
Exclusion Criteria...................................................................................................62
7.3.1.
Part 1 and Active Treatment Extension Phase .........................................................62
8.
DESCRIPTION OF STUDY TREATMENTS........................................................66
8.1.
Description of Investigational Product(s)................................................................66
8.2.
Treatment Administration and Schedule .................................................................66
8.2.1.
Dose Modification or Interruption...........................................................................66
8.2.2.
Overdose ................................................................................................................67
8.3.
Method of Treatment Assignment...........................................................................67
8.4.
Packaging and Labeling..........................................................................................67
8.5.
Investigational Product Accountability and Disposal ..............................................68
8.6.
Investigational Product Compliance........................................................................68
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................69
9.1.
Permitted Concomitant Medications and Procedures...............................................69
9.2.
Prohibited Concomitant Medications and Procedures..............................................70
9.3.
Required Concomitant Medications and Procedures................................................70
10.
STATISTICAL ANALYSES..................................................................................71
10.1.
Overview................................................................................................................71
10.2.
Study Population Definitions ..................................................................................71
10.3.
Sample Size and Power Considerations...................................................................71
10.4.
Background and Demographic Characteristics........................................................72
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2


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
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17
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
10.5.
Subject Disposition.................................................................................................72
10.6.
Efficacy Analysis....................................................................................................72
10.7.
Safety Analysis.......................................................................................................73
10.8.
Interim Analysis .....................................................................................................73
10.9.
Other Topics...........................................................................................................73
10.9.1.
Pharmacokinetic Analysis.......................................................................................73
11.
ADVERSE EVENTS..............................................................................................75
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................75
11.2.
Evaluation of Adverse Events.................................................................................75
11.2.1.
Seriousness.............................................................................................................75
11.2.2.
Severity / Intensity..................................................................................................77
11.2.3.
Causality ................................................................................................................77
11.2.4.
Duration .................................................................................................................78
11.2.5.
Action Taken..........................................................................................................78
11.2.6.
Outcome.................................................................................................................78
11.3.
Abnormal Laboratory Values..................................................................................78
11.4.
Pregnancy...............................................................................................................79
11.4.1.
Females of Childbearing Potential: .........................................................................79
11.4.2.
Male Subjects.........................................................................................................79
11.5.
Reporting of Serious Adverse Events......................................................................79
11.5.1.
Safety Queries ........................................................................................................80
11.6.
Expedited Reporting of Adverse Events..................................................................80
12.
DISCONTINUATIONS .........................................................................................82
12.1.
Subject Stopping Rules...........................................................................................82
12.2.
Dose Group Stopping Rules....................................................................................83
12.3.
Discontinuation Criteria..........................................................................................83
13.
EMERGENCY PROCEDURES.............................................................................85
13.1.
Emergency Contact.................................................................................................85
13.2.
Emergency Identification of Investigational Products .............................................85
14.
REGULATORY CONSIDERATIONS...................................................................86
14.1.
Good Clinical Practice............................................................................................86
14.2.
Investigator Responsibilities ...................................................................................86
&&,
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$7


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
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CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
14.3.
Subject Information and Informed Consent.............................................................86
14.4.
Confidentiality........................................................................................................87
14.5.
Protocol Amendments.............................................................................................87
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................87
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................88
14.8.
Closure of the Study ...............................................................................................88
15.
DATA HANDLING AND RECORDKEEPING.....................................................89
15.1.
Data/Documents.....................................................................................................89
15.2.
Data Management...................................................................................................89
15.3.
Record Retention....................................................................................................89
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................91
16.1.
Study Monitoring and Source Data Verification......................................................91
16.2.
Audits and Inspections............................................................................................91
17.
PUBLICATIONS ...................................................................................................92
18.
REFERENCES.......................................................................................................93
19.
APPENDICES........................................................................................................96
APPENDIX A.
THE CUTANEOUS LUPUS AREA AND SEVERITY INDEX ....................96
APPENDIX B.
SWOLLEN AND TENDER JOINT COUNT – 44 JOINTS ...........................97
APPENDIX C.
PHYSICIAN’S GLOBAL ASSESSMENT ....................................................99
APPENDIX D.
1997 UPDATE OF THE 1982 ACR REVISED CRITERIA FOR 
CLASSIFICATION OF SLE ................................................................................100
APPENDIX E.
HYBRID SELENA SLEDAI........................................................................102
APPENDIX F.
GILLIAM CLASSIFICATION ....................................................................104
APPENDIX G.
PERICARDIAL/PLEURITIC NUMERICAL PAIN SCALE .......................107
APPENDIX H.
FATIGUE VAS ...........................................................................................108
APPENDIX K.
MEDICATIONS THAT INHIBIT CYP3A4 ................................................116
APPENDIX L.
HEPATITIS EXCLUSION CRITERIA........................................................117
APPENDIX O.
SLICC/ACR SLE DAMAGE INDEX..........................................................123
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
19
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
APPENDIX P.
BRITISH ISLE LUPUS ASSESSMENT GROUP 2004 ...............................127
&&,
CCI
CCI
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
20
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
LIST OF TABLES
Table 1:
Part 1......................................................................................................................42
Table 2:
Active Treatment Extension Phase..........................................................................46
&&,
CCI
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
21
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................40
&&,
CCI
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
22
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
1.
INTRODUCTION
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease of unknown etiology 
that has many clinical manifestations. Almost any organ can be involved, but the most common 
manifestations are cutaneous, musculoskeletal and renal (Petri, 2006). Systemic lupus 
erythematosus typically affects young women of childbearing potential between the ages of 15 to 
44. The prevalence of SLE is 300,000 patients in the United States and 4 million patients 
worldwide, with an annual incidence of 15,000 in the United States alone.
The pathogenesis of SLE likely involves an array of components associated with both genetic 
and environmental factors. Disease susceptibility is influenced by genes related to immune 
response and the major histocompatibility complex class I and II genes. Additional susceptibility 
stems from interactions between the hormonal environment and the hypothalamo-pituitary-
adrenal axis. In addition, the development of SLE is associated with a defective immune 
response which affects apoptotic cell clearance and immune complexes. The loss of immune 
tolerance, excess T cell help, defective B cell suppression, and the shifting of T helper 1 (Th1) to 
Th2 and Th17 immune responses leads to B cell hyperactivity and the production of pathogenic 
antibodies. External factors such as chemicals, drugs, ultraviolet light, diet and viruses also 
contribute to the onset of disease (Mok, 2003).
As SLE is a waxing and waning disease, it is often controlled with NSAIDs or low potency 
immunosuppression drugs (antimalarials and low dose corticosteroids) for milder symptomology 
(musculoskeletal manifestation, cutaneous manifestation and serositis). More prolonged and 
potent use of corticosteroids, as well as non-biologic disease modifying anti-rheumatic drugs 
(DMARDs), are standard treatments which are also available to treat those patients who exhibit 
major organ involvement. In conjunction with standard therapy, biological DMARD therapies 
exist to augment treatment for those patients with more extensive disease. Belimumab, a 
monoclonal antibody and B-lymphocyte stimulator-specific inhibitor, has been approved for use 
in conjunction with corticosteroids and other standard therapies for autoantibody-positive SLE. 
In addition, Rituximab, a B-cell depleter, is often used off-label as rescue medication for patients 
unresponsive to standard treatment. 
CC-220 is an orally available immunomodulatory drug having multiple effects on cells of the 
immune system, including B cells, T cells, and innate immune cells of the myeloid lineage.
CC-220 is being developed for the treatment of inflammatory or autoimmune-mediated diseases 
such as SLE. CC-220 binds directly to cereblon (CRBN), a component of the Cullin4A-Ring E3 
ubiquitin ligase cereblon complex (CRL4CRBN), thus resulting in modulation of the ubiquitination 
of particular protein substrates. Lenalidomide, which is structurally similar to CC-220, is also 
known to bind to CRBN and modulate the ubiquitination of proteins (Ito, 2010; Lopez-Girona, 
2012; Zhu, 2011), and was shown to have clinical efficacy in CLE patients in two open label 
studies (Braunstein, 2012; Cortes-Hernandez, 2012).
Two putative CRBN substrates reduced by CC-220 treatment in immune cells are: Ikaros,
encoded by the gene IKZF1 and Aiolos, encoded by the gene Ikaros family Zinc Finger 3 
(IKZF3). Ikaros and Aiolos are members of the Ikaros family of transcription factors that 
regulate hematopoiesis and immunity (John, 2011). While both Ikaros and Aiolos are required 
for B cell development (Ferreiros-Vidal, 2013; Kikuchi, 2009), Aiolos is especially important for 
the differentiation of long-lived antibody-secreting plasma cells (Cortes, 2004). In T cells, Aiolos 
is required for Th17 cell differentiation through a mechanism that involves repression of IL-2 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
23
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
gene transcription (Quintana, 2012). Ikaros is also responsible for repressing IL-2 gene 
transcription in T cells as part of the mechanism of T cell anergy (Bandyopadhyay, 2007). Both 
Ikaros and Aiolos are implicated in the genetic predisposition for SLE, as Genome Wide 
Association Studies have shown that polymorphisms in the IKZF1 and IKZF3 loci are associated 
with an increased risk of developing this disease (Lessard, 2012; Wang, 2012). Recently, 
because of its involvement in the signal transducers and activators of transcription (STAT)4 and 
interferon (IFN) pathways in T cells and plasmacytoid dendritic cells, Ikaros has been proposed 
to play a critical role in the pathogenesis of SLE (Hu, 2013).
The potential for CC-220 to have a therapeutic benefit in the treatment of SLE is supported by 
nonclinical data showing its impact on key pathogenic processes underlying SLE. In nonclinical 
in vitro models, CC-220 inhibits the differentiation of B cells into antibody-secreting 
plasmablasts and plasma cells, which are the source of autoantibodies in SLE. CC-220 has 
shown potent effects on B cell differentiation and function in peripheral blood mononuclear cells 
(PBMCs) obtained from patients with SLE, including the inhibition of total immunoglobulin G 
(IgG) and immunoglobulin M (IgM) production, as well as production of anti-dsDNA and anti-
phospholipid antibodies. CC-220 is also a potent antiproliferative agent in B cell-derived tumor 
cell lines in vitro and demonstrates antitumor activity in multiple myeloma and lymphoma tumor 
xenograft models in vivo. These antiproliferative effects against B cell-derived tumors are likely 
to represent a further manifestation of the effects against normal B cells. CC-220 has anti-
inflammatory effects on the cytokine production pathways of the innate immune response. In 
lipopolysaccharide-stimulated PBMC from SLE patients, CC-220 reduced production of IL-
1alpha, IL-1beta, IL-6, TNF-alpha, IFN-gamma, and IL-12, all of which are overexpressed in 
SLE patient serum (Liu, 2013). In SLE patient-derived T cell responses ex vivo, CC-220 
increases production of IL-2, a homeostatic cytokine that is underexpressed in SLE serum, and 
reduces production of IL-17, which is overexpressed in SLE serum (Liu, 2013). Therefore, CC-
220 is an agent that demonstrates a range of immunomodulatory activities, and its ability to 
inhibit antibody secretion and cytokine production in particular, offers the potential for 
therapeutic efficacy in autoimmune conditions such as SLE. 
In nonclinical safety pharmacology studies, CC-220 did not cause any change in central nervous 
system (CNS) functions in rats or any change in cardiovascular functions or any adverse effect in 
respiratory functions in monkeys. In vitro, there was no significant inhibition of the hERG 
(human ether-à-go-go-related gene) ion channel current by CC-220.
The systemic clearance of CC-220 following intravenous (IV) administration was moderate in 
both rats (≈1/2 hepatic blood flow) and monkeys (≤ 1/5 hepatic blood flow). The volume of 
distribution was moderate to high in rats and monkeys, suggesting good tissue distribution of 
CC-220. Across studies, gender differences in CC-220 exposure were modest in rats and not 
consistently observed in monkeys.
 
Following oral dosing to animals, CC-220 was rapidly absorbed and the 
median tmax generally ranged from 0.5 to 2.0 hours postdose. CC-220 exhibited ≥ 60% oral 
bioavailability in rat and 20% in monkey.
Following oral dosing of CC-220 to rats, systemic exposures of free base was slightly higher 
(30% to 110%) in females than in males, and increased in an approximately dose proportional 
manner within 30 to 300 mg/kg single dose range or 2 to 50 mg/kg/day multiple dose range 
without any notable accumulation. Following multiple oral dosing of CC-220 to monkeys, 
systemic exposure of CC-220 at steady state increased in a greater than dose proportional manner 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
24
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
and there was some accumulation of CC-220 observed (accumulation ratio of 1.0 to 2.6). 
 
Protein 
binding of CC-220 was moderate in mouse, rat, monkey, and human, but higher in female 
rabbit. At 300 ng/mL, the percent (%) bound values were 79.4%, 70.4%, 95.5%, 64.1%, and 
74.8% in mouse, rat, female rabbit, monkey, and human plasma, respectively, and the binding 
was not saturable.
The extent of metabolism was variable among rat, monkey, female rabbit, and human. Eighteen 
metabolites 
 were characterized across species resulting 
from non-enzymatic hydrolysis, multiple oxidations of the morpholino moiety, hydrolysis of the 
oxidative metabolites, and a combination of these pathways. Qualitatively, all metabolites 
formed in human hepatocytes were also formed in hepatocytes of rat or monkey, the two species 
used for preclinical safety testing. CYP3A4/5 was identified as responsible for the oxidative 
metabolism of CC-220 in human liver microsomes. The rates and routes of excretion of CC-220 
in vivo in animal species, and the excretion of CC-220 or its related components into milk, have 
not been evaluated. As CC-220 is a substrate for CYP3A4, concomitant administration with 
strong inhibitors or inducers should be avoided (Appendix K).
CC-220 has moderate intrinsic permeability and was determined to be a substrate for both 
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). CC-220 is a weak inhibitor 
of P-gp (half maximal inhibitory concentration [IC50] > 50 μM) and a moderate inhibitor of 
BCRP (IC50 = 22.3 μM). Because CC-220 is projected to be administered at low doses, the gut 
or systemic concentrations of CC-220 are likely to be lower than the IC50 for inhibition of P-gp 
or BCRP. Therefore, CC-220 is not anticipated to cause any clinically relevant drug-drug 
interactions due to inhibition of these transporters.
In rats, no CC-220-related adverse effects were noted at the highest dose of 20 mg base/kg/day 
(no-observed-adverse-effect-level [NOAEL]) after 6 months of dosing.  CC-220 mean systemic 
exposures of 16100 and 21900 ng•hr/mL (an area under the plasma concentration-time curve 
from time 0 to 24 hours [AUC24hr]) in male and female rats respectively at the NOAEL were 
approximately 600- to 800-fold higher than the estimated steady-state (ss) AUC24hr of 27 
ng•hr/mL at a once daily (QD) dose of 0.6 mg, the highest intended dose to be used in current
Phase 2 and future clinical studies. This ss-AUC24hr at 0.6 mg CC-220 QD was estimated based 
on the ss-AUC24hr determined in healthy subjects receiving 0.3 mg and 1 mg CC-220 QD for 
28 days in the Phase 1 multiple-ascending dose (MAD) study.
In monkeys, multiple systemic effects of CC-220 observed were primarily due to its 
pharmacologic effects on the immune system.  These changes were observed in blood and 
lymphatic organs (decreased peripheral blood B, T, and natural killer (NK) cells as well as 
monocytes, altered cellularity in the B and T cell areas, and increased/altered heterogeneous cell 
mixtures in lymphoid organs), gastrointestinal tract (unformed/watery stool leading to decreased 
body weight gain and increased magnitude of subacute/chronic inflammation in cecum/colon), 
eye (increased incidence of minimal mononuclear cell infiltrates in the uveal tract), and bone 
marrow (myeloid hyperplasia).  The impact of CC-220 treatment on humoral responses (either 
enhancement or attenuation) to keyhole limpet hemocyanin (KLH) in monkeys was dependent 
on the timing of immunization in relation to the timing of CC-220 dosing.  Additional 
CC-220-related effects in monkeys were observed in the pancreas (degranulation/atrophy in 
acinar cells), testes/epididymides (bilateral hypospermatogenesis [partial to complete loss of 
spermatogenic epithelial cells] along with increased spermatogenic epithelial cell debris in 
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EDMS Doc. Number:
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Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
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CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
epididymal lumen), liver (biliary epithelial hypertrophy/hyperplasia with mononuclear/mixed 
inflammatory cell infiltrates), lungs (increased alveolar macrophages and decreased goblet cell 
secretion in trachea), and salivary glands (decreased serous cell secretion in mandibular or 
parotid glands).  Among all CC-220-related systemic effects in monkeys, only peripheral blood 
B cell count was differentially affected by different dose schedules with the greatest decrease 
noted upon QD dosing.
Overall, adverse effects of frequent unformed/watery stools and body weight loss requiring 
palliative care, marked decrease in peripheral blood B cells, significantly decreased cellularity in 
lymphoid organs and bilateral hypospermatogenesis were observed at 0.40 mg base/kg/day in the 
9-month oral toxicity study in monkeys.  Thus, the NOAEL in this study was 0.12 mg 
base/kg/day with a mean AUC24hr of 77.6 ng•hr/mL, which was approximately 3-fold higher than 
the estimated steady state AUC24hr of 27 ng•hr/mL at 0.6 mg CC-220 QD, the highest intended 
dose to be used in current Phase 2 and future clinical studies.
With regards to histopathologic finding in testes/epididymides in monkeys noted at 0.40 mg 
base/kg/day, it is not known at this time if this finding can be reversed or at what time after start 
of CC-220 treatment this change occurred. There were no CC-220-related findings in the 
reproductive organs in female monkeys treated with 0.40 mg base/kg/day up to 9 months and in 
male and female rats treated up to 6 months at a dose of up to 20 mg base/kg/day (CC-220 
exposure of up to 21900 ng·hr/mL). At this time, the implications of this finding in monkeys for 
human male reproductive health and the mechanism for this toxicity are unknown. The death of 
one monkey at 0.75 mg base/kg/day on Day 22 of the 1-month dose schedule study was 
associated with CNS-related clinical signs and diffused astrogliosis.  These CNS findings in a 
single animal were unlikely to be causally related to CC-220 based on the lack of CNS-related 
effects in monkeys receiving doses of up to 1, 0.75, and 0.4 mg base/kg/day for 1, 3, and 
9 months, respectively.
CC-220 was not mutagenic in the Ames assay. In an in vitro clastogenicity assay, CC-220 was 
negative after 4 hours with metabolic activation (S9) and 20 hours without S9. However, 
CC-220 was positive in the in vitro clastogenicity assay after a 4-hour treatment without 
S9. Further in vivo genetic toxicity testing with CC-220 in rats at the maximum tolerated dose 
for 3 days did not cause an increase in bone marrow micronucleus formation or any 
deoxyribonucleic acid (DNA) damage in the liver (Comet assay). These negative endpoints in
vivo genotoxicity assays generated the weight of evidence that is considered sufficient to 
demonstrate a lack of significant genotoxicity risk with CC-220 in humans.
In a dose-range finding embryofetal development toxicity study in pregnant rabbits, CC-220 
related developmental toxicities (decreased mean fetal body weight, increased incidences of 
small thymus and fused sternebrae) were observed primarily at 50 mg base/kg/day. However,
CC-220 belongs to a class of drugs that is teratogenic. In light of this, detailed pregnancy 
avoidance/mitigation strategies have been incorporated into the protocol (Section 4.2.7).
As of 01 May 2015, 2 clinical trials have been completed in 129 healthy subjects over the dose 
range of 0.03 to 6 mg. Study CC-220-CP-001 was a randomized, double-blind, placebo-
controlled, single ascending-dose (SAD) Phase 1 study to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of a single oral dose of CC-220 in healthy 
subjects. Study CC-220-CP-002, was a 3-part, multiple-ascending dose (MAD) study to evaluate 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
26
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
the safety, tolerability, PK, and PD of multiple doses of CC-220 and to evaluate the relative 
bioavailability of a formulated CC-220 capsule in healthy subjects.
Following oral administration of CC-220, systemic exposure increased in a dose-proportional 
manner. The median time to reach maximum observed plasma concentration (Cmax) was 
 
, and steady-state was reached 
 after daily dosing. Drug 
accumulated in plasma after multiple daily dosing with exposure ratios 
 
 Coadministration with a high-fat meal did not change the overall exposure when CC-
220 was administered as a single dose. 
CC-220 did not show significant renal elimination of unchanged drug 
 
The terminal 
elimination half-life (t1/2) of CC-220 ranged from 
. No significant 
differences were seen in the oral bioavailability 
 
 
The PD effects after single or multiple doses of CC-220 included: a reduction in intracellular 
Aiolos protein levels in both the CD19+ B cell and the CD3+ T cell populations at doses ≥ 0.3 
mg; a reduction in the absolute number of CD19+ B cells in a largely dose-dependent manner at 
doses ≥ 0.3 mg; enhancement of CD3 antibody-induced production of T cell cytokines, such as 
IL-2 and IFN-γ; reduction of lipopolysaccharide (LPS)-induced production of cytokines such as 
IL-1β and TNF-α.
In both clinical pharmacology studies, there were no subjects who reported treatment-emergent 
adverse events (TEAEs) that were serious or that resulted in death. In both studies, changes in 
vital signs and electrocardiograms (ECGs) were minimal and clinically unremarkable.  In Study 
CP-001, the most common TEAEs were diarrhea and TEAEs that were related to study 
procedure, ie, application site erythema related to the ECG patch. All TEAEs in Study CP-001 
were mild in severity with the exception of one case of moderate urticaria and none led to
discontinuation of IP. Changes in laboratory values were minimal and clinically unremarkable in 
Study CP-001. In Study CP-002, the most common TEAEs were rash (4 CC-220 subjects), 
neutropenia (4 CC-220 subjects), and upper respiratory tract infection (URTI, 2 placebo and 2 
CC-220 subjects). A majority of TEAEs were mild in severity while all cases of neutropenia 
were severe. A total of 4 subjects reported TEAEs that led to study discontinuation (rash, white 
blood cells [WBC] in urine, and mydriasis). The clinically significant laboratory values included 
elevated liver function tests in 3 subjects (2 placebo, 1 CC-220) and neutropenia in 4 subjects (all 
CC-220). At CC-220 1 mg QD for 28 days, 4 of 6 subjects had dose-limiting toxicities of Grade 
3 neutropenia after Day 21 and dosing with IP was discontinued. Per discontinuation of IP, 
neutrophil counts recovered toward normal values by Day 28. 
This will be the first CC-220 study conducted in subjects with SLE. 
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies and adverse event profile of the IP.
This study will be conducted in compliance with the protocol, GCP and the applicable regulatory 
requirement(s).
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
27
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
2.
STUDY OBJECTIVES
2.1.
Part 1
2.1.1.
Primary
∀
To evaluate the safety and tolerability of CC-220 for subjects with SLE
2.1.2.
Secondary
∀
To describe the pharmacokinetics (PK) of CC-220 for subjects with SLE
 
 
 
 
2.2.
Active Treatment Extension Phase
2.2.1.
Primary
∀
To evaluate the long-term safety and tolerability of CC-220 in subjects with SLE 
who completed Part 1 of the core study
2.2.2.
Secondary
∀
To evaluate the long-term efficacy of CC-220 in subjects with SLE who 
completed Part 1 of the core study
 
 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
28
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
3.
STUDY ENDPOINTS
3.1.
Part 1
3.1.1.
Primary
∀
Safety (type, frequency, severity, and relationship of adverse events [AEs] to CC-
220, laboratory, ECG, physical examination or other changes) and tolerability
3.1.2.
Secondary
∀
Pharmacokinetics: PK of CC-220 in plasma, eg, AUCt, AUCτ, AUCinf, Cmax, Cmin, 
tmax, t1/2. CL/F and Vz/F will be evaluated at Day 1, Day 15, Day 29, Day 57 and 
Day 85/Early Termination.
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
29
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
∀
 
 
 
 
 
3.2.
Active Treatment Extension Phase
3.2.1.
Primary
∀
Safety:
o
Safety (type, frequency, severity, and relationship of adverse events [AEs] to 
CC-220, laboratory, ECG, physical examination or other changes) and 
tolerability
3.2.2.
Secondary
∀
Efficacy:
o
Change in the Hybrid SELENA SLEDAI by ≥ 4 units by visit
o
Change from Baseline in the Hybrid SELENA SLEDAI by visit
o
Change from Baseline in Swollen and Tender Joint Count score by visit
o
Change from Baseline in CLASI Activity score by visit
o
Change from Baseline in the PGA by visit
o
Change from Baseline in the BILAG 2004 by visit
o
Change from Baseline in the Pericardial/Pleuritic Pain Scale by visit
o
Change from Baseline in Fatigue VAS by visit
o
Change from Baseline in CLASI Damage score by visit
o
Change from Baseline in SLICC/ACR SLE Damage Index by visit
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
30
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
31
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
4.
OVERALL STUDY DESIGN
4.1.
Study Design
This is a pilot, Phase 2, randomized, placebo-controlled, double-blind, multicenter study to 
evaluate the preliminary efficacy, safety, tolerability, pharmacokinetics, pharmacodynamics and 
pharmacogenetics of CC-220 in SLE subjects with skin involvement. 
This study will be conducted in 2 parts.
Part 1
Part 1 is a randomized, double-blind, placebo-controlled, ascending dose study to evaluate the 
safety and tolerability of CC-220 in SLE subjects. 
Subject participation in Part 1 will consist of 3 phases:
!
Pre-treatment Screening Phase: up to 42 days prior to the first dose of the 
investigational product (IP) 
!
Treatment Phase: up to 84 days
!
Observation Phase: 84 day post-treatment (subjects who consent and qualify for the 
ATEP will NOT enter the Observational Phase and will directly enter the ATEP)
A total of approximately 40 subjects will be randomized into 4 dose groups with a 4:1 ratio of 
CC-220 (0.3 mg every other day [QOD], 0.3 mg everyday [QD], 0.6 mg and 0.3 mg on 
alternating days and 0.6 mg QD) or matching placebo (8 subjects in the CC-220 arm and 2 
subjects in the placebo arm for each dose group) using an Interactive Voice Response System 
(IVRS). Subjects will be randomized into the first two dose groups of 0.3 mg QOD and 0.3 mg 
QD in parallel. Following confirmation of safety of the first two dose groups, remaining subjects 
will then be randomized into the 0.6 mg and 0.3 mg on alternating days and 0.6 mg QD dose 
groups in a sequential, dose-ascending manner (first the 0.6 mg and 0.3 mg on alternating days 
dose group followed by the 0.6 mg QD dose group). The Treatment Phase will be up to 84 days 
in duration for all dose groups. Subjects who discontinue IP early and all subjects who complete 
the 84 day treatment phase (who do not consent to enroll into the ATEP) will enter into the 
Observational Follow-up Phase for an 84 day period. In all cases of early termination from the 
study, subjects will be encouraged to complete an Early Termination Visit. See Figure 1 for 
graphical representation of the Part 1 dosing administration schedule.
All subjects will be allowed to remain on stable doses of hydroxychloroquine, chloroquine, 
and/or quinacrine for ≥ 4 weeks prior to their baseline visit and throughout the study. No 
additional systemic immunosuppressives will be permitted.  In addition, as needed (PRN) 
treatment with systemic anti-pruritics and/or systemic analgesics will be permitted; subjects must 
stop using all systemic anti-pruritics 48 hours prior to all study visits and systemic analgesics 12 
hours prior to all study visits. Oral non-steroidal anti-inflammatory drugs (NSAIDs) may be 
used, but must be stopped 12 hours prior to all study visits. Use of oral corticosteroids will be 
permitted only at doses of 10 mg or less per day and must be maintained at a stable dose during 
study participation. Inhaled corticosteroids for use in a disease other than lupus, eg, asthma, will 
be allowed. No IV (intravenous) or IM (intramuscular) corticosteroids will be permitted during 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
32
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
the study. No other topical (with the exception of potency class 6 and 7 topicals only), local or 
systemic treatments for dermatological manifestations of SLE will be permitted. 
Following completion of the first 28 days of the treatment phase by at least 8 subjects in Dose 
Group 1 (0.3 mg QOD) and 8 subjects in Dose Group 2 (0.3 QD), an assessment of safety and 
tolerability will be conducted. If Dose Groups 1 and 2 are deemed to have acceptable safety and 
tolerability, subjects will continue to receive investigational product for up to 84 days and 
enrollment of subjects into Dose Group 3 (0.6 mg and 0.3 mg on alternating days) will be 
initiated. Following completion of the first 28 days of the treatment phase by at least 8 subjects 
in Dose Group 3 (0.6 mg and 0.3 mg on alternating days), an assessment of safety and 
tolerability will be conducted. If Dose Group 3 is deemed to have acceptable safety and 
tolerability, subjects will continue to receive investigational product for up to 84 days and 
enrollment of subjects into Dose Group 4 (0.6 mg QD) will be initiated. Following completion of 
the first 28 days of the treatment phase by at least 8 subjects in Dose Group 4 (0.6 mg QD), an 
assessment of safety and tolerability will be conducted. If Dose Group 4 is deemed to have 
acceptable safety and tolerability, subjects will continue to receive investigational product for up 
to 84 days. 
Subjects will remain on their assigned treatment for up to 84 days. In the event a subject 
experiences clinically significant IP-related adverse events (AEs), a dose interruption for up to 
14 days will be permitted (see Section 12.1). If a subject is unable to remain on their assigned 
dose, he/she may reduce their dose to the next lowest dosing regimen. Dose reductions will occur 
as follows:
!
Subjects on 0.6 mg QD will reduce their dose to 0.6 mg/0.3 mg on alternating days
!
Subjects on 0.6 mg/0.3 mg on alternating days will reduce their dose to 0.3 mg QD
!
Subjects on 0.3 mg QD will reduce their dose to 0.3 mg QOD
!
Subjects on 0.3 mg QOD will reduce their dose to placebo 
A subject will only be permitted to reduce their dose one time during the study. The decision to 
modify IP dosing will be based on the rules provided in Section 12.1. The sponsor should be 
notified of the intent to dose reduce prior to a change in dosing.
Subjects who discontinue from the study prior to completing 28 days of treatment may be 
replaced (for up to a total of 10 subjects for Part 1) at the discretion of the sponsor. 
Active Treatment Extension Phase
The Active Treatment Extension Phase (ATEP) is an extension of the core CC-220-SLE-001 
study to evaluate the long-term efficacy and safety/tolerability of CC-220 in SLE subjects who 
completed Part 1 of the core study. 
Subjects who complete the Treatment Phase of Part 1 of the core study (CC-220-SLE-001) will
be eligible to receive CC-220 in the ATEP for up to 2 years. All subjects who participate in the 
ATEP will receive the same active treatment they received during their participation in Part 1 
with the exception of those on placebo or 0.3 mg QOD (see below for information on dosing for 
these subjects).  
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
33
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Subjects who complete the Treatment Phase of Part 1 of the core study will immediately be 
eligible to enter this phase of the study and should be enrolled immediately to avoid dose 
interruption. In the event the ATEP has not been implemented by subjects’ study sites at the time 
they have completed the treatment phase for Part 1, subjects will enter the Observation Phase of 
the core study and be eligible to enroll in the ATEP upon implementation of ATEP amendment. 
There were no time restrictions on how long subjects can be off CC-220 prior to entering the 
ATEP as long as they completed treatment in Part 1 of the core study, but with the 
implementation of Protocol Amendment 5, enrollment into the ATEP is now closed. Subjects 
who terminate the treatment phase of Part 1 early will not be eligible for entry into the ATEP.
Subject participation consists of two phases:
!
Active Treatment Extension Phase: Up to 2 years
!
Observational Follow-up Phase: 28 days
Subjects receiving CC-220 0.3 mg QOD or CC-220 0.3 mg QD during their participation in the 
core study will be assigned to receive CC-220 0.3 mg QD during the ATEP. Subjects receiving 
CC-220 0.6 mg/0.3 mg on alternating days during their participation in the core study will 
remain on the same assigned dose during the ATEP. Subjects receiving CC-220 0.6 mg QD 
during their participation in the core study were originally permitted to enter the ATEP on the 
same dose. However, based on data that has become available for Part 1 (see Section 4.2.3), any 
subject originally enrolled in the ATEP on the 0.6 mg QD dose should be dose reduced to the 0.6 
mg/0.3 mg on alternating days dose upon implementation of Protocol Amendment 5. 
Subjects receiving placebo during their participation in the core study (Part 1) will receive the 
CC-220 dose given to those on active drug in their respective cohort. For example, if a subject 
was taking placebo in Dose Group 3 of Part 1, he or she would receive CC-220 0.6 mg/0.3 mg on 
alternating days during the ATEP. However, based on data that has become available for Part 1 
(see Section 4.2.3), any subject who was on placebo in the 0.6 mg QD cohort for Part 1 and 
originally entered the ATEP on 0.6 mg QD should be dose reduced to 0.6/0.3 mg QD on 
alternating days upon implementation of Protocol Amendment 5. 
For subjects who are eligible to roll directly into the ATEP, Week 12 (Visit 10) of Part 1 
may be on the same day as Visit 1 of the ATEP. All Visit 10 (Part 1) and Visit 1 (ATEP) 
procedures must be conducted as outlined in Table 1 and Table 2. Please note that subjects 
rolling directly into the ATEP who have both Week 12 (Visit 10) of Part 1 and Visit 1 of the 
ATEP on the same day, will only undergo a subset of assessments for Visit 1 of the ATEP 
(indicated in Table 2). If the subject remains eligible for entry into the ATEP following Visit 1 
assessments, drug will be dispensed and the subject will begin the ATEP.  Subjects entering the 
ATEP who cannot hold their Week 12 (Visit 10) of Part 1 and Visit 1 of the ATEP on the same 
day, can hold their Visit 1 of the ATEP at any time after their sites has received IRB approval. 
However, once 14 days have elapsed since a subject has had their Week 12 (Visit 10) of Part 
1, they must undergo the ATEP Screening Visit and all assessments listed for Visit 1 of the 
ATEP in Table 2 if they wish to enter the ATEP. As long as a subject comes in for their 
Visit 1 ATEP within 14 days after their Part 1 Week 12 (Visit 10) they will only need to 
complete the subset of assessments identified under footnote b of Table 2.
All subjects will be allowed to remain on stable doses of hydroxychloroquine, chloroquine, 
and/or quinacrine for ≥ 4 weeks prior to their baseline visit and throughout the study. Subjects on 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
34
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
antimalarials will be permitted to modify or stop their treatment at any time during the ATEP.
Methotrexate (7.5 mg – 25 mg per week), leflunomide (maintenance dosing must not exceed 20 
mg daily) or sulfasalazine (dosing not to exceed 3 g daily) will be permitted, although no other 
additional systemic immunosuppressives will be permitted. In addition, PRN treatment with 
systemic anti-pruritics and/or systemic analgesics will be permitted. However, subjects must stop 
using all systemic anti-pruritics 48 hours prior to all study visits and systemic analgesics 12 
hours prior to all study visits. Oral NSAIDs may be used, but must be stopped 12 hours prior to 
all study visits. Use of oral corticosteroids will be permitted only at doses of 10 mg or less per 
day and must be maintained at a stable dose during study participation. Inhaled corticosteroids 
for use in a disease other than lupus, eg, asthma, will be allowed. No IV or IM corticosteroids 
will be permitted during the study.  No other topical (with the exception of potency class 6 and 7 
topicals only), local or systemic treatments for dermatological manifestations of SLE will be 
permitted.
Thromboprophylaxis with low dose aspirin, low molecular weight heparin or other equivalent 
antithrombotic or anticoagulant is required unless the investigator determines that, based on the 
totality of the subjects’ risk factors for thrombosis, thromboprophylaxis is not required or is 
contraindicated.
If any additional prophylaxis is needed, it should be based on the local standard of care and the 
investigator’s best judgement after careful consideration of the benefit versus the potential risk 
for the individual subject.
Subjects will remain on their assigned treatment for up to 2 years. In the event a subject 
experiences clinically significant IP-related AEs, a dose interruption for up to 14 days will be 
permitted (see Section 12.1). If a subject is unable to remain on their assigned dose, he/she may 
reduce their dose to the next lowest dosing regimen. Dose reductions will occur as follows:
!
Subjects on 0.6 mg QD will reduce their dose to 0.6 mg/0.3 mg on alternating days
!
Subjects on 0.6 mg/0.3 mg on alternating days will reduce their dose to 0.3 mg QD
!
Subjects on 0.3 mg QD will be terminated from the study
A subject will only be permitted to reduce their dose one time during the study (subjects who 
originally came into the ATEP on 0.6 mg QD and dose reduce to 0.6/0.3 mg QD on alternating 
days upon implementation of Protocol Amendment 5 will be eligible for one additional dose 
reduction in the ATEP). The decision to modify IP dosing will be based on the rules provided in 
Section 12.1. The sponsor should be notified of the intent to dose reduce prior to a change in 
dosing.
Subjects will have regularly scheduled visits to assess IP activity and safety. Required 
assessments will be completed as depicted in Table 2.
Upon completion of, or discontinuation from the ATEP, all subjects (including premature 
discontinuations) will enter a 28 day Observational Follow-up Phase. Subjects who discontinue 
IP early should complete an Early Termination Visit.
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
applicable regulatory requirements.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
35
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
4.2.
Study Design Rationale
4.2.1.
Duration of Treatment
The length of study participation for each subject in Part 1 is 210 days (Up to a 42-day Screening 
Phase, 84-day Treatment Phase and an 84-day Observational Follow-Up Phase). The length of 
study participation for each subject in the ATEP is up to 2 years and 1 month (up to a 2-year 
ATEP and a 4-week post-treatment Observational Follow-Up Phase). Subjects who participate in 
both Part 1 and the ATEP will participate in the study for a total of approximately 2 years and 6 
months.
4.2.2.
Study Population
The study population will consist of male and female subjects 18 years of age and older at the 
time of signing the ICD. 
Subjects in Part 1 are required to have:
!
An established diagnosis of SLE as defined by the 1997 Update of the 1982 ACR 
Revised Criteria for Classification of SLE at Screening (Appendix D) and a minimum 
Hybrid SELENA SLEDAI score of ≥ 4 points.
Subjects in the Active Treatment Extension Phase are required to have:
!
Completed the CC-220-SLE-001 core study (Part 1).
4.2.3.
Dose and Dose Interval 
The primary objective of this study is to determine the safety and tolerability of CC-220 in 
subjects while on a stable standard of care for the treatment of SLE over a 12-week period. To 
achieve this objective, 0.3 mg QD and 0.6 mg QD were selected based upon available data to 
support the safe administration of these doses in the SLE population and the likelihood that these 
doses will demonstrate safety and efficacy in a 12-week study.
The nonclinical PK, metabolism, toxicity and clinical pharmacology studies conducted to date 
were used to characterize the toxicity profile of CC-220 and to provide information with regard 
to the planned doses in this study. Specifically, the 28-day monkey study and the Phase 1 
clinical pharmacology CC-220-CP-001 and CC-220-CP-002 studies (described in the 
Investigator’s Brochure [IB]) with regard to target organ toxicity, NOAEL, and safety margins 
support the planned doses and regimens in this 12-week study.
The 0.3 mg QOD was selected as the lowest dose, based upon the demonstrated effect on Aiolos 
protein levels in lymphocytes, the reduction in peripheral B cells after a single 0.3 mg dose, and 
the sustained increase in T cell IL-2 production observed with the 0.3 mg every 3 days (Q3D) 
dose. The dose of 0.3 mg QD is supported by the Phase 1 data that showed that 0.3 mg QD x 28-
day dose was well tolerated in healthy subjects and exhibited sustained effects on multiple PD 
parameters.  The 0.3 mg QD dose x 28 days demonstrated a significant reduction in CD19+ B 
cells, and a reduction in CD3+ T cells.
The highest planned dose of 0.6 mg QD was based upon data which is lower than the dose (1 mg 
QD dosed for 28 days) at which the dose-limiting toxicity of Grade 3 neutropenia was observed 
in healthy subjects. A dose of 0.6 mg QD was selected to better understand the safety/PD profile 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
36
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
of CC-220 in SLE subjects. Since 0.6 mg QD was not tested in healthy subjects, the cohort of 
0.6 mg QD commenced only after the 0.3 mg QD dose was deemed to be safe and well 
tolerated. Because grade 3 neutropenia was observed at the 1 mg QD dose, neutrophil counts 
were closely monitored, and dose modification criteria were pre-specified in the protocol 
(Section 12). Based on PK/PD modeling, higher pharmacological effects were anticipated from 
the 0.6 mg QD over the 0.3 mg QD dose. Therefore, based upon the tolerated dose of 0.3 mg 
QD x 28 days, and the PK/PD modeling, the 0.3 mg and 0.6 mg QD doses were selected for this 
study.
Data from Part 1 of CC-220-SLE-001 have revealed that there was a significant increase in 
plasma cells and a trend for increasing CD4 and CD8 T cells in patients receiving the 0.6 mg QD 
dose. Additionally, Grade 3 neutropenia and dermatitis were observed with the 0.6 mg QD dose. 
As a result, any subject enrolled in the ATEP on the 0.6 mg QD dose should be dose reduced to 
0.6 mg/0.3 mg on alternating days. Subjects in the ATEP taking 0.3 mg QD and 0.6/0.3 mg QD 
on alternating days should continue their IP as these doses were shown to reduce key SLE 
cytokines with a less pronounced side effect profile.
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies and adverse event profile of
CC-220.
4.2.4.
Blinding
Part 1 of this study are randomized, double-blind and placebo-controlled to reduce the potential 
for bias and validate the results observed. 
4.2.5.
Concomitant Medications
All subjects will be allowed to remain on stable doses of hydroxychloroquine, chloroquine, 
and/or quinacrine for ≥ 4 weeks prior to their baseline visit and throughout the study. In addition, 
while subjects are enrolled in the ATEP, they will be permitted to modify or stop their 
antimalarial treatment at any time. During the placebo-controlled phase, no additional systemic 
immunosuppressives will be permitted. During the ATEP, methotrexate, leflunomide or 
sulfasalazine will be permitted if clinically indicated, although no other additional systemic 
immunosuppressives will be permitted. In addition, as needed PRN treatment with systemic anti-
pruritics and/or systemic analgesics will be permitted, however, subjects must stop using all 
systemic anti-pruritics 48 hours prior to all study visits and systemic analgesics 12 hours prior to 
all study visits. Oral NSAIDs may be used, but must be stopped 12 hours prior to all study visits. 
Use of corticosteroids will be permitted only at doses of 10 mg or less per day, and the dose must 
remain stable for the duration of the subject’s participation in the study. No IV or IM 
corticosteroids will be permitted during the study. Inhaled corticosteroids for use in a disease 
other than lupus, eg, asthma, will be allowed. Only use of topical steroids that fall into potency 
classes 6 and 7 will be permitted during the study. No other topical, local or systemic treatments 
for dermatological manifestations of SLE will be permitted.
Thromboprophylaxis with low dose aspirin, low molecular weight heparin or other equivalent 
antithrombotic or anticoagulant is required unless the investigator determines that, based on the 
totality of the subjects’ risk factors for thrombosis, thromboprophylaxis is not required or is 
contraindicated.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
37
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Medication doses and treatment regimens should remain generally stable throughout the course 
of the study. 
4.2.6.
Efficacy
The efficacy assessments included in this proof-of-concept (PoC) protocol target some of the key 
clinical manifestations, eg, skin, joint, etc, of SLE and may provide information on the potential 
of CC-220 to treat them.  These evaluations, which include the Hybrid SELENA SLEDAI, 
CLASI, etc, are accepted, well-known assessments that are frequently used in SLE clinical 
studies.  The potential for use of these scales, or a composite of these scales, to be included in 
future studies will also be explored.
4.2.7.
Safety
General and specific safety precautions such as the use of clinical investigators highly 
experienced in this indication, frequent study visits, careful ongoing monitoring of clinical 
(including physical and eye examinations), ECGs and laboratory findings by the sponsor, have 
been implemented in this protocol. 
CC-220 is a thalidomide analog and new immunomodulatory drug.  Suppression of bone 
marrow-derived blood cell-forming elements (with or without infection) is the primary toxicity 
finding for immunomodulatory compounds. Therefore, safety monitoring will include repeated 
hematology (white blood cell [WBC] count with differential) and platelet counts.  In addition, 
routine chemistry (total protein, albumin, calcium, phosphorous, glucose, uric acid, total 
bilirubin, alkaline phosphatase, aspartate aminotransferase (AST)/serum glutamic oxaloacetic 
transaminase (SGOT), alanine aminotransferase (ALT)/ serum glutamic-pyruvic transamine 
(SGPT), sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, 
estimated glomerular filtration rate [eGFR] in mL/min using the Modification of Diet in Renal 
Disease formula (MDRD eGFR – as calculated and reported by the central laboratory), protein 
creatinine ratio, lactate dehydrogenase (LDH), and magnesium), and urinalyses (to measure urine 
sediment, albumin and protein), will be assessed at frequent intervals.
CC-220 has been shown to impact B-cell differentiation, including inhibition of IgG and IgM 
production in PBMCs obtained from patients with SLE. Quantification of total IgG, IgM and 
immunoglobulin A (IgA) will be assessed in this study. 
Due to the minimal to mild degranulation/atrophy in pancreatic acinar cells observed in the 
monkeys treated for 3 months, (which were most likely secondary to animals’ clinical condition) 
serum level for micronutrients (eg, apolipoproteins, total cholesterol, and lipid-soluble vitamins 
[A,D,E,K]) in addition to lipase and amylase will also be monitored throughout the study.
To monitor for the potential attenuation of vaccine effectiveness due to CC-220, tetanus toxoid, 
pneumococcal, and influenza titers will be monitored during the course of the study.
To monitor for possible immune activation, high sensitivity C-reactive protein (CRP), 
erythrocyte sedimentation rate (ESR) and fibrinogen will be measured during the study. 
Several pre-dose electrocardiographic (12-lead) recordings will be obtained throughout the study 
and assessed by a central (cardiologist) reader.  The cardiologist will interpret all ECGs with 
relevance to PR interval, QRS duration, heart rate and R-R interval, QT and QTc.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
38
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Due to the potential immunomodulatory effects of CC-220, subjects will be screened (and 
excluded) for evidence of active viral hepatitis infections (hepatitis B and C) utilizing the 
screening hepatitis panel.
During toxicology testing there were uveal tract findings. As a result, ophthalmological 
examinations conducted by a qualified ophthalmologist will be required. Testing will include 
visual acuity and slit lamp exams with fluorescein staining following pupillary dilation. In 
addition, toxicology testing yielded testicular findings. Consequently, testosterone, FSH and LH 
will be monitored for all male subjects randomized into the study.
Study personnel are expected to be vigilant with respect to serious or opportunistic infections.
In order to reduce the potential for clinically significant immunosuppression anticipated by the 
use of concomitant therapy with CC-220 and high-dose corticosteroids, subjects will be 
permitted to use no more than 10 mg/day (or equivalent) of oral prednisone (or its equivalent). 
Due to the elevated risk of thromboembolic events associated with lupus and CC-220, 
thromboprophylaxis with low dose aspirin, low molecular weight heparin or other equivalent 
antithrombotic or anticoagulant is required unless the investigator determines that, based on the 
totality of the subjects’ risk factors for thrombosis, thromboprophylaxis is not required or is 
contraindicated.
If any additional prophylaxis is needed, it should be based on the local standard of care and the 
investigator’s best judgement after careful consideration of the benefit versus the potential risk 
for the individual subject.
Although embryofetal developmental studies in non-clinical species with CC-220 have not yet 
been conducted, CC-220 belongs to a class of drugs that is teratogenic. In light of this, detailed 
pregnancy avoidance/mitigation strategies have been incorporated into the protocol.  These 
include:
!
Regular medically supervised pregnancy testing for FCBP.  Investigational product 
will not be dispensed until negative pregnancy test results have been confirmed by the 
Investigator.
!
Specific birth control requirements for all subjects.  At each visit, the Investigator 
must confirm with FCBP that she is continuing to use two reliable methods of birth 
control.  Males (including those who have had a vasectomy) must use barrier 
contraception (condoms) when engaging in sexual activity with a FCBP. 
!
Counseling regarding pregnancy/breastfeeding precautions, potential risks of fetal 
exposure, handling of IP and blood/sperm/semen donations will be conducted at a 
minimum of every 28 days. 
!
Pregnancy testing and counseling if a subject misses her menstrual period, or if her 
pregnancy test or menstrual bleeding is abnormal.  Investigational product will be 
discontinued during this evaluation.
!
Immediate discontinuation of CC-220 if pregnancy or a positive pregnancy test 
occurs in a subject who is a FCBP.  If pregnancy or a positive pregnancy test occurs 
in the partner of a male subject, the Investigator must be notified immediately.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
39
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
!
No more than a 28-day supply of IP may be dispensed at a time. 
4.2.7.1.
Internal Celgene Monitoring at the Study Level
All safety measures, which are assessed at each study visit by the collection of adverse events 
and changes in concomitant medications, monitoring of vital signs and laboratory results 
collected from the scheduled visits, will be reviewed on an ongoing basis at the subject level by 
the internal Celgene study team. All serious adverse events (SAEs) will also be collected, 
reviewed, analyzed and reported as required by local regulations.
4.2.7.2.
Internal Celgene Safety Monitoring of CC-220 at the Compound Level – Role of 
the Safety Management Team
In addition to daily safety monitoring conducted by Investigators, site study personnel, and by 
the Celgene study team; cumulative and interval AEs, SAEs, discontinuations and laboratory 
findings will be reviewed by a Safety Management Team (SMT) internally at Celgene. The 
review follows the Council for International Organizations for Medical Sciences, Working 
Group VI (CIOMS VI) recommendation. The SMT is comprised of lead representatives from 
multiple Celgene functions engaged in the CC-220 development program.
4.2.8.
Pharmacokinetic 
Markers  
Pharmacokinetic measures are incorporated into the study to assess the extent of exposure and to 
explore the relationship between IP exposure and response.
 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
40
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Figure 1: Overall Study Design
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
41
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
4.3.
Study Duration
The study duration for each subject in Part 1 is 210 days (Up to a 42-day Screening Phase, 84-day Treatment Phase and an 84-day 
Observational Follow-Up Phase). The length of study participation for each subject in the ATEP is up to 2 years and 1 month (up to a 
2-year ATEP and a 28-day post-treatment Observational Follow-Up Phase). Subjects who participate in both Part 1 and the ATEP will 
participate in the study for a total of approximately 2 years and 6 months.
4.4.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the study, 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 pre-specified in the protocol 
and/or the Statistical Analysis Plan, whichever is the later date.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
42
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
5.
TABLE OF EVENTS
Table 1:
Part 1
Pre-
treatment
Phase
Treatment Phase
Observational Follow-Up Phasee
Visit(s)
±1 Day – for all visits
1
Screening
2
Baseline
3
4
5
6
7-9
10
Final Treatment 
Visit / Early 
Termination Visit
11
12
Day(s)
-42
1
8
15
22
29
43, 57, 71
85
Day 113
4 weeks
Post-treatment
Day 169
12 weeks Post-
treatment
Study Entry
Informed Consent
X
-
-
-
-
-
-
-
-
-
Intensive PK Sub-study Consent
X
-
-
-
-
-
-
-
-
-
Inclusion/Exclusion Criteria
X
X
-
-
-
-
-
-
-
-
Medical History
X
-
-
-
-
-
-
-
-
-
Safety Assessments
Ophthalmology Exams
X
-
-
-
-
-
-
X
-
-
Complete Physical Exam
X
-
-
-
-
-
-
X
-
X
Targeted Physical Exam
-
X
-
-
X
-
Day 57 
-
X
-
Vital Signs
X
X
X
X
X
X
X
X
X
X
Hepatitis B and C 
X
-
-
-
-
-
-
-
-
-
Hematology, Chemistry and Urinalysis
X
X
-
X
-
X
X
X
X
X
IgA, IgM and IgG 
X
-
-
-
-
-
Day 57
X
-
-
Inflammation Panel
-
X
X
X
-
X
Day 57
X
X
-
Serum β-HCG Pregnancy Testa
X
X
-
-
-
X
Day 57
X
-
X
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
43
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Table 1:
Part 1 (Continued)
Pre-
treatment
Phase
Treatment Phase
Observational Follow-Up Phasee
Visit(s)
±1 Day – for all visits
1
Screening
2
Baseline
3
4
5
6
7-9
10
Final Treatment 
Visit / Early 
Termination Visit
11
12
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1
8
15
22
29
43, 57, 71
85
Day 113
4 weeks
Post-treatment
Day 169
12 weeks 
Post-treatment
Urine Pregnancy Testb
-
X
X
X
X
X
X
-
X
-
Tetanus Toxoid Titerf
-
X
-
-
-
-
-
X
-
X
Apolipoproteins, total cholesterol and lipid-
soluble vitamins A, D, E and K
-
X
-
-
-
X
Day 57
X
X
-
PT, INR and PTT
-
X
-
-
-
-
Day 43
X
-
X
12-Lead ECG
X
X
X
-
-
-
Day 43
X
X
-
Adverse Events
X
X
X
X
X
X
X
X
X
X
Prior/Concomitant Meds and Procedures
X
X
X
X
X
X
X
X
X
X
Testosterone, FSH and LHc
-
X
-
-
-
-
-
X
-
-
Celgene Pregnancy Prevention Counseling 
Program (CPPCP)
X
X
X
X
X
X
X
X
X
-
Efficacy Assessments
CLASI Activity
X
X
-
X
-
X
Day 57
X
X
X
CLASI Damage
-
X
-
-
-
-
-
X
-
-
Hybrid SELENA SLEDAI
X
X
-
X
-
X
Day 57
X
X
X
Swollen and Tender Joint Count
-
X
-
X
-
X
Day 57
X
X
X
PGA
-
X
-
X
-
X
Day 57
X
X
X
Pericardial/Pleuritic Pain Scale
X
X
-
X
-
X
Day 57
X
X
X
SLICC/ACR SLE Damage Index
-
X
-
-
-
-
-
X
-
-
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EDMS Doc. Number: 
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
44
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Table 1:
Part 1 (Continued)
Pre-
treatment
Phase
Treatment Phase
Observational Follow-Up Phasee
Visit(s)
±1 Day – for all visits
1
Screening
2
Baseline
3
4
5
6
7-9
10
Final Treatment 
Visit / Early 
Termination Visit
11
12
Day(s)
-42
1
8
15
22
29
43, 57, 71
85
Day 113
4 weeks
Post-treatment
Day 169
12 weeks 
Post-treatment
PK/
 Assessments
Sparse PK Blood Collection
-
-
-
X
-
X
Day 57
X
-
-
Intensive PK Blood Collectiond
-
X
-
X
-
X
Day 57
X
-
-
Investigational Product
Dispense IP
-
X
-
X
-
X
X
X
-
-
IP Compliance
-
-
X
X
X
X
X
X
-
-
HCG = beta human chorionic gonadotropin; ECG = electrocardiogram; IgG = immunoglobulin G; IgM = immunoglobulin M; IgA = immunoglobulin A; IP = investigational 
product; PK = pharmacokinetics; VAS = visual analog scale; PPRMP= Pregnancy Prevention Risk Management Plans; PT=prothrombin time; INR=internationalized normalized 
ratio; PTT=partial thromboplastin time; HBsAg=Hepatitis B surface antigen; CLASI=Cutaneous Lupus Area and Severity Index; PGA=physician global assessment; SLEDAI= 
Systemic Lupus Erythematosus Disease Activity Index;
 
 FSH=follicle-stimulating hormone; LH=luteinizing hormone; IRB=institutional review board.
a FCBP are required to have 2 negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting IP.  The first pregnancy test must be performed within 10 to 
14 days prior to the start of IP and the second test must be performed within 24 hours of starting IP.  The subject may not receive IP until the Investigator has verified that 
the results of these pregnancy tests are negative.  FCBP with 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 Day 113 and Day 169 following IP discontinuation (if urine pregnancy test is positive on Day 113, a serum pregnancy test 
must be conducted to confirm result).  If menstrual cycles are irregular or do not occur, the pregnancy testing must occur weekly for the first 28 days and then every 14 days 
while on study, at treatment discontinuation and at 14 and 28 days following treatment discontinuation. 
b 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 and within 28 days of discontinuing investigational product.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
45
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
c Collection of these analytes must occur at the same time of day (± 1 hour) at the Baseline (Visit 2) and Day 85 (End of Treatment or Early Termination Visit) for males only. 
For example, if collected at the Baseline Visit at 9 AM, the Final Treatment/Early Termination Visit sample must be collected between 8 and 10 AM.  
d On Day 1 and Day 29 PK blood samples will be collected at pre-dose (Time=0 hours), 1, 2, 3, 4, between 6 and 8 hours and 24 hours (±5 hours) after administration of IP. 
e Subjects who discontinue treatment early should enter into the Observational Follow-up Phase. Subjects who elect to enter the ATEP (at sites which have IRB approval for the 
ATEP) will not enter the Observational Follow-Up Phase and directly enter the ATEP. Those subjects who conclude their treatment at a site which does not have IRB approval 
for the ATEP must enter the Observational Follow-Up Phase. Subjects who would like to enter ATEP, but whose site does not have IRB approval may enter the Observational 
Follow-Up Phase and then enter the ATEP once the site’s IRB approves the amendment containing the ATEP.
f If a subject is planning to receive a primary booster dose of pneumococcal vaccine at any time during the study, a prevaccination blood sample should be obtained to measure the 
prevaccination titer.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
46
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Table 2:
Active Treatment Extension Phase
Year 1
Year 2
Observational 
Follow-Upi
Visit(s)
±1 Day – for all visitsh
0
Screening
1a
Baseline 
for ATEP
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
27
Final 
Treatment 
Visit / Early 
Termination 
Visit
28
Week(s)
-6
0
1
2
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92
96
100
Study Entry
Informed Consent
X
Xb
-
-
- -
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/Exclusion Criteria
X
Xb
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Safety Assessments
Ophthalmology Exams
-
X
-
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
Complete Physical Examc
X
X
-
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
Targeted Physical Examc
-
-
X X
X X
X
X
X
-
X
X
X
X
X
-
X
X
X
X
X
-
X
X
X
X
X
-
X
Vital Signs
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
Hepatitis B and C
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Hematology, Chemistry and 
Urinalysisd
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
Amylase and Lipase
-
Xb
-
-
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
X
eGFR, protein creatinine ratio
X
Xb
-
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
IgA, IgM and IgG
X
X
-
-
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
X
Inflammation Panel
-
X
-
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
X
Serum β-HCG Pregnancy 
Teste
X
X
-
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
X
Urine Pregnancy Teste
-
Xb
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
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
47
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Table 2:
Active Treatment Extension Phase (Continued)
Year 1
Year 2
Observational 
Follow-Upi
Visit(s)
±1 Day – for all visitsh
0
Screening
1a
Baseline for 
ATEP
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
27
Final 
Treatment 
Visit / Early 
Termination 
Visit
28
Week(s)
-6
0
1
2
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92
96
100
Tetanus toxoid, pneumococcal 
and influenza titersj
-
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
-
-
X
-
Apolipoproteins, total 
cholesterol and lipid-soluble 
vitamins A, D, E and K
-
X
-
-
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
PT, INR and PTT
-
X
-
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
Lupus 
Autoantibody/Complement 
Panel
X
X
-
-
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
Lupus Anti-Phospholipid 
Profile
-
X
-
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
12-Lead ECG
X
X
X
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
X
Adverse Events
X
Xb
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
Prior/Concomitant Meds and 
Procedures
X
Xb
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
Testosterone, FSH and LHf
-
X
-
-
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
-
-
-
-
X
-
Celgene Pregnancy Prevention 
Counseling Program 
(CPPCP)g
X
Xb
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
Efficacy Assessments
BILAG 2004
X
Xb
X
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
X
CLASI Activity
X
X
X
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
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X
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X
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
48
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Table 2:
Active Treatment Extension Phase (Continued)
Year 1
Year 2
Observational 
Follow-Upi
Visit(s)
±1 Day – for all 
visitsh
0
Screening
1a
Baseline for 
ATEP
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
27
Final 
Treatment 
Visit / Early 
Termination 
Visit
28
Week(s)
-6
0
1
2
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92
96
100
CLASI Damage
-
X
X
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
X
Hybrid SELENA 
SLEDAI
X
X
X
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
X
Swollen and Tender 
Joint Count
-
X
X
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
X
PGA
-
X
X
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
X
Pericardial/Pleuritic 
Pain Scale
X
X
X
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
X
SLICC/ACR SLE 
Damage Index
-
X
X
-
X
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
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X
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Fatigue VAS
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X
-
X
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-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
-
X
-
Investigational IP
Dispense IP
-
Xb
-
X X X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
IP Compliance
-
-
X X X X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
49
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
HCG = beta human chorionic gonadotropin; ECG = electrocardiogram; IgG = immunoglobulin G; IgM = immunoglobulin M; IgA = immunoglobulin A; IP = investigational 
product; VAS = visual analog scale; PPRMP= Pregnancy Prevention Risk Management Plans; PT=prothrombin time; INR=internationalized normalized ratio; PTT=partial 
thromboplastin time; CLASI=Cutaneous Lupus Area and Severity Index; PGA=physician global assessment; SLEDAI= Systemic Lupus Erythematosus Disease Activity Index; 
 FSH=follicle-stimulating hormone; 
LH=luteinizing hormone; BILAG=British Isles Lupus Assessment Group; 
; ATEP=Active Treatment 
Extension Phase; FCBP=females of child bearing potential; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CO2=carbon dioxide; 
; SLICC/ACR SLE= Systemic Lupus International Collaborating Clinics/American College of Rheumatology 
Systemic Lupus Erythematosus.
a For subjects who are rolling directly into the ATEP, Week 12 (Visit 10) of Part 1 may be conducted on the same day as Visit 1 of the ATEP. Visit 1 must be completed only after
the Part 1 Week 12 (Visit 10) of the core study has been completed. In the instance that these visits occur on the same day, only a subset of assessments for Visit 1 of the ATEP
will need to be conducted (see Footnote b below). Drug may be dispensed for the ATEP as long as the subject successfully completes Visit 1 of the ATEP and remains eligible 
for entry. See Footnote e for specific pregnancy requirements. 
b These are the only assessments that need to be done for Visit 1 of the ATEP for subjects who are having their Part 1 Week 12 (Visit 10) on the same day as their Visit 1 
of the ATEP. Subjects who come into the site for their Visit 1 of the ATEP greater than 14 days after their Part 1 Week 12 (Visit 10) must undergo the ATEP
Screening Visit and the full Visit 1 of the ATEP as listed in the table above. In the event a subject comes in for their Visit 1 ATEP within 14 days after their Part 1 
Week 12 (Visit 10) they will only need to complete the subset of assessments identified with the footnote b notation.  
c At every visit both weight and waist circumference (measured at both the umbilicus and the level of the anterior iliac crests) will be measured to determine the subject’s risk for 
metabolic syndrome.
d A full chemistry panel will be run quarterly (every 3 months). At the visits falling in between the quarterly visits, partial chemistry panels will be run. These will consist of the 
following labs: albumin, alkaline phosphate, ALT, AST, BUN, calcium, chloride, CO2, creatinine, potassium, sodium, total bilirubin, total protein and glucose (non-fasting).
e FCBP are required to have 2 negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting IP.  The first pregnancy test must be performed within 10 to 14 days 
prior to the start of IP and the second test must be performed within 24 hours of starting IP.  The subject may not receive IP until the Investigator has verified that the results of 
these pregnancy tests are negative.  FCBP with regular cycles must have pregnancy testing weekly (except for Week 3) for the first 28 days of study participation and then every 
28 days while on study, at study discontinuation and at Week 100 following IP discontinuation (if urine pregnancy test is positive on Week 100, a serum pregnancy test must be 
conducted to confirm result).  If menstrual cycles are irregular or do not occur, the pregnancy testing must occur weekly (except for Week 3) for the first 28 days and then every 
14 days while on study, at treatment discontinuation and at 14 and 28 days following treatment discontinuation.
f Collection of these analytes must occur at the same time of day (± 1 hour) at the Baseline (Visit 1) and at each subsequent visit (every 6 months) for males only. For example, 
if collected at the Baseline Visit at 9 AM, the Final Treatment/Early Termination Visit sample must be collected between 8 and 10 AM.
g 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 and within 28 days of discontinuing investigational product.
h The visit window of ± 1 day for the ATEP is based off the first visit (Visit 1) of the ATEP – any days out of visit window from a subject’s involvement in Part 1 should be reset 
upon their enrollment into the ATEP. 
i Subjects who discontinue early or complete the treatment period enter into the Observational Follow-up Phase.
j
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
50
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
6.
PROCEDURES
Study Entry
Required assessments will be completed as depicted in Table 1 and Table 2.
!
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 sub-study 
portion of the ICD (the Intensive PK sub-study) prior to the initiation of any study 
procedures and indicate whether or not they consent to participate in this portion of 
the study. All subjects entering the ATEP will have to provide informed consent in 
order to participate.
!
Relevant medical history (including relevant GI symptoms, neurological symptoms, 
alcohol and tobacco use, etc) information will be collected for each subject.
!
Information regarding prior/concomitant medication usage will be collected for each 
subject. At the screening and baseline visits, concomitant medications should be 
checked against the list of prohibited medications to ensure required washout times 
have been met. If a subject does not meet the medication washout requirements, the 
study visit must be rescheduled. 
Safety Assessments
Note: On the days of study visits, subjects will take their IP dose at the site.
Required assessments will be completed as depicted in Table 1 and Table 2.  Assessments may 
be conducted at other times during the study if felt to be clinically warranted by the Investigator.
The safety assessments may be conducted by a physician, physician assistant, nurse practitioner, 
or study nurse. Ideally, the safety assessor should be the same individual throughout the course 
of each subject’s participation at a site.
!
Information regarding all AEs regardless of causal relationship to IP (CC-220 or 
placebo), occurring at any time for the duration of the study, from the time of signing 
the ICD up to and including the Observation Phase, will be collected. 
!
Vital signs include temperature, pulse, and seated blood pressure. These will be 
collected at every visit. Blood pressure will be measured after the subject has been 
seated and resting quietly for 5 minutes. 
Note: On study visits where ECGs and PK evaluations are performed, blood pressure 
measurements should be completed first. Pre-dose ECGs should then be performed, 
followed by pre-dose PK blood draws and IP dosing. 
!
Complete physical examinations will include height (Screening Visit) and weight
(frequency of collection will dependent on the phase of the study - to be done in street 
clothes, no shoes), skin, nasal cavities, eyes, ears, respiratory, cardiovascular, 
gastrointestinal, neurological, lymphatic, and musculoskeletal system evaluations. For 
the ATEP, weight and waist circumference (measured at both the umbilicus and the 
level of the anterior iliac crests) will be obtained at every visit. Results of the 
physical examinations will be recorded only in the source documents. Clinically 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
51
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
significant abnormal findings identified during the Screening physical examination 
will be recorded on the e-CRF as medical history; clinically significant findings 
identified during the final treatment visit physical examination will be recorded as 
adverse events. Gynecological and urogenital examinations will not be done unless 
for cause.
!
Targeted physical examinations will include evaluation of the skin, respiratory, 
cardiovascular, lymphatic, and musculoskeletal systems.  Results of the physical 
examinations will be recorded only in the source documents.  Clinically significant 
abnormal findings identified during the targeted physical examinations will be 
recorded on the eCRF as adverse events.  Gynecological and urogenital examinations 
will not be done unless for cause. For the ATEP, weight and waist circumference 
(measured at both the umbilicus and the level of the anterior iliac crests) will be 
obtained at every visit.
!
Standard 12-lead ECGs will be obtained at most study visits. In cases where ECG and 
PK timepoints coincide, a ±15 minute window will be allowed for assessment 
completion (ECG should always be assessed first). All ECGs from Visit 2 onward 
should be performed ≤ 15 minutes apart after the subject has been in the supine 
position for 3 minutes.
∀
At Screening: one ECG will be performed
∀
At required treatment visits: 3 ECGs will be done pre-dose
∀
In the Observational Follow-up Phase: one ECG will be performed
Stimulatory agents and/or medications, eg, caffeine, energy drinks, licorice, 
theophylline, etc, should be avoided prior to ECG administration. 
The same ECG equipment will be used throughout the study.  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 Bazett’s and Fridericia’s 
formula.
!
Laboratory Assessments
∀
Pregnancy testing (urine and/or serum) for all FCBP
∀
Chemistry (including total protein, albumin, calcium, phosphorus, glucose, uric 
acid, total bilirubin, alkaline phosphatase, AST [SGOT], ALT [SGPT], lipase,
amylase, sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, lactate dehydrogenase, [LDH], magnesium)
∀
Hematology (complete blood count with differential and platelets, absolute white 
blood cell counts)
∀
Apolipoproteins, total cholesterol and lipid-soluble vitamins (A, D, E, K)
∀
Prothrombin time (PT); internationalized normalized ratio (INR); partial 
thromboplastin time (PTT)
∀
Urinalysis (microscopic and quantitative protein)
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
52
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
∀
eGFR, protein creatinine ratio
∀
Tetanus toxoid, pneumococcal, and influenza titers
∀
Inflammation panel (including erythrocyte sedimentation rate [ESR], fibrinogen, 
high sensitivity C-reactive protein [hs-CRP], serum amyloid A)
∀
Hepatitis screen (includes testing for hepatitis B surface antigen and antibody, 
hepatitis B core antibodies (IgG/IgM) and antibodies to hepatitis C)
∀
Quantitative assessment of immunoglobulins [immunoglobulin A (IgA), 
immunoglobulin M (IgM) and immunoglobulin G (IgG)] 
∀
Lupus anti-phospholipid profile (lupus anticoagulant, anti-cardiolipin antibodies 
and phosphatidylserine)
∀
Testosterone, FSH and LH for males only. Collection of these analytes must 
occur at both the Baseline and Final Treatment/Early Termination Visits at the 
same time of day (± 1 hour). For example, if collected at the Baseline Visit at 9 
AM, the Final Treatment/Early Termination Visit sample must be collected 
between 8 and 10 AM. During the ATEP, testosterone, FSH and LH testing will 
be conducted every 6 months.
Detailed instructions for sample collection, processing, storage, shipping and 
handling will be provided to the sites in a separate manual. 
!
Ophthalmological examinations will be conducted by a qualified ophthalmologist. 
Testing will include visual acuity and slit lamp exams with fluorescein staining 
following pupillary dilation, focusing on the anterior chamber, iris and anterior 
vitreous (unless use of fluorescein is contraindicated, eg, due to hypersensitivity).
!
Celgene Pregnancy Prevention Counseling Program (CPPCP)
Efficacy Assessments
In the event that a subject has taken systemic analgesics or NSAIDs within 12 hours of a study 
visit and/or systemic anti-pruritics within 48 hours of a visit, their visit should be rescheduled. 
Health assessment questionnaires must 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. CLASI, Swollen and Tender Joint Counts, Hybrid SELENA 
SLEDAI, SLICC/ACR SLE Damage Index, PGA and BILAG 2004 assessments must be 
conducted by a physician, physician assistant, or qualified nurse practitioner. The trained 
investigator/sub-investigator conducting efficacy assessments should remain the same 
throughout the study.  
!
CLASI Activity Score Assessment
The CLASI Activity Score (Appendix A) 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 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
53
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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. 
!
CLASI Damage Score Assessment
The CLASI Damage Score (Appendix A) 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. 
!
Physician Global Assessment (PGA)
The PGA (Appendix C) 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
This is a physician administered instrument used to gauge a subject’s overall state of 
health. A 10% increase (0.3 points) is considered a clinically relevant worsening of 
disease.
!
Swollen and Tender Joint Count
Using this tool, joint tenderness and swelling will be noted as “present” or “absent,” 
with no quantitation of severity (Appendix B). 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.
!
Hybrid SELENA SLEDAI
The hybrid SELENA SLEDAI (Appendix E) measures disease activity through 
assessment of 24 lupus manifestations using a weighted score of 1 to 8 points. A 
decrease of 4 or greater points in the Hybrid SELENA SLEDAI is considered 
clinically meaningful. A manifestation is recorded if it is present over the previous 10 
days regardless of severity or whether it has improved or worsened. What 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
54
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
differentiates the hybrid SELENA SLEDAI from the SELENA SLEDAI is the 
definition of proteinuria. The Hybrid SELENA SLEDAI defines proteinuria as > 0.5 
gm/24 hours – ‘new onset or recent increase of more than 0.5 gm/24 hours’ has been 
removed from the definition.
!
Pericardial/Pleuritic Numerical Pain Scale
Each scale (Appendix G) is scored using numerical values of 1 through 10 with 1 
representing ‘no pain’ and 10 representing ‘worst possible pain’. Both pain scales will 
be self-administered by the subject and gauge the severity of their SLE pain related to 
pericardial and pleuritic discomfort. Any indication from subjects or study 
assessments, aside from pain, which indicate clinically significant pericardial or 
pleuritic manifestations of SLE must be thoroughly investigated. If clinically 
significant SLE related complications are found, the subject should be discontinued 
from the study into the Observational Follow-up Period and treated appropriately.
!
SLICC/ACR SLE Damage Index
The SLICC/ACR Damage Index (Stoll, 2005; Appendix O) 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.
!
British Isles Lupus Assessment Group 2004 (BILAG) 
The BILAG 2004 (Isenberg, 2005; Appendix P) 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). Disease activity is categorized into five levels, Grades A-E.
 
 
 
 
 
 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
55
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
!
 
 
 
 
 
 
 
 
 
 
 
 
!
Fatigue Visual Analog Scale
The Fatigue VAS (Gilboe, 2001; Appendix H) will evaluate SLE related fatigue using 
a 0-100 mm VAS scale. A Fatigue VAS will allow the subject to indicate the degree 
of SLE related fatigue they experienced over the previous week. 
!
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
!
 
 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
56
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
57
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Other Assessments
Pharmacokinetics 
All subjects will participate in sparse PK as a participant in the main study (unless they elect to 
participate in the intensive PK sub-study). Completion of intensive pharmacokinetics requires the 
subject to have consented using the sub-study informed consent form. Both intensive and sparse 
PK samples will be collected to evaluate CC-220 PK.
 
 Dosing and sample collection information including CC-220 dose level, dosing date, 
dosing time (24 hour clock), and actual PK blood sampling time (24 hour clock) should be 
accurately documented on the appropriate eCRF pages.
Part 1 
Sparse PK Sampling
All other subjects who do not participate in the intensive PK portion of the study will have sparse 
PK samples collected.
Pharmacokinetic blood samples (approximately 12 mL total) will be collected in subjects (unless 
the site does not have PK capabilities) who do not participate in intensive PK sampling at the 
following timepoints:
!
Days 15, 29, 57 and 85: one pre-dose sample per visit.
Intensive PK Sampling
Participation in the intensive PK assessment will be an optional sub-study for which a separate 
consent will be signed at screening. Frequent collection of PK blood samples (approximately 57 
mL total) will be performed in approximately 4 subjects per treatment group (a total of 32 
subjects at the minimum) at the following timepoints:
!
Visit 2 (Baseline – Day 1): pre-dose (Time = 0 hours), 1, 2, 3, 4, between 6 and 8 
hours and 24 hours (± 5 hours) after administration of IP.
!
Visit 4 (Day 15): one pre-dose sample per visit
!
Visit 6 (Day 29): pre-dose (Time = 0 hours), 1, 2, 3, 4, between 6 and 8 hours and 24 
hours (± 5 hours) after administration of IP.
!
Visits 8 and 10 (Days 57 and 85): one pre-dose sample per visit 
The IVRS will be used to ensure inclusion of a minimum of 4 intensive PK participants per dose 
group.
Pharmacokinetic samples should be collected within the following collection windows:
!
-30 to -5 minutes for the pre-dose sample
!
± 10 minutes for the samples collected at timepoints of 1 to 4 hours
!
± 20 minutes for the samples collected at the timepoint of between 6 and 8 hours
!
± 5 hours for the sample collected at the timepoint of 24 hours (this sample must be 
collected prior to the second dose)
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
58
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
At each timepoint, approximately 3 mL of blood will be collected.  The CC-220 concentration in 
plasma will be determined. Specific details regarding the collection, processing, storage, and 
shipment of PK samples will be provided in a separate document.
On all PK visits, subjects must bring their IP to the study center and IP must be administered to 
subjects at the study center after the collection of the pre-dose PK blood sample.  Subjects will 
be asked to report the date and time of their last IP dose (prior to the current study visit day) to 
the study staff during their visit at the study center. The IP dosing time on the day of the PK 
sample collection should also be documented by the study staff. 
In cases where ECG and PK timepoints coincide, a ± 15 minute window will be allowed for 
completion of PK (the ECG should always be assessed first).
No PK will be measured in the ATEP.
 
 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
59
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
Part 1
Approximately 40 subjects (not including screen failures) will be enrolled at multiple 
(approximately 40) North American sites.
Active Treatment Extension Phase
Approximately 75% of subjects from Part 1 are projected to enroll into the ATEP. Of the 
subjects who enroll into the ATEP, approximately 60% are projected to complete the 2 year 
treatment phase. In total approximately 18 subjects are expected to complete the ATEP.
7.2.
Inclusion Criteria
Note: All applicable inclusion and exclusion criteria must be evaluated at both the 
Screening and Baseline Visits. Subjects entering the ATEP must be re-evaluated for 
inclusion and exclusion criteria, with the exception of SELENA SLEDAI score. 
Subjects may be re-screened twice.  Laboratory values for eligibility criteria must be confirmed 
within 42 days prior to randomization (Baseline Visit Day 1).
Subjects must satisfy the following criteria to be enrolled in the study:
7.2.1.
Part 1
Age/Gender
1. Male or female 18 years of age or older
2. Understand and voluntarily sign an ICD prior to the initiation of any study related 
assessments/procedures
3. Able to adhere to the study visit schedule and other protocol requirements.
Disease Specific
4. The subject has an established diagnosis of systemic lupus erythematosus (SLE) as 
defined by the 1997 Update of the 1982 ACR Revised Criteria for Classification of SLE 
at screening (Appendix D). The diagnosis is fulfilled provided that at least 4 criteria are 
met or have been met in the past. 
5. Disease history of SLE ≥ 6 months at baseline 
6. A minimum Hybrid SELENA SLEDAI score of ≥ 4 points at Baseline†.
Pregnancy 
7. Females of childbearing potential (FCBP)1 must:
                                               
1 A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not 
undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea 
following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had 
menses at any time in the preceding 24 consecutive months).
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
60
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
!
Have two negative pregnancy tests as verified by the study doctor prior to starting 
study therapy. She must agree to ongoing pregnancy testing during the course of the 
study, and after end of study therapy. This applies even if the subject practices true 
abstinence* from heterosexual contact.
!
Either commit to true abstinence* from heterosexual contact (which must be reviewed 
on a monthly basis) or agree to use, and be able to comply with, effective 
contraception without interruption, 28 days prior to starting IP, during the study 
therapy (including dose interruptions), and for 28 days after discontinuation of study 
therapy. 
8. Male subjects must:
!
Practice true abstinence* or agree to use a condom 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 IP discontinuation, even if 
he has undergone a successful vasectomy. 
9. Male subjects must agree not to donate semen or sperm during therapy and for at least 90
days following the discontinuation of IP.
10. All subjects must:
!
Understand that the IP could have potential teratogenic risk
!
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. 
Concomitant Medications
11. If the subject is using oral corticosteroids, the daily dose must be less than or equal to 10 
mg of prednisone or equivalent during the study; the dose must be stable over the 4 
weeks preceding randomization and throughout the study. 
12. Subjects taking hydroxychloroquine, chloroquine and/or quinacrine must be on a stable 
dose for at least 4 weeks prior to their baseline visit and throughout the study. 
13. All subjects taking hydroxychloroquine, chloroquine or quinacrine during the study must 
have documentation of a normal ophthalmologic examination performed within 1 year of 
the Baseline Visit.
                                               
* 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.)
† The SELENA SLEDAI score may be used to qualify a subject at the Baseline Visit without receipt of labs 
performed as part of the SELENA SLEDAI as long as the subject demonstrates a minimum score of 4.
&&,
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
61
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
14. For subjects not taking corticosteroids, or antimalarials, the last dose (in case of previous 
use) must be at least 4 weeks prior to screening. 
7.2.2.
Active Treatment Extension Phase
Age/Gender
1. Male or female 18 years of age or older
15. Understand and voluntarily sign an ICD prior to the initiation of any study related 
assessments/procedures
16. Able to adhere to the study visit schedule and other protocol requirements.
Pregnancy 
17. Females of childbearing potential (FCBP)2 must:
!
Have two negative pregnancy tests as verified by the study doctor prior to starting 
study therapy. She must agree to ongoing pregnancy testing during the course of the 
study, and after end of study therapy. This applies even if the subject practices true 
abstinence* from heterosexual contact.
!
Either commit to true abstinence* from heterosexual contact (which must be reviewed 
on a monthly basis) or agree to use, and be able to comply with, effective 
contraception without interruption, 28 days prior to starting IP, during the study 
therapy (including dose interruptions), and for 28 days after discontinuation of study 
therapy. 
18. Male subjects must:
!
Practice true abstinence* or agree to use a condom 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 IP discontinuation, even if 
he has undergone a successful vasectomy. 
19. Male subjects must agree not to donate semen or sperm during therapy and for at least 90 
days following the discontinuation of IP.
20. All subjects must:
!
Understand that the IP could have potential teratogenic risk
!
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
                                               
2 A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not 
undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea 
following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had 
menses at any time in the preceding 24 consecutive months).
* 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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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
62
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
!
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. 
Concomitant Medications
21. If the subject is using oral corticosteroids, the daily dose must be less than or equal to 10 
mg of prednisone or equivalent during the study; the dose must be stable over the 4 
weeks preceding randomization and throughout the study. 
22. Only use of topical steroids that fall into potency Classes 6 and 7 will be permitted during 
the study. No other topical, local or systemic treatments for dermatological 
manifestations of SLE will be permitted.
23. All subjects taking hydroxychloroquine, chloroquine or quinacrine during the study must 
have documentation of a normal ophthalmologic examination performed within 1 year of 
the Baseline Visit.
24. For subjects not taking corticosteroids the last dose (in case of previous use) must be at 
least 4 weeks prior to screening. 
7.3.
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, subjects may have repeat assessments performed 
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.  Laboratory values for eligibility criteria must be confirmed within 42 days prior 
to randomization (baseline day 1). In the event a subject is entering the ATEP without 
undergoing the ATEP screening period, assessment of the criteria should be based off Visit 1 of 
the ATEP instead of screening
7.3.1.
Part 1 and Active Treatment Extension Phase
Concomitant Medications and Procedures
1. The subject has been treated with intra-articular, intramuscular or IV pulse corticosteroids 
within 4 weeks of screening. 
25. The subject has received high dose oral prednisone (> 100 mg/day) within 4 weeks of 
screening.
26. The subject has undergone plasmapheresis within 4 weeks of screening.
27. The subject has received methotrexate, sulfasalazine, leflunomide, tacrolimus, 
cyclosporine A, azathioprine, mycophenolate mofetil or iv immunoglobulin (IVIG) 
within 4 weeks of screening. Note: methotrexate, sulfasalazine, ophthalmological 
cyclosporine or leflunomide will be permitted for concomitant use during the ATEP.
28. Previous use of melphalan.
29. The subject has received cyclophosphamide within 8 weeks of screening.
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cyc


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
63
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
30. Prior use of benlysta, abatacept, tocilizumab, adalimumab, infliximab, etanercept and 
other anti-TNF inhibitors within 12 weeks of screening.
31. The subject has been treated with biological therapy (eg, fusion proteins, therapeutic 
proteins, monoclonal antibodies or antibody fragments) within 8 weeks or 5 half-lives of 
screening. 
32. The subject has received B-cell depleting or modulating agents, such as rituximab or anti-
CD22 therapy, within 6 months prior to screening OR has received B-cell depleting 
agents from which the subject’s B-cell count has not yet normalized (ie, CD20+ B-cell 
count is less than 200 and the absolute lymphocyte count [ALC] is less than 1500/μL). 
33. St. John’s Wort within one month of screening.
34. Strong inhibitors or inducers of CYP3A4/5 at least one week prior to dosing and during 
the course of study (Please refer to Appendix K for examples of medications). Grapefruit 
or related products ≤ 1 week prior to dosing and throughout the study.
35. The subject has participated in a clinical trial and has received an investigational product 
within 30 days, 5 pharmacokinetic half-lives or twice the duration of the biological effect 
of the investigational product (whichever is longer) prior to screening; OR participation
in two or more investigational drug trials within 12 months of screening.
36. Unwilling to abstain from the use of prescription or non-prescription drugs, including: 
agents known to interact with CC-220, erythropoietin stimulation factors; herbal and 
dietary supplements (vitamins are permitted) or alternative medicine during study 
participation.
37. The subject has a planned or received immunization with a live or live attenuated vaccine 
within 2 months prior to administration of the first dose of IP and for 2 months after 
administration of the last dose of IP.
38. Have a planned surgical procedure or a history of any other medical disease laboratory 
abnormality, or condition that, in the opinion of the investigator, makes the subject 
unsuitable for the study. 
Disease Severity
39. Unstable lupus nephritis defined as: eGFR of less than 50 mL/1.73 m2.
40. CNS disease, including active severe CNS lupus (including seizures, psychosis, organic 
brain syndrome, cerebrovascular accident (CVA), cerebritis or CNS vasculitis) requiring 
therapeutic intervention within 6 months of screening. 
Concomitant Disease
41. The subject has New York Heart Association (NYHA) Class III or IV congestive heart 
failure.
42. Presence of hepatitis B surface antigen (HBsAG).  Subjects may have a positive anti-
hepatitis B core antibody (anti-HBc) if the anti-hepatitis B surface antibody (anti-HBs) is 
positive as well (Appendix L). Note: for the ATEP, this exclusion will only apply to
those subjects who come in for the ATEP greater than 14 days after their Part 1 Week 12 
(Visit 10).
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42. P


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
64
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
43. Antibodies to hepatitis C at Screening. Note: for the ATEP, this exclusion will only apply 
for those subjects who come in for the ATEP greater than 14 days after their Part 1 Week 
12 (Visit 10).
44. The subject has a known positive history of antibodies to human immunodeficiency virus 
(HIV) or HIV disease or acquired immune deficiency syndrome (AIDs).
45. Has a history of an organ transplant (eg, heart, lung, kidney, liver) or hematopoietic stem 
cell/marrow transplant. 
46. Malignancy or history of malignancy, except for:
!
treated (ie, cured) basal cell or squamous cell in situ skin carcinomas; 
!
treated (ie, cured) cervical intraepithelial neoplasia (CIN) or carcinoma in situ of the 
cervix with no evidence of recurrence within 5 years of Screening
47. Systemic bacterial infections requiring treatment with oral or injectable antibiotics, or 
significant viral or fungal infections, within 4 weeks of Screening. Any treatment for 
such infections must have been completed and the infection cured, at least 2 weeks prior 
to Screening and no new or recurrent infections prior to the Baseline visit.
48. History of venous thrombosis or any thromboembolic events within 2 years of screening.
49. Clinical evidence of significant unstable or uncontrolled acute or chronic disease not due 
to SLE (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, renal, 
neurological, malignancy, psychiatric or infectious disease) which in the opinion of the 
investigator could put the subject at undue risk or confound study results.
50. Presence of active uveitis or any other clinically significant ophthalmological finding.
51. History or current diagnosis of peripheral neuropathy.
Laboratory Criteria
52. Hematology: 
!
Neutrophil count ≤1.5 x 109/L (subjects entering the ATEP within 14 days can have a 
neutrophil count as low as 1.0 x 109/L)
!
Hb ≤9 g/dL
!
Lymphocyte count ≤500/mm3 or 0.50 x 109/L 
!
Platelet count ≤100 x 109/L 
!
Serum immunoglobulin (Ig) levels: IgG ≤ the lower limit of normal (LLN) 
!
Liver function tests: 
∀
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2x upper 
limit of normal (ULN)
∀
Alkaline phosphatase and bilirubin > 1.5 x ULN (isolated bilirubin > 1.5 ULN is 
acceptable if bilirubin is fractionated and direct bilirubin < 35%).
53. Any clinically significant abnormalities on ECG, which, in the opinion of the investigator 
would interfere with safe participation in the study.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
65
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
General
54. The subject is unlikely to comply with the study protocol or is unsuitable for any other 
reason, as judged by the investigator or medical monitor. 
55. Substance dependence or abuse within six months of the Screening Visit which, in the 
opinion of the investigator, would interfere with the patient’s safety or ability to comply 
with the study procedures. 
56. History of sensitivity to any of the investigational products/placebo, or components 
thereof or a history of drug or other allergy that, in the opinion of the investigator or 
Medical Monitor, contraindicates their participation. The subject has a history of severe 
allergic reactions to or hypersensitivity to any component of the IP or placebo.
57. History of tuberculosis (TB). Subjects with a history of TB who have completed a 
standard course of treatment (documented) are eligible for study entry.
58. Pregnant or nursing (breast-feeding) females.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
66
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
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. CC-220 will be provided by the sponsor in a 0.3 mg 
formulated capsule 
. In addition, the 
sponsor will provide matching placebo identical in appearance to CC-220 0.3 mg formulated 
capsule. Excipients of the formulation include 
 
8.2.
Treatment Administration and Schedule
8.2.1.
Dose Modification or Interruption
Subjects will remain on their assigned treatment for up to 12 weeks in Part 1 and up to 100 
weeks for the ATEP. 
In the event a subject experiences clinically significant IP-related adverse events, a dose 
interruption for up to 14 days will be permitted (see Section 12.1). If a subject is able to recover 
from their IP-related adverse event per Section 12.1, he/she will reduce their dose to the next 
lowest dosing regimen. Dose reductions will occur as follows:
!
Subjects on 0.6 mg QD will reduce their dose to 0.6 mg/0.3 mg on alternating days
!
Subjects on 0.6 mg/0.3 mg on alternating days will reduce their dose to 0.3 mg QD
!
Subjects on 0.3 mg QD will:
o
reduce their dose to 0.3 mg QOD (Part 1 only)
o
be terminated from the study (ATEP only)
!
Subjects on 0.3 mg QOD will reduce their dose to placebo (Part 1 only)
A subject will only be permitted to reduce their dose one time during the study. Subjects who 
originally came into the ATEP on 0.6 mg QD and dose reduce to 0.6/0.3 mg QD on alternating 
days upon implementation of Protocol Amendment 5 will be eligible for one additional dose 
reduction during the ATEP. The decision to modify IP dosing will be based on the rules provided 
in Section 12.1. The sponsor should be notified of the intent to dose reduce prior to a change in 
dosing. 
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. 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
67
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
8.2.2.
Overdose
Overdose, as defined for this protocol, applies to protocol-required dosing of the IP 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 overdose definition will apply to 
only CC-220 (or matching placebo). Other required or optional non-IP intended for prophylaxis 
of certain side effects, etc, are excluded from this definition. Overdose for this protocol, on a per 
dose basis, is defined as ingestion of ≥4 capsules of CC-220 (or matching placebo) in any 24-
hour period whether by accident or intentionally. Adverse Events associated with an overdose 
must be collected on the Adverse Events page of the CRF for all overdosed subjects, but the 
overdose itself is not considered an AE. 
8.3.
Method of Treatment Assignment
After the informed consents have been signed, subjects will be assigned a subject ID by IVRS 
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. At the Baseline Visit (Day 1), subjects 
who meet the eligibility criteria shall be enrolled using IVRS to receive either the assigned CC-
220 dose or placebo.
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 0022002). 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 0023002).
Designated study personnel at the investigational sites will be assigned password protected, 
coded identification numbers, which give them authorization to call into the IVRS to enroll 
and/or randomize subjects, as well as re-supply and discontinue subjects from the study. 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 answered, the IVRS will assign a subject 
ID number. Confirmation of the subject ID will be sent to the investigational site, Celgene and/or 
its representative.
During the study, the pharmacy or authorized study personnel at the investigational site will 
dispense coded investigational product kits in accordance with the randomization number 
assigned by the IVRS. Authorized personnel will call IVRS to confirm the medication number 
assigned to the subject at the time of or prior to dispensing to a subject.
8.4.
Packaging and Labeling
The Investigator(s) or designee(s) is responsible for accounting for all IP that is issued to and 
returned by the subject during the course of the study.
The Investigator(s) or designee (s) is responsible for taking an inventory of each IP shipment 
received and comparing it with the accompanying IP accountability form.  The Investigator(s) or 
designee (s) will verify the accuracy of the information on the form, sign and date it, retain a 
copy in the study file and return a copy to Celgene. At the investigational site, all IP will be 
stored in a locked, safe area to prevent unauthorized access.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
68
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Investigational product should be stored according to instructions on the labeled drug product, 
away from direct sunlight and protected from excessive heat and cold.
Celgene will instruct the Investigator on the return, disposal and/or destruction of investigational 
product and/or medical device materials if applicable. 
Site staff must make every effort to retrieve all IP supplies for subjects. 
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.
8.5.
Investigational Product Accountability and Disposal
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for Investigational Product return, disposal, and/or destruction including responsibilities for the 
site vs. Celgene (or designee).
8.6.
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.
Overall compliance is defined as taking between 75% and 120% of dispensed IP.  In the event of 
gross compliance problems (eg, missing more than 4 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) sponsor must be contacted to decide whether dosing should resume 
or whether the subject should be terminated from the study and enter into the Observational
Follow-up Period.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
69
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
9.
CONCOMITANT MEDICATIONS AND PROCEDURES
9.1.
Permitted Concomitant Medications and Procedures
Use of the following concomitant medications is permitted.  These include: 
!
≤ 10 mg/day of oral prednisone (or equivalent) and the dose must remain stable for 
the duration of the subject’s study participation
!
Inhaled corticosteroids for use in a disease other than lupus, eg, asthma, will be 
allowed. 
!
Only use of topical steroids that fall into potency classes 6 and 7 will be permitted 
during the study.
!
Oral NSAIDs may be used, but must be stopped 12 hours prior to all study visits. 
!
Concurrent treatment with stable doses of hydroxychloroquine, chloroquine, or 
quinacrine will be permitted, provided the subject has been on a stable dose for at 
least 4 weeks prior to their baseline visit and remains on the same dose throughout the 
study. Subjects participating in the ATEP will be permitted to modify or stop their 
antimalarial treatment at any time.
!
Systemic analgesics or systemic anti-pruritic medications (systemic analgesics must 
be stopped 12 hours prior to all study visits and systemic anti-pruritics 48 hours 
prior to all study visits)
!
One-a-day vitamins recommended by the physician for a deficiency are permitted. 
!
Thromboprophylaxis with low dose aspirin, low molecular weight heparin or other 
equivalent antithrombotic or anticoagulant is required unless the investigator 
determines that, based on the totality of the subjects’ risk factors for thrombosis, 
thromboprophylaxis is not required or is contraindicated.
If any additional prophylaxis is needed, it should be based on the local standard of 
care and the investigator’s best judgement after careful consideration of the benefit 
versus the potential risk for the individual subject.
!
Granulocyte-macrophage colony stimulating factor (GM-CSF) may be prescribed by 
the investigator, if appropriate, to treat a subject who discontinues from IP as a result 
of an ANC of < 1000 cells/μL (1.0 x 109/L). This subject must enter the Post-
treatment Observational Follow-up Phase of the study.
!
Methotrexate (7.5 mg – 25 mg per week), leflunomide (maintenance dosing must not 
exceed 20 mg daily), sulfasalazine (dosing not to exceed 3 g daily) or ophthalmologic 
cyclosporine will be permitted during the ATEP.
Subjects must check with study personnel before initiating the use of prescribed or 
over-the-counter medications during the study.
Medication doses and treatment regimens should remain generally stable throughout the course 
of the study. 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
70
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
In the event a subject requires a surgical or invasive procedure during the course of the study, the 
sponsor must be contacted to discuss whether or not the subject is eligible to continue. 
9.2.
Prohibited Concomitant Medications and Procedures
Refer to Section 7.3 for a comprehensive list of prohibited concomitant medications and 
procedures.
9.3.
Required Concomitant Medications and Procedures
Thromboprophylaxis with low dose aspirin, low molecular weight heparin or other equivalent 
antithrombotic or anticoagulant is required unless the investigator determines that, based on the 
totality of the subjects’ risk factors for thrombosis, thromboprophylaxis is not required or is 
contraindicated.
&&,
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
71
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
10.
STATISTICAL ANALYSES
10.1.
Overview
The primary objective of the statistical analysis for Part 1 is to evaluate the safety and tolerability 
of CC-220 for subjects with SLE.
For Part 1, the placebo treated subjects in the three dose groups will be merged and will be 
considered as a one treatment group in the final efficacy and safety analyses.
For the ATEP, the treatment groups will be combined from Part 1 and the ATEP to form one 
treatment group for each dose level/regimen. Additionally, all treatment groups will be combined 
into a total group.
10.2.
Study Population Definitions
Safety analyses will be based on the safety population, which will include all subjects who are 
randomized and receive at least one dose of IP.  Subjects will be included in the treatment group 
corresponding to the IP they actually received for the analyses using the safety population.  For 
most subjects, this will be the treatment group to which they are randomized.  Subjects who take 
an IP that differs from the assigned one, according to the randomization schedule, the entire 
Double-blind Placebo-controlled period will be included in the treatment group corresponding to 
the IP they actually received.
  The 
ITT analysis set will consist of all subjects who are randomized as specified in the protocol and 
receive at least one dose of IP.  Subjects who are randomized in error and who do not receive any 
dose of IP will be excluded from the ITT analysis set.  Subjects will be included in the treatment 
group to which they are randomized for the ITT analyses.
The per protocol (PP) analysis set will consist of all subjects included in the ITT analysis set who 
have at least one post-baseline efficacy evaluation and no critical protocol violations as described 
in the SAP.
The PK population will include all subjects in the safety population with at least one non-missing 
plasma concentration data. All analysis of PK data will be based on the PK population and 
subjects will be analyzed according to the treatment group to which they were randomized.
 
10.3.
Sample Size and Power Considerations
For Part 1, a total of approximately 40 subjects in total will be randomized into 4 dose groups 
with a 4:1 ratio of CC-220 (0.3 mg QOD, 0.3 mg QD, 0.6/0.3 mg alternating QD, 0.6 mg QD) or 
matching placebo (8 subjects in the CC-220 arm and 2 subjects in the placebo arm for each dose 
group) using an IVRS.
The sample size was based on prior clinical experience and no formal sample size or power 
calculation was performed.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
72
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
10.4.
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.
10.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases.  A summary of subjects enrolled by site will be provided. Protocol 
deviations will be summarized using frequency tabulations.
10.6.
Efficacy Analysis
No multiplicity adjustment will be conducted for this Phase 2 pilot study.  Therefore, p-values 
and CIs from any efficacy analyses should be interpreted with caution.  They should be used as 
measures of strength of association between treatment effect and endpoint, rather than formal 
criteria to claim statistical significance.  All efficacy analyses will be conducted using the ITT
population. 
 
 
 
 
 
 
 
 
Active Treatment Extension Phase
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) for 
baseline, specified time points, and change from baseline in efficacy measures with continuous 
variables will be summarized by visit and by initial treatment group in Part 1. No p-values will 
be provided other than the descriptive statistics. Missing data will not be imputed and only 
observed results will be utilized.
 
 
Proportion and frequency of the subjects for the hierarchical data will be summarized by visit (if 
applicable) by initial treatment group in Part 1, and combined similar to continuous variables. No 
p-values will be provided. Missing data will not be imputed and only observed results will be 
utilized.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
73
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
10.7.
Safety Analysis
The safety analyses will be performed using the safety population as defined in Section 10.2.
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA) coding system. Adverse events occurring during the Treatment Phase and the 
Observation Phase will be tabulated for each Part 1. 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, including weight, 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.
10.8.
Interim Analysis
Part 1
Following completion of the first 28 days of the Treatment Phase by 8 subjects of each dose 
group, assessments of safety and tolerability will be conducted. Unblinded interim analyses may 
be performed by a group that is independent of the study team for administrative purposes, which 
includes the potential to discontinue any treatment group. If conducted, the details of this 
analysis including the scope of distribution will be documented in a separate charter/analysis 
plan.
10.9.
Other Topics
10.9.1.
Pharmacokinetic Analysis
The Pharmacokinetic analysis will be performed using the PK population as defined in Section 
10.2.
Pharmacokinetic parameters (AUC, Cmax, tmax, t1/2. CL/F and Vz/F) in plasma will be estimated 
from the CC-220 versus time data using noncompartmental analysis. Descriptive statistics will 
be provided for CC-220 concentrations and PK parameters, and the results will be presented in 
tabular and graphic form as appropriate.
 
 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
74
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
 
 
 
 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
75
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An adverse event (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 11.3), regardless of 
etiology. Any worsening (ie, 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. 
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 8.2.2 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 an 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 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 84 days after the last dose of IP for Part 1 and until 28 days after the last dose of IP for the 
ATEP, and those SAEs made known to the investigator at any time thereafter that are suspected 
of being related to IP. AEs and serious adverse events (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.
11.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
11.2.1.
Seriousness 
A serious adverse event (SAE) is any AE occurring at any dose that:
!
Results in death;
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1.2.1.


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
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CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
!
Is life-threatening (ie, 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.
!
An elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline.
!
A procedure that is planned (ie, planned prior to starting 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.
!
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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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
77
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome.
11.2.2.
Severity / Intensity
For both AEs and SAEs, the Investigator must assess the severity / intensity of the event. 
The severity of AEs will be graded based upon the subject’s symptoms according to the 
following scale:
Mild 
!
Asymptomatic or mild symptoms; clinical or diagnostic observations only
!
Intervention not indicated
!
Activities of daily living (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 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.
11.2.3.
Causality 
The Investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
Means a causal relationship of the adverse event to IP 
administration is unlikely or remote, or other medications, 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
78
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event.
Suspected:
Means 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 Celgene, please provide the name of the 
manufacturer when reporting the event.
11.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
11.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event. 
11.2.6.
Outcome
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae or death (due to the SAE). The 
investigator will report the outcome of the event for both AEs and SAEs.
11.3.
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
!
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 
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eed to
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
79
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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).
11.4.
Pregnancy
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.
The exposure of any pregnant female (eg, caregiver, pharmacist, study coordinator, or monitor) 
to CC-220 is also an immediately reportable event.
11.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated β-HCG or a positive pregnancy test 
in a female of childbearing potential regardless of disease state) occurring while the subject is on 
IP, or within 28 days of the subject’s last dose of IP, 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 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.
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.
11.4.2.
Male Subjects
If a female partner of a male subject taking investigational product 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.
11.5.
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, 
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11.5.
11


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
80
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
or other appropriate method, 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 the last study visit [84 days after the last 
dose of IP for Part 1 and 28 days after the last dose of IP for the ATEP]) or any SAEs made 
known to the Investigator at any time thereafter that are suspected of being related to IP.  SAEs 
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 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 
Celgene and the IRB/EC.
11.5.1.
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.
11.6.
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 serious adverse reactions (SUSARs) will be reported in an 
expedited manner in accordance with 21 CFR 312.32.
Celgene 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 (ie, 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 Celgene and the IRB/EC.  (See Section 15.3 for record retention 
information).
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
81
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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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&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
82
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
12.
DISCONTINUATIONS
12.1.
Subject Stopping Rules
Laboratory 
∀
Presence of any of the following laboratory results will require repeat testing 
within 3 to 7 days of the original test. Subjects should withhold their prescribed IP 
dose pending receipt of their repeat test results. If the result(s) demonstrate that 
the subject’s laboratories have normalized, they may continue in the study at a 
reduced dose (see Section 8.2.1). If the result(s) fall within the specified stopping
rule criteria listed below, an additional retest within 11 to 14 days of the original 
result will be permitted (IP should continue to be withheld during this re-testing 
period). If, after 11 to 14 days, the result(s) falls within the criteria below, subjects 
are required to be discontinued from the study. If the result(s) demonstrate that the 
subject’s laboratories have normalized, they may continue in the study at a 
reduced dose (see Section 8.2.1).
Laboratories for subjects exhibiting the following criteria must be repeated 
within 3 days:
!
White blood cells (WBC) ≤ 1500/mm3 (≤ 1.5 x 109/L) or ≥16,000/mm3 (≥ 16 
x 109/L)
!
Platelet count ≤75,000/μL (≤75 x 109/L) 
!
Absolute neutrophil count (ANC) ≤ 1000 cells/μL (1.0 x 109/L)
Granulocyte-macrophage colony stimulating factor (GM-CSF) may be 
prescribed by the investigator, if appropriate, to treat a subject who 
discontinues from IP as a result of an ANC of < 1000 cells/μL (1.0 x 
109/L). This subject must enter the Post-treatment Observational Follow-up 
Phase of the study.
!
MDRD eGFR < 30 mL/min
!
AST/SGOT or ALT/SGPT ≥5 x ULN
!
AST/SGOT or ALT/SGPT > 3 x ULN and total bilirubin > 2 x ULN
Laboratories for subject exhibiting the following criteria must be repeated 
within 7 days:
!
AST/SGOT or ALT/SGPT > 3 x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or:

Eosinophilia (> 7%) Note: for subjects in the ATEP eosinophilia must 
be greater than 12%.

Hemoglobin ≤ 8 g/dL 

Total bilirubin ≥ 2.5 mg/dL
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
83
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Development of the Following Adverse Events/SAEs
!
Recurrent infections requiring in-patient treatment and/or parenteral 
antibiotics 
!
A thromboembolic event (eg, deep vein thrombosis, thrombotic 
cerebrovascular or cardiovascular events) 
!
Peripheral neuropathy
!
Life-threatening or disabling rash or blistering
!
Uveitis or other clinically significant ophthalmological findings
!
Pregnancy
The continued eligibility of subjects who experience the following events should be 
discussed with the Medical Monitor to determine if the subject is eligible to continue 
in the study. The Medical Monitor should be contacted or the Sponsor should be 
consulted concerning any subject that has an AE leading to drug interruption lasting 
for more than 4 days.
∀
Other SAEs (eg, potential drug reaction or allergy)
∀
Presence of any other new onset, severe organ/system manifestations that 
interfere with activities of daily living, require medical intervention(s) for 
≥ 7 days and/or hospitalization 
∀
Any prolonged infection with symptoms lasting greater than two weeks and/or 
requiring antibiotic treatment greater than 10 days in duration
Note: Only one dose reduction will be permitted per subject (with the exception of those 
subjects entering the ATEP on 0.6 mg QD who must be dose reduced based upon Protocol 
Amendment 5 and who will be eligible for one additional dose reduction in the ATEP). Any 
laboratory values which fall into the subject stopping criteria following a dose reduction 
require discontinuation of the subject from the study.
12.2.
Dose Group Stopping Rules
The cumulative safety data for a dose group will be reviewed on a regular basis, including the 
number of subjects who met the above stopping rules after each dose group completes dosing. If 
3 or more subjects experience a severe or serious AE which leads to discontinuation, the safety 
management team (SMT) will be notified and the sponsor will determine if dose escalation will 
be stopped.
12.3.
Discontinuation Criteria
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study:
!
Adverse event(s)
!
Lack of therapeutic effect 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
84
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
!
Withdrawal of consent
!
Death
!
Lost to follow-up
!
Protocol violation
The reason for discontinuation should be recorded in the CRF and in the source documents.
Celgene is to be notified of all discontinuations from IP.
Subjects who discontinue from the study prior to completing 28 days of treatment may be 
replaced at the discretion of the sponsor. 
&&,
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
85
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
13.
EMERGENCY PROCEDURES
13.1.
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 Celgene/CRO 
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. 
13.2.
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 thorough the IVRS by using 
an emergency unblinding personal identification number (PIN), and the investigator should call 
IVRS for unblinded dose information.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
86
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
14.
REGULATORY CONSIDERATIONS
14.1.
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 Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International 
Conference on Harmonization (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.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene 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. 
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 
document 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.
At the time results of this study are made available to the public, Celgene 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.
14.3.
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 informed consent document 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 
informed consent document 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 informed 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
87
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
consent document.  The revised informed consent document 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.
14.4.
Confidentiality
Celgene 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). Celgene requires 
the Investigator to permit Celgene'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 informed consent document, it is the responsibility of the Investigator to obtain 
such permission in writing from the appropriate individual.
14.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene 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.
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, informed consent document, 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 Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Celgene 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.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
88
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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 informed consent document 
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 Celgene and the 
IRB/EC prior to use.
14.7.
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.
14.8.
Closure of the Study
Celgene reserves the right to terminate this study 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 Celgene 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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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
89
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
15.
DATA HANDLING AND RECORDKEEPING 
15.1.
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.
15.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene 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.
15.3.
Record Retention
Essential documents must be retained by the Investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. 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 informed consent documents 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, Celgene, 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 Celgene 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 Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
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/Institution should take measures to prevent accidental or premature destruction of 
these documents.
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16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
16.1.
Study Monitoring and Source Data Verification
Celgene 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 investigator meeting.  Prior to enrolling subjects into the study, a 
Celgene 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 Celgene 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.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene 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/IECs, 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 Celgene immediately.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
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17.
PUBLICATIONS
The results of this study may be published in a medical publication, journal, or may be used for 
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.  
 
 
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EDMS Doc. Number:
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18.
REFERENCES
Aletaha D, Smolen JS. The definition and measurement of disease modification in inflammatory 
rheumatic diseases. Rheum Dis Clin North Am 2006;32:9-44.
Bandyopadhyay S, Dure M, Paroder M, Soto-Nieves N, Puga I, Macian F. Interleukin 2 gene 
transcription is regulated by Ikaros-induced changes in histone acetylation in anergic T cells. 
Blood 2007;109:2878-86.
Braunstein I, Goodman NG, Rosenbach M, Okawa J, Shah A, Krathen M. Lenalidomide therapy 
in treatment-refractory cutaneous lupus erythematosus: Histologic and circulating leukocyte 
profile and potential risk of a systemic lupus flare. J Am Acad Dermatol 2012; 66:571-82. 
Bruce B, Fries JF. The Stanford health assessment questionnaire: a review of its history, issues, 
progress, and documentation. J Rheumatol 2003;30:167-78. 
 
Cortes M, Georgopoulos K. Aiolos is required for the generation of high affinity bone marrow 
plasma cells responsible for long-term immunity. J Exp Med 2004;199(2):209-19.
Cortes-Hernandez J, Avila G, Vilardell-Tarres M, Ordi-Ros J. Efficacy and safety of 
lenalidomide for refractory cutaneous lupus erythematosus. Arthritis Research & Therapy 2012;
14:R265.
David-Bajar KM, Davis BM. Pathology, immunopathology, and immunohistochemistry in 
cutaneous lupus erythematosus. Lupus 1997;6:145-57.
Ferreiros-Vidal I, Carroll T, Taylor B, Terry A, Liang Z, Bruno L, et al. Genome-wide 
identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification 
and pre-B-cell differentiation. Blood 2013;121(10):1769-82.
 
 
Gilboe IM, Kvien TK, Husby G. Disease course in systemic lupus erythematosus: changes in 
health status, disease activity, and organ damage after 2 years. J Rheumatol 2001;28:266-74.
 
Hu SJ, Wen LL, Hu X, Yin XY, Cui Y, Yang S. IKZF1: a critical role in the pathogenesis of 
systemic lupus erythematosus? Mod Rheumatol 2013;23(2):205-9. 
Isenberg DA, Rahman A, Allen E, Farewell V, Akil M, Bruce IN, et al. BILAG 2004. 
Development and initial validation of an updated version of the British Isles Lupus Assessment 
Group’s disease activity index for patients with systemic lupus erythematosus. Rheumatology 
(Oxford) 2005;44(7):902-6. 
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-57.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
94
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y. Identification of a primary target of 
thalidomide teratogenicity. Science 2010;327: 1345–50.
John LB, Ward AC. The Ikaros gene family: transcriptional regulators of hematopoiesis and 
immunity. Mol Immunol 2011;48 (9-10): 1272-8. 
 
 
 
Kikuchi H, Yamashita K, Nakayama M, Toyonaga K, Tsuneyoshi I, Takasaki M, et al. Lacking 
of Aiolos accelerates pre-mature B cell apoptosis mediated by BCR signaling through elevation 
in cytochrome c release. Biochim Biophys Acta 2009;1793(7): 1304-14.
Lessard CJ, Adrianto I, Ice JA, Wiley GB, Kelly JA, Glenn SB, et al. Identification of IRF8, 
TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a 
large-scale multiracial replication study. Am J Hum Genet. 2012;90(4):648-60. 
Liu CC, Kao AH, Manzi S, Ahearn JM. Biomarkers in systemic lupus erythematosus: challenges 
and prospects for the future. Ther Adv Musculoskel Dis 2013 5(4): 210-233.
Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi A, Kang J, et al. Cereblon is a direct protein 
target for immunomodulatory and antiproliferative activities of lenalidomide and 
pomalidomide. Leukemia 2012;26: 2326–35.
Mast EE, Margolis HS, Fiore AE, Brink EW, Goldstein ST, Wang SA, et al. A comprehensive 
immunization strategy to eliminate transmission of hepatitis B virus infection in the United 
States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: 
immunization of infants, children, and adolescents. MMWR Recomm Rep 2005;54(RR-16):1-
31.
Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol 2003 July;56(7): 
481-90. 
Petri M. Systemic lupus erythematosus and related diseases: clinical features. Chap 27. In: 
McKay IR, Rose NR, editors. The autoimmune diseases. 4th ed. New York: Academic press; 
2006. p. 351-6.
Quintana FJ., Jin H, Burns EJ., Nadeau M, Yeste A, Kumar D, et al. Aiolos promotes TH17 
differentiation by directly silencing II2 expression. Nat Immunol 2012;13(8):770-7.
Rothfield N, Sontheimer RD, Bernstein M. Lupus erythematosus: systemic and cutaneous 
manifestations. Clin Dermatol 2006;24(5):348-62.
Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargos R, et al. The Assessment 
of SpondyloArthritis International Society (ASAS) handbook: a guide to assess 
spondyloarthritis. Ann Rheum Dis 2009;68; Suppl 2:ii1-44.
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t al. Lack
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pus ery
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
95
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
Sontheimer RD. The lexicon of cutaneous lupus erythematosus – a review and personal 
perspective on the nomenclature and classification of the cutaneous manifestations of lupus 
erythematosus. Lupus 1997;6(2):84-95.
Stoll T, Sutcliffe N, Mach J, Klaghofer R, Isenberg DA. Analysis of the relationship between 
disease activity and damage in patients with systemic lupus erythematosus – a 5-yr prospective 
study. Rheum 2004;43:1039-1044. 
Wang C, Ahlford A, Järvinen TM, Nordmark G, Eloranta ML, Gunnarsson I, et al. Genes 
identified in Asian SLE GWASs are also associated with SLE in Caucasian populations. Eur J 
Hum Genet 2013: 21(9):994-9.
 
 
Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, et al. Cereblon expression is 
required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 2011;
118:4771–79.
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EDMS Doc. Number:
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Protocol CC-220-SLE-001
Celgene Corporation
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19.
APPENDICES
APPENDIX A. THE CUTANEOUS LUPUS AREA AND SEVERITY 
INDEX
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EDMS Doc. Number:
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APPENDIX B. SWOLLEN AND TENDER JOINT COUNT – 44 JOINTS
44 Joint Score:  Upper Extremity Joint Counts
Please write in the appropriate code for every joint using the Pain/Tenderness and Swelling Codes.
Pain/Tenderness Codes
Swelling Codes
Y
= Pain/tenderness 
Y
= Swelling
N
= No pain/tenderness
N
= No swelling
ND = Not Done
ND = Not Done
Joints
Right Side
Left Side
Pain/Tenderness
Swelling
Pain/Tenderness
Swelling
Y    N    ND
Y   N   ND
Y    N    ND
Y    N    ND
Sternoclavicular
Acromioclavicular
Shoulder
Elbow
Wrist
MCPC 1
MCP 2
MCP 3
MCP 4
MCP 5
PIP 1
PIP 2
PIP 3
PIP 4
PIP 5
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EDMS Doc. Number:
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APPENDIX B. SWOLLEN AND TENDER JOINT COUNT – 44 JOINTS 
(Continued)
44 Joint Score:  Lower Extremity Joint Counts
Please write in the appropriate code for every joint using the Pain/Tenderness and Swelling Codes.
Pain/Tenderness Codes
Swelling Codes
Y
= Pain/tenderness 
Y
= Swelling
N
= No pain/tenderness
N    = No swelling
ND = Not Done
ND= Not Done
Joints
Right Side
Left Side
Pain/Tenderness
Swelling
Pain/Tenderness
Swelling
Y    N    ND
Y    N    ND
Y    N    ND
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Knee
Ankle
MTP 1
MTP 2
MTP 3
MTP 4
MTP 5
Sieper, 2009.
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EDMS Doc. Number:
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APPENDIX C. PHYSICIAN’S GLOBAL ASSESSMENT
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APPENDIX D. 1997 UPDATE OF THE 1982 ACR REVISED CRITERIA 
FOR CLASSIFICATION OF SLE
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APPENDIX D. 1997 UPDATE OF THE 1982 ACR REVISED CRITERIA 
FOR CLASSIFICATION OF SLE (Continued)
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APPENDIX E. HYBRID SELENA SLEDAI
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APPENDIX E. HYBRID SELENA SLEDAI (Continued)
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APPENDIX F.
GILLIAM CLASSIFICATION
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APPENDIX F.
GILLIAM CLASSIFICATION (Continued)
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APPENDIX F.
GILLIAM CLASSIFICATION (Continued)
(David-Bajar, 1997; Rothfield, 2006; Sontheimier, 1997).
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APPENDIX G. PERICARDIAL/PLEURITIC NUMERICAL PAIN SCALE
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APPENDIX H. FATIGUE VAS
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&&,
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&&,
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APPENDIX K. MEDICATIONS THAT INHIBIT CYP3A4
Compound
(Brand Names)
Azole Antifungals
Ketoconazole (Nizoral, Ketozole)
Itraconazole (Sporanox)
Fluconazole (Diflucan)
HIV Protease Inhibitors
Ritonavir (Norvir, Kaletra)
Indinavir (Crixivan)
Saquinavir (Invirase, Fortovase)
Nelfinavir (Viracept)
Macrolide Antibiotics
Erythromycin (Benzamycin, Eyrc, E-glades, Erygel, E-solve 2, Akne-Mycin, Eryderm, Sansac, Erythro-Statin, 
Erymax, Staticin, T-Stat, C-solve-2, Erycetter, PCE, Ery-Tab, E-Mycin, E-Base, E.E.S., Eryped, E.E.S 200, 
E.E.S 400, Pediamycin, Eryzole, Erythrocin)
Clarithromycin (Prevpac, Biaxin)
Telithromycin 
Serotonin Reuptake Inhibitors (SSRI’s)
Nefazodone (Serzone)
Fluvoxamine (Luvox)
Antiemetics
Aprepitant (Emend)
Antihypertensives
Diltiazem (Taztia, Cartia, Cardizem, Dilt-CD, Dilacor, Teczem, Tiamate, Trizac)
Verapamil (Tarka, Verelan, Isoptin, Covera-HS, Calan)
Others
Grapefruit juice
Atazanavir
CYP3A Inducers
CYP Enzymes
Strong Inducers
≥ 80% decrease in AUC
CYP3A
Carbamazepine, phenytoin, 
rifampin, St. John’s 
wort(herbal)
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APPENDIX L. HEPATITIS EXCLUSION CRITERIA
Exclusion Criteria
!
Subjects who meet any of the Hepatitis B criteria described in the table below are 
ineligible for the study.
Source:  Mast, 2005.
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EDMS Doc. Number:
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Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
121
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
&&,
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EDMS Doc. Number:
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Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
122
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
&&,
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
123
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
APPENDIX O. SLICC/ACR SLE DAMAGE INDEX
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
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CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
APPENDIX O.  SLICC/ACR SLE DAMAGE INDEX (Continued)
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
125
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
APPENDIX O.  SLICC/ACR SLE DAMAGE INDEX (Continued)
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
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CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
APPENDIX O.  SLICC/ACR SLE DAMAGE INDEX (Continued)
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127
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
APPENDIX P.
BRITISH ISLE LUPUS ASSESSMENT GROUP 2004
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EDMS Doc. Number:
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Protocol CC-220-SLE-001
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128
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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EDMS Doc. Number:
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Protocol CC-220-SLE-001
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Confidential and Proprietary
129
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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EDMS Doc. Number:
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Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
130
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
&&,
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EDMS Doc. Number:
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Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
131
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
&&,
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Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
132
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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EDMS Doc. Number:
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Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
133
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
&&,
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EDMS Doc. Number:
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Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
134
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
135
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
136
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
&&,
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
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Confidential and Proprietary
137
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
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EDMS Doc. Number:
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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EDMS Doc. Number:
CC-220
Summary of Changes CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
3
CC-220-SLE-001 Amendment 6 Final: 18 Jun 2018
1.
JUSTIFICATION FOR AMENDMENT
Protocol Amendment 6 contains changes to the study 
 
 regarding thromboembolic risk and prophylaxis.
Key changes to the protocol included in this amendment are summarized below.
!
Update the thromboprophylaxis requirements and recommendations 
The thromboprophylaxis requirements for study participation were updated as follows:
-
The use of aspirin was changed from recommended to mandatory use of 
thromboprophylaxis with low dose aspirin, low molecular weight heparin or other 
equivalent antithrombotic or anticoagulant unless the investigator determines that, 
based on the totality of the subjects’ risk factors for thrombosis, thromboprophylaxis 
is not required or is contraindicated.
-
If any additional prophylaxis is needed, it should be based on the local standard of 
care and the investigator’s best judgement after careful consideration of the benefit 
versus the potential risk for the individual subject.
Subjects with lupus are already at an increased risk for thromboembolism from their disease and 
other potential underlying factors. The investigator will be prompted to carefully evaluate the 
risk/benefit for subject’s participation in the study based on the totality of thromboembolic risk 
factors (antiphospholipid status, hormonal contraceptives, corticosteroids, smoking, obesity, 
immobilization, etc.) in addition to CC-220 exposure.
These changes were implemented to help mitigate the increased risk of thromboembolic events 
observed with the class of medications which CC-220 belongs to, in subjects with lupus.
Revised Sections: Protocol Summary, Section 4.1 Study Design, Section 4.2.5 Concomitant 
Medications, Section 4.2.7 Safety, Section 9.1 Permitted Concomitant Medications and 
Procedures, Section 9.3 Required Concomitant Medications and Procedures
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
3
CC-220-SLE-001 Final: 17 Mar 2017
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
Removal of Part 2
Based on Amendment 5, Part 2 of the CC-220-SLE-001 protocol will not be conducted. All 
references to Part 2 of the study in this protocol are no longer applicable, so they have been 
removed. 
Rather than conduct Part 2, the decision was made by the Sponsor to conduct this part of the 
study under a separate “stand-alone” Phase 2B protocol. The decision to create a separate 
protocol was made due to modifications in the targeted study population, the sample size, and the 
CC-220 doses being tested. A separate protocol will allow for greater operational efficiency as 
the study is expanded to new countries/sites and provide greater clarity to the study design. The 
decision to separate Part 2 from CC-220-SLE-001 was not based on any safety concerns.  
Revised Sections: 
!
Part 2 was pervasive throughout the protocol – nearly every section has been 
modified.  
Removal of the 0.6 mg once daily (QD) dose from the Active Treatment Extension Phase 
(ATEP)
Data from the now completed Part 1 of CC-220-SLE-001 has revealed that there was a 
significant increase in plasma cells and a trend for increasing CD4 and CD8 T cells in subjects 
receiving the 0.6 mg QD dose. Additionally, Grade 3 neutropenia and dermatitis were observed 
with the 0.6 mg QD dose. Based upon this information it was decided that this is not a dose the
Sponsor will pursue in the exploration of CC-220 in systemic lupus erythematosus (SLE). As a 
result, any subject enrolled in the ATEP on the 0.6 mg QD dose will be dose reduced to the 0.6 
mg/0.3 mg on alternating days dose upon the implementation of this amendment. Subjects in the 
ATEP taking 0.3 mg QD and 0.6/0.3 mg QD on alternating days should continue their 
investigational product (IP), as these doses were shown to reduce key SLE cytokines with a less 
pronounced side effect profile. It should be noted that this mandatory reduction in dose does not
count as the dose reduction afforded to each subject one time during the ATEP.
Revised Sections: 
!
Protocol Summary
!
Section 4.1, Study Design
!
Section 4.2.3, Dose and Dose Interval
!
Section 8.2.1, Dose Modification or Interruption
!
Section 12.1, Subject Stopping Rules
Addition of an Early Termination Visit to the ATEP 
Amendment 4 of the protocol failed to include an Early Termination Visit for the ATEP portion 
of the protocol. As it is important to capture key efficacy and safety measures for subjects who 
stop the ATEP early, a mechanism to capture these data was added. This amendment has added 
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
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4
CC-220-SLE-001 Final: 17 Mar 2017
an Early Termination Visit to the ATEP to provide sites with a specific set of assessments that 
will be captured for all subjects who do not complete the ATEP.
Revised Sections: 
!
Protocol Summary
!
Section 4.1, Study Design
!
Section 5, Table of Events, Table 2
Clarification of adverse event (AE) collection duration following cessation of IP for the 
ATEP
Amendment 4 of the protocol specified that AEs should be recorded for 84 days following 
cessation of study drug. This was appropriate for Part 1 of the study given the 84-day 
Observational Follow-up Phase. However, the ATEP only has a 28-day Observational Follow-up 
Phase so the protocol was updated to specify that AEs should only be recorded up to 28 days 
following cessation of study drug for those subjects in the ATEP.
Revised Sections: 
!
Section 11.1, Monitoring, Recording and Reporting of Adverse Events
!
Section 11.5, Reporting of Serious Adverse Events
PRN (as needed) and stable use of non-steroidal anti-inflammatory drugs (NSAIDs)
Up through Amendment 4 of the protocol, only PRN use of NSAIDs was addressed. During the 
ATEP, many sites have sought clarification of how to treat PRN versus stable use of NSAIDs –
specifically with regard to whether both groups of these NSAID users should stop NSAID 
treatment 12 hours prior to study visits. In order to clarify that subjects on a stable dose of 
NSAIDs or NSAIDs PRN must stop their medication 12 hours prior to a study visit, the protocol 
was modified to indicate that any NSAID use requires cessation 12 hours prior to a study visit.  
Revised Sections: 
!
Protocol Summary
!
Section 4.1, Study Design
!
Section 4.2.5, Concomitant Medications
!
Section 9.1, Permitted Concomitant Medications and Procedures 
Updated CC-220 study information
Additional CC-220 information obtained since the last protocol amendment was added to 
provide the most current information for ongoing and completed studies using CC-220.
Revised Sections: 
!
Section 1, Introduction
Clarification of ATEP enrollment closure
Protocol Amendment 4 imposed no time restriction between when a subject completed Part 1 
and when they entered into the ATEP. For the current amendment, language was inserted to 
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!


EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
5
CC-220-SLE-001 Final: 17 Mar 2017
clarify that no additional subjects would be permitted to enter the ATEP upon implementation of 
Protocol Amendment 5.
Revised Sections:
!
Protocol Summary
!
Section 4.1, Study Design
 
 
Clarification of permitted concomitant medications
Many of the study sites queried the medical monitor about use of topical steroids and 
ophthalmologic cyclosporine during the ATEP. As a result, clarification language was added to 
specify what was permitted and what was excluded during treatment in the ATEP.
Revised Sections:
!
Section 7.2.2, Inclusion Criteria, Active Treatment Extension Phase
!
Section 7.3.1, Exclusion Criteria, Part 1 and Active Treatment Extension Phase
!
Section 9.1, Permitted Concomitant Medications and Procedures
Clarification of overdose language
Based upon discussions during the development of the subsequent CC-220 SLE protocol, the 
overdose language was modified to be consistent across CC-220 studies.
Revised Sections:
!
Section 8.2.2, Overdose
Duration of birth control after cessation of study drug in male subjects
Based upon recommendation from nonclinical colleagues, modification of the duration male 
subjects must agree to abstinence or condom use following cessation of study drug was extended 
to 90 days.
Revised Sections:
!
Sections 7.2.1 and 7.2.2, Inclusion Criteria
Pregnancy testing for females of child bearing potential (FCBPs) with irregular or no 
menses during the ATEP
Language was modified to clarify that FCBPs with irregular or no menses during the ATEP 
should have pregnancy testing every 14 days while on study, at treatment discontinuation and at 
14 and 28 days following treatment discontinuation.
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EDMS Doc. Number:
CC-220
Protocol CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
6
CC-220-SLE-001 Final: 17 Mar 2017
Revised Sections:
!
Sections 7.2.1 and 7.2.2, Inclusion Criteria
Clarification of birth control language following cessation of study drug
Based upon recommendation from nonclinical colleagues, modification of the duration male 
subjects must agree to abstinence or condom use following cessation of study drug was extended 
to 90 days.
Revised Sections:
!
Sections 7.2.1 and 7.2.2, Inclusion Criteria
Removal of Pharmacogenetic Assessments
As pharmacogenetic assessment was only included in the Part 2 of the original CC-220-SLE-001 
protocol, no pharmacogenetics analyses will be conducted in this protocol.
Revised Sections: 
!
Part 2 was pervasive throughout the protocol – every section which mentioned the 
pharmacogenetic component of the study has been removed.  
Minor changes have been made throughout the document for clarity and consistency.
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EDMS Doc. Number:
CC-220
Summary of Changes CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
3
CC-220-SLE-001 Amendment 4 Final: 05 Jan 2016
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
A new medical monitor was put onto the study so the medical monitor information was 
updated.
Revised section: MEDICAL MONITOR/EMERGENCY CONTACT INFORMATION
!
The primary reason for amending the protocol was to add an active treatment extension 
phase (ATEP) to allow subjects who were deriving benefit from CC-220 in either Part 1 
or Part 2 of the core study to continue to receive treatment for up to an additional 2 years. 
The following changes have been made to make accommodations for this added study 
phase:
o
The addition of the ATEP to the study required that additional objectives were 
specified for the newly added study phase
Revised sections: PROTOCOL SUMMARY: Objectives 
o
The Study Design Section of the PROTOCOL SUMMARY was amended to 
define the new ATEP and detail how it will interact with the currently ongoing 
core study (Part 1 and Part 2).

The study now features 3 parts (Part 1, Part 2 and ATEP) instead of 2 parts

For subjects completing Part 1 or Part 2 of the study who elect to enter the
ATEP, the Observation Follow-Up Phase will be delayed until the 
conclusion of their involvement with the ATEP.

A detailed description of the ATEP and the logistics of how subjects 
completing Part 1 or Part 2 of the core study can enter the ATEP were 
added to the PROTOCOL SUMMARY.

An expanded list of concomitant medications will be permitted for 
subjects participating in the ATEP. This added flexibility with 
concomitant medication was added to accommodate for potential changes 
in treatment during the extended two-year period of study involvement.   

An explanation of the rules for dose reduction and/or interruption for 
subjects in the ATEP was added. 
Revised sections: PROTOCOL SUMMARY: Study Design
o
The Study Population Section of the PROTOCOL SUMMARY was modified to 
define the population for the newly added ATEP.
Revised sections: PROTOCOL SUMMARY: Study Population
o
The Length of Study Section of the PROTOCOL SUMMARY was modified to 
incorporate the ATEP duration.
Revised sections: PROTOCOL SUMMARY: Length of Study
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EDMS Doc. Number:
CC-220
Summary of Changes CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-SLE-001 Amendment 4 Final: 05 Jan 2016
o
The Study Treatments Section of the PROTOCOL SUMMARY was modified to 
include the dosing paradigm for the ATEP. It details how there will be no placebo 
or 0.3 mg every other day (QOD) dosing in the ATEP.
Revised sections: PROTOCOL SUMMARY: Study Treatments
o
Additional vaccine titer monitoring was added to the protocol to assess for the 
potential attenuation of vaccine effectiveness due to CC-220. In addition, to 
tetanus, both pneumococcal and influenza titers were added.  
Revised sections: PROTOCOL SUMMARY: Overview of Safety Assessments
o
Analysis of amylase was added to the safety assessments in order to enhance 
(lipase already being measured for pancreatic function) monitoring for any 
changes in pancreatic function of the subjects on CC-220.
Revised sections: PROTOCOL SUMMARY: Overview of Safety Assessments
o
Language added to specify that ATEP will not include any pharmacokinetics 
(PK), pharmacogenetics (PG) or pharmacodynamics (PD) analyses.
Revised sections: PROTOCOL SUMMARY: Overview of Pharmacokinetic, 
Pharmacogenetic, and Pharmacodynamic Assessments
o
 
 
 
 
  
Revised sections: PROTOCOL SUMMARY:
o
Additional information regarding animal data not available at the time of the last 
amendment was added to the Introduction Section of the protocol.
Revised sections: Section 1 Introduction 
o
 
Revised sections: Section 2.3 ATEP
o
The addition of the ATEP to the study required that additional endpoints were 
specified for the newly added study phase.
Revised sections: Section 3.3 ATEP
o
Modifications to the study design and study population section of the protocol 
(Section 4) mirror those made to the PROTOCOL SUMMARY study design and 
study population section detailed above. 
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EDMS Doc. Number:
CC-220
Summary of Changes CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
5
CC-220-SLE-001 Amendment 4 Final: 05 Jan 2016
Revised sections: Section 4.1 Study Design and Section 4.2 Study Design 
Rationale
o
Modifications to the duration of treatment section of the protocol were made to 
add the ATEP. 
Revised sections: 4.2.1 Duration of Treatment
o
Language stating that the ATEP would not be blinded was added.
Revised sections: 4.2.4 Blinding
o
Additional concomitant medications will be permitted for subjects enrolled into 
the ATEP (as described in the PROTOCOL SUMMARY changes detailed 
above). In addition, the recommendation of anti-platelet or anti-coagulation use 
was expanded beyond just those subjects with a history of thromboembolic events 
to all subjects. This modification was implemented based upon the 
recommendation by the safety review team responsible for monitoring the safety 
of CC-220 in this trial.
Revised sections: Section 4.2.5 Concomitant Medications
o
Additional titers for monitoring of attenuation of vaccines while on CC-220 and 
amylase for the monitoring of pancreatic function (as indicated above in the 
PROTOCOL SUMMARY) were added to Safety Section of the protocol.
Revised sections: Section 4.2.7 Safety
o
The original study schematic was modified to include the newly added ATEP.
Revised sections: Figure 1 Overall Study Design
o
The study duration was modified based upon the newly added ATEP (same as 
described above in the PROTOCOL SUMMARY and Section 4.2.1 Duration of 
Treatment).
Revised sections: Section 4.3 Study Duration
o
Additional footnotes were added to the Schedule of Assessments for Part 1 and 
Part 2 of the study detailing study drug dispensation and logistics surrounding 
who and when subjects will enter the Observational Follow-Up Phase depending 
on their participation in the ATEP.
Revised sections: Table 1: Part 1 and Table 2: Part 2
o
A Schedule of Assessments Table was added to detail the visit structure, 
assessments, and assessment schedule for the newly added ATEP.
Revised sections: Table 3: ATEP
o
The Study Entry section was updated with inclusion of an Informed Consent 
Document (ICD) for the ATEP. The safety assessments section was modified to 
include a measure of weight and waist circumference during all complete physical 
assessments to monitor for obesity in the study subjects in the ATEP. Information 
on  additional vaccine titers, amylase testing and frequency of hormone testing in 
the ATEP was also added to this section. The rationale for additional titers and 
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EDMS Doc. Number:
CC-220
Summary of Changes CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
6
CC-220-SLE-001 Amendment 4 Final: 05 Jan 2016
amylase testing have been explained above. The information specifying the 
frequency of hormone testing was added as this monitoring will be at different 
intervals during the ATEP versus Part 1 or Part 2 of the study.  
Revised sections: Section 6: Procedures: Study Entry and Safety Assessments
o
The BILAG 2004 assessment was added to the battery of efficacy assessments 
planned for the subjects participating in the ATEP. As stated above, this 
instrument was added to provide us with additional information on how CC-220 is 
impacting the lupus population. 
Revised sections: Section 6: Procedures: Efficacy Assessments
o
 
 
 
 
 
  
o
The study population section was modified to incorporate the newly added ATEP.
Revised sections: Section 7.1: Number of Subjects and Sites
o
Instructions with regard to inclusion criteria for subjects entering the ATEP was 
added. In addition, clarification regarding use of the SELENA Systemic Lupus 
Erythematosus Disease Activity Index (SLEDAI) for inclusion was added. Sites 
will be permitted to use non-lab components of the SELENA SLEDAI to qualify 
patients for enrollment in the event that the laboratory results associated with the 
SELENA SLEDAI have not been received. 
Revised sections: Section 7.2 Inclusion Criteria, 7.2.3: ATEP
o
Instructions with regard to exclusion criteria for subjects entering the ATEP were 
added. In addition, the exclusion criterion for the minimum allowable platelet 
count was lowered to allow for greater flexibility for study entry.
Revised sections: Section 7.3.1: Part 1, Part 2 and ATEP
o
Instructions with regard to dose modification or interruption for subjects 
participating in the ATEP were added.
Revised sections: Section 8.2.1: Dose Modification or Interruption
o
Information regarding additional permitted concomitant medication for subjects 
participating in the ATEP was added.
Revised sections: Section 9.1: Permitted Concomitant Medications and 
Procedures
o
Additional information was added to detail statistical analyses to be conducted for 
subjects participating the ATEP.
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EDMS Doc. Number:
CC-220
Summary of Changes CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
7
CC-220-SLE-001 Amendment 4 Final: 05 Jan 2016
Revised sections: Section 10.1: Overview, Section 10.6: Efficacy Analysis, and 
Section 10.8: Interim Analysis
&&,
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&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
CC-220
Summary of Changes CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
3
CC-220-SLE-001 Amendment 3 Final: 11 Jun 2015
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
To allow for greater enrollment flexibility, the following modifications were made to the 
protocol:
o
The entrance criterion dictating a minimum immunoglobulin M (IgM) level was 
removed from the protocol
Revised Sections: Section 6 Procedures; Section 7.3 Exclusion Criteria
o
The timeframe of systemic lupus erythematosus (SLE) diagnosis per ACR 
Revised Criteria was modified to include past as well as present fulfillment of 4 of 
the 11 criteria required
Revised Section: Section 7.2 Inclusion Criteria
o
Dose levels of antimalarials (hydroxychloroquine, chloroquine, or quinacine) 
permitted during the study were made less restrictive
Revised Sections: Protocol Summary; Section 4.1 Study Design; Section 4.2.5 
Concomitant Medications; Section 7.2 Inclusion Criteria; Section 9.1 Permitted 
Concomitant Medications and Procedures
o
Cyclophosphamide washout duration shortened by one month 
Revised Section: Section 7.3.1 Exclusion Criteria
o
The definition of unstable lupus nephritis was made less restrictive through a 
decrease in estimated glomerular filtration rate (eGFR) and removal of the 
exclusion based on proteinuria
Revised Section: Section 7.3 Exclusion Criteria
o
The time by which subjects are required to taper to 10 mg of oral corticosteroids 
or less was moved from screening to randomization
Revised Section: Section 7.2 Inclusion Criteria
o
The time required for subjects to withdraw from concomitant medications and 
procedures (from 8 weeks to 4 weeks for azathioprine and mycophenalate mofetil; 
from 12 to 6 months for rituximab or anti-CD22 therapy) was reduced by half
Revised Section: Section 7.3 Exclusion Criteria
o
IgA and IgG testing was moved from Baseline to Screening in Table 1 Part 1 and 
Table 2 Part 2 of the Table of Events.
Revised Section: Section 5 Table of Events, Table 1 and Table 2
o
The screening period was extended 2 weeks to a total of 6 weeks to allow subjects 
more flexibility for laboratory retesting in order to reduce the potential for screen 
failure
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EDMS Doc. Number:
CC-220
Summary of Changes CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
4
CC-220-SLE-001 Amendment 3 Final: 11 Jun 2015
Revised Sections: Protocol Summary; Section 4.1 Study Design; Section 4.2.1 
Duration of Treatment; Section 4.2 Study Design Rationale, Figure 1; Section 4.3 
Study Duration; Section 5 Table of Events, Table 1 and Table 2; Section 7.2 
Inclusion Criteria; Section 7.3 Exclusion Criteria
!
The site personnel permitted to conduct safety and efficacy assessments during the study 
was clarified
Revised Sections: Protocol Summary; Section 6 Procedures
!
Clarification regarding use of inhaled and topical corticosteroids was added
Revised Sections: Protocol Summary, Section 4.1 Study Design; Section 4.2.5 
Concomitant Medications; Section 9.1 Permitted Concomitant Medications and 
Procedures
!
Description of the ophthalmological exams was added to provide greater clarity
Revised Sections: Protocol Summary; Section 6 Procedures
!
Subject stopping rules and dose group stopping rules were modified to provide greater 
clarity
Revised Sections: Section 12.1 Subject Stopping Rules; Section 12.2 Dose Group 
Stopping Rules
!
 
 
 
 
 
 
Revised Sections: Protocol Summary; Section 1 Introduction; Section 4.2.7 Safety; 
Section 5 Table of Events, Table 1 and Table 2; Section 6 Procedures; Section 7.2 
Inclusion Criteria    
!
Protocol was modified to allow all electrocardiograms (ECGs) from Visit 2 onward to be 
measured ≤15 minutes apart versus the original duration of only ≤ 5 minutes
Revised Sections: Section 6 Procedures
!
Pregnancy language was revised by safety
Revised Section: 11.4 Pregnancy
!
Modifications were made to the standard language defining investigator responsibilities
Revised Section: 14.2 Investigator Responsibilities 
!
Appendix M Pregnancy Prevention Risk Management Plans was deleted
Revised Sections: Appendix M; Section 5 Table of Events, Table 1 and Table 2; Section 
7.2 Inclusion Criteria
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EDMS Doc. Number:
CC-220
Summary of Changes CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
5
CC-220-SLE-001 Amendment 3 Final: 11 Jun 2015
!
 
!
Additional language was added to Inclusion Criterion 10 for Part 1 and Inclusion 
Criterion 13 for Part 2. The additional language specifies that pregnancy counseling will 
be administered as described in the Pregnancy Prevention Plan.
Revised Section: Section 7.2.1 Part 1, Section 7.2.2 Part 2  
!
Under laboratories which require repeated testing with 7 days, the percentage of 
eosinophilia was modified to be > 7%. This was done to reduce the amount of 
unnecessary alerts based on potential seasonal and/or perennial allergies.
Revised section: Section 12.1 Subject Stopping Rules
&&,
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EDMS Doc. Number:
CC-220
Summary of Changes CC-220-SLE-001 
Celgene Corporation
Confidential and Proprietary
3
Amendment #2: 19 Sep 2014
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
A minimum Hybrid SELENA SLEDAI score was added to the inclusion criteria for 
both Part 1 and Part 2 to ensure that subjects coming into the study have a minimum 
level of active disease.
!
The requirement to discontinue subjects based upon an increase in the Hybrid 
SELENA SLEDAI score was removed, as it has been determined that such a 
restrictive requirement will result in a disproportionate number of subject 
discontinuations. 
&&,
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EDMS Doc. Number:
CC-220
Summary of Changes CC-220-SLE-001
Celgene Corporation
Confidential and Proprietary
3
Amendment # 1: 24 Jul 2014
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Antineutrophil cytoplasmic antibodies (ANCA), cell bound complement activated 
products (CB-CAPs) and B2 Glycoprotein 1 IgG/IgM laboratory assessments have been 
removed from the protocol in order to streamline laboratory assessments in the study.
!
The SLICC/ACR SLE Damage Index was added to the protocol to explore the impact 
CC-220 has on the mitigation of damage to various organ systems resulting from SLE.
!
Hepatitis B viral DNA by PCR testing has been removed as specific antibody results 
(indicating chronic versus acute infection) will not be required for this study. 
!
A more comprehensive description of the PG portion of the protocol was added to the 
protocol in order to clarify the intent of this substudy.
!
To allow for greater enrollment flexibility, up to 2 rescreens instead of a single rescreen 
will now be permitted per protocol.
!
Editorial changes have also been made to sections throughout the protocol to enhance 
clarity.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PILOT, PHASE 2, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, 
STUDY TO EVALUATE EFFICACY, SAFETY, TOLERABILITY, PHARMACOKINETICS, 
PHARMACODYNAMICS AND PHARMACOGENETICS OF CC-220 IN SUBJECTS WITH 
SYSTEMIC LUPUS ERYTHEMATOSUS
STUDY DRUG:
CC-220
PROTOCOL NUMBER:
CC-220-SLE-001 – Part 1
DATE FINAL:
25Jul2016
Prepared by:
On behalf of
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
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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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ............................................................................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................8
2.
INTRODUCTION..................................................................................................11
3.
STUDY OBJECTIVES...........................................................................................12
3.1.
Primary Objective...................................................................................................12
3.2.
Secondary Objectives .............................................................................................12
4.
INVESTIGATIONAL PLAN .................................................................................13
4.1.
Overall Study Design and Plan ...............................................................................13
4.2.
Study Endpoints .....................................................................................................14
4.2.1.
Primary Endpoint....................................................................................................15
4.2.2.
Secondary Endpoints ..............................................................................................16
4.3.
Stratification, Randomization, and Blinding............................................................20
4.4.
Sample Size Determination.....................................................................................21
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................22
5.1.
Reporting Conventions ...........................................................................................22
5.2.
Baseline Definition.................................................................................................22
5.3.
Time Points ............................................................................................................22
5.4.
Analysis Populations ..............................................................................................23
5.4.1.
Intent-to-Treat Analysis Set ....................................................................................23
5.4.2.
Per Protocol Analysis Set........................................................................................23
5.4.3.
Safety Population....................................................................................................23
5.4.5.
Pharmacokinetic Population....................................................................................24
6.
SUBJECT DISPOSITION......................................................................................25
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................26
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................27
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
3
8.1.
Demographics.........................................................................................................27
8.2.
Baseline Characteristics..........................................................................................27
8.3.
Medical History......................................................................................................28
8.4.
Prior and Concomitant Medications........................................................................28
8.4.1.
Prior Medications ...................................................................................................28
8.4.2.
Concomitant Medications .......................................................................................28
8.5.
Prior and Concomitant Procedures..........................................................................28
8.5.1.
Prior Procedures .....................................................................................................28
8.5.2.
Concomitant Procedures.........................................................................................29
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................30
9.1.
Treatment Duration.................................................................................................30
9.2.
Treatment Compliance............................................................................................30
11.
SAFETY ANALYSIS ............................................................................................32
11.1.
Adverse Events.......................................................................................................32
11.1.1.
All Treatment-emergent Adverse Events.................................................................33
11.1.2.
Drug-related Treatment-emergent Adverse Events..................................................33
11.1.3.
Treatment-emergent Adverse Events by Maximum Severity...................................33
11.1.4.
Serious Treatment-emergent Adverse Events..........................................................33
11.1.5.
Treatment-emergent Adverse Events Leading to Drug Interruption and 
Leading to Drug Withdrawal ..................................................................................34
11.1.6.
Treatment-emergent Adverse Events Leading to Deaths .........................................34
11.2.
Clinical Laboratory Evaluations..............................................................................34
11.3.
Vital Sign Measurements........................................................................................35
11.4.
Electrocardiograms.................................................................................................35
11.5.
Ophthalmological Examination...............................................................................35
11.6.
Physical Examination .............................................................................................35
11.7.
Tetanus Toxoid.......................................................................................................35
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
4
13.
PHARMACOKINETIC ANALYSIS......................................................................37
15.
INTERIM ANALYSIS...........................................................................................39
16.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................40
17.
REFERENCES.......................................................................................................41
18.
APPENDICES........................................................................................................42
18.1.
Handling of Dates...................................................................................................42
18.1.1.
Calculations Using Dates........................................................................................42
18.2.
Date Imputation Guideline......................................................................................43
18.2.1.
Adverse Events.......................................................................................................43
18.2.2.
Prior/Concomitant Medications/Procedures ............................................................44
18.2.3.
Medical History......................................................................................................45
18.3.
Marked Abnormalities Criteria ...............................................................................45
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................8
Table 2:
Plasma Pharmacokinetic Parameters.......................................................................17
Table 3:
Imputation Rules for Partially Missing Adverse Event Start Date ...........................44
Table 4:
Imputation Rules for Partially Missing Prior/Concomitant 
Medication/Procedure Start Dates...........................................................................44
Table 5:
Imputation Rules for Partially Missing Prior/Concomitant Medication Stop 
Dates ......................................................................................................................45
Table 6:
Imputation Rules for Partially Missing Medical History Start Dates........................45
Table 7:
Laboratory Marked Abnormality Criteria................................................................45
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
8
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation
Description
ACR
American College of Rheumatology
ADaM
Analysis Dataset Model
AE
Adverse event
ALT
Alanine aminotransferase/ serum glutamic-pyruvic transaminase (SGPT)
AST
Aspartate aminotransferase/ serum glutamic-oxaloacetic transaminase (SGOT)
ATC
Anatomical Therapeutical Chemical
BMI
Body mass index
BQL
Below the quantifiable limit
CI
Confidence interval
CLASI
Cutaneous Lupus Area and Severity Index
CRP
C-reactive protein
CV
Coefficient of variation
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
ESR
Erythrocyte sedimentation rate
GeoCV
Geometric coefficient of variation
Hgb
Hemoglobin
hs-CRP
High sensitivity C-reactive protein
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IP
Investigational product
IM
Intramuscular
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
9
Abbreviation
Description
ITT
Intent-to-treat
IV
Intravenous
IVRS
Interactive voice response system
IWRS
Interactive web response system
LDH
Lactate dehydrogenase
LS
Least-squares
MDRD
Modification of Diet in Renal Disease formula
MedDRA
Medical Dictionary for Regulatory Activities
NSAID
Nonsteroidal anti-inflammatory drug
PD
Pharmacodynamic
PGA
Physician’s global assessment
PK
Pharmacokinetic
PP
Per protocol
PRN
As needed
PT
Preferred term
QD
Once daily
QOD
Once every other day
RBC
Red blood cells
SAP
Statistical analysis plan
SD
Standard deviation
SE
Standard error 
SLE
Systemic lupus erythematosus
SLEDAI
Systemic lupus erythematosus Disease Activity Index
SLICC
Systemic Lupus International Collaborating Clinics
SOC
System organ class
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
US
United States
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
10
Abbreviation
Description
VA
Visual acuity
WBC
White blood cells
WHODD
World Health Organization Drug Dictionary
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
11
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-220-SLE-001 “A Pilot, Phase 2, Randomized, Placebo-Controlled, Double-Blind 
Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and 
Pharmacogenetics of CC-220 in Subjects with Systemic Lupus Erythematosus (SLE).” This SAP 
pertains to Part 1 of the study design only. Analysis of Part 2 of the study design will be 
presented in a separate document. This SAP contains definitions of analysis populations, derived 
variables, and statistical methods for the analysis of efficacy, safety, pharmacokinetic (PK), and 
pharmacodynamic (PD) parameters.
The analyses in this SAP include:
1. Safety and efficacy analyses based on a database cut after eight subjects from each dose 
group have completed 28 days of treatment or have discontinued early (referred to as the 
Day 28 database hereafter); 
2.
 safety, PK, 
analyses based on a database cut after all subjects have 
completed Day 85/Visit 10 with 12 weeks of observational follow-up or have 
discontinued early (referred to as the Day 169 database hereafter). 
This SAP provides a more technical and detailed elaboration of the statistical analyses, as 
outlined and/or specified in the CC-220-SLE-001 study protocol dated 05Jan2016. The SAP will 
be finalized and approved prior to the unblinding of the final Part 1 database. All statistical 
analyses detailed in this SAP will be conducted using SAS® Version 9.2 or higher.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
12
3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective is for Part 1 study
!
To evaluate the safety and tolerability of CC-220 for subjects with SLE
3.2.
Secondary Objectives
The secondary objective of the study is for Part 1 study
!
To describe the PK of CC-220 for subjects with SLE
 
 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
13
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a pilot, Phase 2, randomized, placebo-controlled, double-blind, multicenter study to 
evaluate the preliminary efficacy, safety, tolerability, pharmacokinetics, pharmacodynamics 
and pharmacogenetics of CC-220 in SLE subjects with skin involvement.
This study will be conducted in three parts, below is the study design for part 1.
Part 1 is a randomized, double-blind, placebo-controlled, ascending dose study to evaluate 
the safety and tolerability of CC-220 in SLE subjects.
Subject participation in Part 1 will consist of 3 phases:
!
Pre-treatment Screening Phase: up to 42 days prior to the first dose of 
the investigational product (IP)
!   Treatment Phase: up to 84 days
!
Observational Follow-up Phase: 84 day post-treatment (subjects who consent
and qualify for the Active Treatment Extension Phase [ATEP] will NOT enter 
the Observational Follow-up Phase and will directly enter the ATEP)
A total of approximately 40 subjects will be randomized into 4 dose groups with a 4:1 ratio of 
CC-220 (0.3 mg every other day [QOD], 0.3 mg everyday [QD], 0.6 mg and 0.3 mg on 
alternating days and 0.6 mg QD) or matching placebo (8 subjects in the CC-220 arm and 2 
subjects in the placebo arm for each dose group) using an Interactive Voice Response System 
(IVRS). Subjects will be randomized into the first two dose groups of 0.3 mg QOD and 0.3
mg QD in parallel. Following confirmation of safety of the first two dose groups, remaining 
subjects will then be randomized into the 0.6 mg and 0.3 mg on alternating days and 0.6 mg
QD dose groups in a sequential, dose-ascending manner (first the 0.6 mg and 0.3 mg on 
alternating days dose group followed by the 0.6 mg QD dose group). The Treatment Phase 
will be up to 84 days in duration for all dose groups. Subjects who discontinue IP early and all 
subjects who complete the 84-day Treatment Phase (who do not consent to enroll into the
ATEP) will enter into the Observational Follow-up Phase for an 84-day period. In all cases of
early termination from the study, subjects will be encouraged to complete an Early 
Termination Visit. See protocol Figure 1 for graphical representation of the Part 1 dosing 
administration schedule.
All subjects will be allowed to remain on stable doses of hydroxychloroquine, chloroquine, 
and/or quinacrine for ≥ 4 weeks prior to their baseline visit and throughout the study. No 
additional systemic immunosuppressives will be permitted. In addition, as needed (PRN) 
treatment with systemic anti-pruritics and/or systemic analgesics will be permitted; subjects
must stop using all systemic anti-pruritics 48 hours prior to all study visits and systemic 
analgesics 12 hours prior to all study visits. Oral non-steroidal anti-inflammatory drugs
(NSAIDs) may be used PRN, but must be stopped 12 hours prior to all study visits. Use of oral
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
14
corticosteroids will be permitted only at doses of 10 mg or less per day and must be maintained 
at a stable dose during study participation. Inhaled corticosteroids for use in a disease other 
than lupus, eg, asthma, will be allowed. No IV (intravenous) or IM (intramuscular)
corticosteroids will be permitted during the study. No other topical (with the exception of
potency class 6 and 7 topicals only), local or systemic treatments for dermatological 
manifestations of SLE will be permitted.
Following completion of the first 28 days of the treatment phase by at least 8 subjects in Dose 
Group 1 (0.3 mg QOD) and 8 subjects in Dose Group 2 (0.3 QD), an assessment of safety
and tolerability will be conducted. If Dose Groups 1 and 2 are deemed to have acceptable 
safety and tolerability, subjects will continue to receive investigational product for up to 84 
days and enrollment of subjects into Dose Group 3 (0.6 mg and 0.3 mg on alternating days) 
will be initiated. Following completion of the first 28 days of the treatment phase by at least 8 
subjects in Dose Group 3 (0.6 mg and 0.3 mg on alternating days), an assessment of safety
and tolerability will be conducted. If Dose Group 3 is deemed to have acceptable safety and 
tolerability, subjects will continue to receive investigational product for up to 84 days and
enrollment of subjects into Dose Group 4 (0.6 mg QD) will be initiated. Following completion
of the first 28 days of the treatment phase by at least 8 subjects in Dose Group 4 (0.6 mg QD), 
an assessment of safety and tolerability will be conducted. If Dose Group 4 is deemed to have 
acceptable safety and tolerability, subjects will continue to receive investigational product for 
up to 84 days.
Subjects will remain on their assigned treatment for up to 84 days. In the event a subject 
experiences clinically significant IP-related adverse events (AEs), a dose interruption for up 
to 14 days will be permitted (see protocol Section 12.1). If a subject is unable to remain on 
their assigned dose, he/she may reduce their dose to the next lowest dosing regimen. Dose 
reductions will occur as follows:
!   Subjects on 0.6 mg QD will reduce their dose to 0.6 mg/0.3 mg on alternating days
!   Subjects on 0.6 mg/0.3 mg on alternating days will reduce their dose to 0.3 mg QD
!   Subjects on 0.3 mg QD will reduce their dose to 0.3 mg QOD
!   Subjects on 0.3 mg QOD will reduce their dose to placebo
A subject will only be permitted to reduce their dose one time during the study. The decision
to modify IP dosing will be based on the rules provided in protocol Section 12.1. The 
sponsor should be notified of the intent to dose reduce prior to a change in dosing.
Subjects who discontinue from the study prior to completing 28 days of treatment may 
be replaced (for up to a total of 10 subjects for Part 1) at the discretion of the sponsor.
Subjects who participate in Part 1 of the study will not be permitted to participate in Part 2 of 
the study.
4.2.
Study Endpoints
Safety, 
PK,
endpoints are listed in Sections 4.2.1 through 4.2.3.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
15
4.2.1.
Primary Endpoint
The primary endpoints will assess safety and tolerability.
The following safety parameters will be evaluated throughout the duration of the study:
!
Adverse events
∀
Type, frequency, severity and relationship of AEs to IP
∀
Number of subjects who discontinue IP due to any AE
!
Laboratory evaluations for hematology, serum chemistry, and urinalysis will be 
collected. 
∀
Laboratory parameters for hematology will include: red blood cells (RBC), 
hemoglobin (HgB), hematocrit, white blood cells (WBC) and differential 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils [percent and 
absolute]), and platelet count.
∀
Laboratory parameters for serum chemistry will include: total protein, albumin, 
calcium, phosphorus, glucose, uric acid, total bilirubin, alkaline phosphatase, 
aspartate aminotransferase (AST; serum glutamic-oxaloacetic transaminase 
[SGOT]), alanine aminotransferase (ALT; serum glutamic pyruvic transaminase 
[SGPT]), lipase, sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, lactate dehydrogenase (LDH), and magnesium. Additionally, The 
central lab will calculate and report the estimated glomerular filtration rate 
(eGFR) in mL/min using the Modification of Diet in Renal Disease formula 
(MDRD eGFR).
∀
Laboratory parameters for urinalysis dipstick include: microscopic and 
quantitative protein.
∀
Laboratory parameters for micronutrients include: apolipoproteins, total 
cholesterol, and lipid-soluble vitamins A,D,E,K) 
∀
Laboratory parameters for inflammation panel include: high sensitivity C-reactive 
protein (hs-CRP), erythrocyte sedimentation rate (ESR), fibrinogen, and serum 
amyloid A.
∀
Laboratory parameters for assessment of immunoglobulins include:
immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A 
(IgA).
∀
Laboratory parameters for assessment of blood clotting include: prothrombin 
time, internationalized normalized ratio, and partial thromboplastin time.
!
Laboratory endpoints include:
∀
Number and percentage of subjects with marked abnormalities (see Section 18.3)
∀
Observed value and change from Baseline over time 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
16
∀
Shift from Baseline to postbaseline time points and to the worst postbaseline 
value in terms of normal/abnormal (low or high) in hematology and serum 
chemistry laboratory parameters
!
Vital signs and weight endpoints include:
∀
Change from Baseline over time in vital sign parameters (temperature, pulse, 
weight and seated blood pressure) 
∀
Shift from Baseline to postbaseline time-points and to worst postbaseline value in 
terms of normal/abnormal (see Section 11.3) in blood pressure and pulse
!
Electrocardiogram (ECG, 12-lead) recordings will be obtained throughout the study 
and assessed by a central (cardiologist) reader. The cardiologist will interpret all 
ECGs with relevance to PR interval, QRS duration, heart rate and R-R interval, QT 
and QTc. The ECG endpoints include:
∀
Change from Baseline over time in ECG parameters 
∀
Number and percentage of subjects with clinically significant electrocardiogram 
findings
∀
Shift from Baseline to postbaseline time points and to worst postbaseline value in 
terms of normal/abnormal in ECG findings
!
Physical examination will include skin, nasal cavities, eyes, ears, respiratory, 
cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal system 
evaluations. Results of the physical examinations will be recorded only in the source 
documents, however clinically significant changes in physical examination findings
will be captured as AEs.
!
Ophthalmological examinations will include visual acuity (VA) and slit lamp exams 
with fluorescein staining following papillary dilation. Ophthalmological endpoints 
include:
∀
Number and percentage of subjects with clinically significant ophthalmological 
findings
!
Change from Baseline in tetanus toxoid titer at Day 85/Early Termination and 
Day 113
4.2.2.
Secondary Endpoints
The secondary endpoints will assess the PK of CC-220 in plasma. 
 
4.2.2.1.
Pharmacokinetic Parameters
The plasma concentration-time data will be used to determine the PK parameters at Day 1 and 
Day 29. Standard noncompartmental analysis methods (Phoenix WinNonLin 6.3) will be utilized 
to obtain the PK parameters presented in Table 2.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
17
Table 2:
Plasma Pharmacokinetic Parameters
Parameter
Description
AUCt
Area under the plasma-concentration time curve from time zero to the last 
measurable concentration
AUCτ
Area under the plasma-concentration time curve over one dosing interval from 
time zero to τ
AUCinf
Area under the plasma-concentration time curve from time zero to infinity
Cmax
Peak plasma concentration
Ctrough
Trough plasma concentration
tmax
Time to reach peak plasma concentration
t1/2
Half-life
CL/F
Apparent oral clearance
Vz/F
Apparent volume of distribution
 
 
 
 
 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
18
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Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
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Confidential and Proprietary
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
20
 
 
 
 
 
4.3.
Stratification, Randomization, and Blinding
Approximately 40 subjects will be randomized into 4 dose groups with a 4:1 ratio of CC-220 
(0.3 mg QOD, 0.3 mg QD, 0.6 mg and 0.3 mg on alternating days and 0.6 mg QD) or matching 
placebo (8 subjects in the CC-220 arm and 2 subjects in the placebo arm for each dose group). 
Subjects will be randomized into the first two dose groups of 0.3 mg QOD and 0.3 mg QD in 
parallel. Following confirmation of safety of the first two dose groups, remaining subjects will 
then be randomized into the 0.6 mg and 0.3 mg on alternating days and 0.6 mg QD dose groups 
in a sequential, dose-ascending manner (first the 0.6 mg and 0.3 mg alternating QD dose group 
followed by the 0.6 mg QD dose group). 
Randomization Scheme;
Dose group 1 and Dose group 2:
1. Dose groups 1 and 2 will be enrolled at the same time. The subjects are randomized into 
either Dose group 1 or Dose group 2, stratified by Intensive PK or Non-Intensive PK. When the 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
21
number of Non-Intensive PK subjects reaches approximately 8 per dose group, only Intensive 
PK subjects will be enrolled.
2. Then, the subjects will be randomized to CC-220 or placebo with a 4:1 ratio.
Dose group 3 and Dose group 4:
1. After the interim analysis of Dose group 1 and Dose group 2, Dose group 3 will be enrolled. 
The subjects will be randomized to CC-220 or placebo with a 4:1 ratio. If the number of 
Non-Intensive PK subjects reaches approximately 8, only Intensive PK subjects will be enrolled. 
After the interim analysis of Dose group 3, Dose group 4 will be randomized in the same manner 
as Dose group 3.
Treatment assignments will be blinded throughout the study. After all Part 1 subjects have 
completed Day 85/Visit 10 with 12 weeks of observational follow-up or have discontinued early, 
and the database has been locked, treatment will be unblinded.
All randomization schedules will be generated and implemented by an external vendor of the 
study IVRS/IWRS.
Following completion of the first 28 days of the Treatment Phase by 8 subjects from each dose 
group, assessments of safety and tolerability will be conducted. Tables, listings, and graphs for 
disposition, exposure, demographics, efficacy measures, TEAEs, laboratory values, and vital 
signs will be summarized. The treatment will be kept blinded and tabulations will be presented as 
a single aggregate group. The first interim analysis will occur with Dose groups 1 and 2 
combined since these two dose groups are enrolled simultaneously.
Additional interim analyses, if applicable, (see Section 15) may be performed by an independent 
team who is not involved in the conduct and data management of the study.
4.4.
Sample Size Determination
The sample size was based on prior clinical experience and no formal sample size or power 
calculation was performed.
For Part 1, a total of approximately 40 subjects will be randomized to 4 dose groups with a 4:1 
ratio of CC-220 (0.3 mg QOD, 0.3 mg QD, 0.6/0.3 mg alternating QD, 0.6 mg QD) or matching 
placebo (8 subjects in the CC-220 arm and 2 subjects in the placebo arm for each dose group) 
using an IVRS.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
22
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
Summary statistics for continuous variables include sample size (n), mean, standard deviation 
(SD), median, minimum, and maximum. All mean and median values will be formatted to one 
more decimal place than the measured value. Standard deviation values will be formatted to two 
more decimal places than the measured value. Minimum and maximum values will be presented 
to the same number of decimal places as the measured value. The frequency summary for 
categorical variables includes number and percentage. All percentages will be rounded to one 
decimal place. Number and percentage values will be presented as xx (xx.x). All analysis and 
summary tables will have the population sample size for each treatment group in the column 
heading. Any p-values (2-sided) will be presented with four decimal places. All laboratory data 
will be reported using standard international units.
In data derivations requiring the date of the first dose of IP dispensed at a specific visit, in the 
absence of a definitive record of this date, the study drug dispense date (from the study drug 
accountability records) associated with that visit, or if this date is also missing, then the visit 
date, will be used to estimate the date of the first dose of IP in question. In the absence of a 
definitive record of the date of the last dose of IP for subjects who have completed the study or 
have discontinued early, the date of the Day 85/Visit 10 visit or the discontinuation visit will be 
used to estimate the last dose date for subjects who have completed the study or have 
discontinued early and have the discontinuation visit; for subjects who have discontinued but do 
not have the discontinuation visit, the last “follow-up” date (ie, the maximum date among the 
subject’s records of study visits, study drug records, AEs [start and end dates], concomitant 
medications/procedures, laboratory, vital signs, and ECG) will be used to estimate the last dose 
date.
In the event of dose interruption or reduction (see Section 4.1), the subject will be included in the 
treatment group to which they were originally assigned.
For Part 1, the placebo treated subjects in the four dose groups will be combined and will be 
considered as one treatment group in the final efficacy and safety analyses.
5.2.
Baseline Definition
The baseline is defined as the last value measured on or before the day of the first dose of IP.
5.3.
Time Points
Time points (including the scheduled study days per protocol, the end of treatment, and the 
observational follow-up visit) in all analyses are based on the visits/study days as recorded in the 
database. 
Appropriate dates (eg, date of measurement or date of specimen collection) will first be used to 
ensure only data (including data from scheduled, unscheduled, discontinuation, and 
observational follow-up visits) measured or collected within the specific analysis period are 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
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23
included, and then the visits/study days as recorded in the database will be used to assign one 
value (possibly missing) to each time point at the subject level according to the following rules:
!
If a value is available at a scheduled visit (eg, Day 15/Visit 4), then that value will be 
used for the study day, regardless of whether a value is available from an unscheduled 
visit (eg, Visit 4.01) that is associated with the scheduled visit.
!
If the value at a scheduled visit is missing but a value is available at an associated 
unscheduled visit, the value from the associated unscheduled visit will be used for the 
study day. If values from more than one associated unscheduled visit (eg, Visits 4.01 
and 4.02) are available, then the one from the first associated unscheduled visit (eg, 
Visit 4.01) will be used for the study day.
!
If the value at a scheduled visit is missing and there is no value available from an 
associated unscheduled visit, the value at the study day will be missing.
!
A value from the discontinuation visit (for a discontinued subject) will be mapped to 
the next scheduled visit after the last visit the subject has completed.
!
The end of treatment is defined as the last postbaseline visit among all the scheduled 
and unscheduled visits and, if applicable, the discontinuation visit; the observational 
follow-up visit is not included in the derivation of the end of treatment value.
5.4.
Analysis Populations
5.4.1.
Intent-to-Treat Analysis Set
The Intent-to-Treat (ITT) analysis set will consist of all subjects who are randomized as specified 
in the protocol and who receive at least one dose of IP. 
 
 Subjects will be included in the treatment group to which they 
are randomized for the ITT analyses. Subjects who are randomized in error and who do not 
receive any dose of IP will be excluded from the ITT analysis set.
5.4.2.
Per Protocol Analysis Set
The per protocol (PP) analysis set will consist of all subjects in the ITT analysis set who have at 
least one post-baseline efficacy evaluation and no significant protocol violations.
5.4.3.
Safety Population
The Safety Population will include all subjects who are randomized and receive at least one dose 
of IP. The safety analyses will be based on the Safety Population. Subjects will be included in 
the treatment group corresponding to the IP they actually received for the safety analyses. For 
most subjects, this will be the treatment group to which they are randomized. For subjects who 
take an IP that differs from the assigned one, according to the randomization schedule, the entire 
double-blind placebo-controlled period will be included in the treatment group corresponding to 
the IP they actually received. If a subject undergoes a dose reduction (see protocol section 8.2) 
the subject will be included in the treatment group corresponding to the initial IP that they
receive.
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take an IP
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oubl
ouble


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
24
  
 
 
5.4.5.
Pharmacokinetic Population  
The PK population will include all subjects in the safety population with at least one non-missing 
plasma concentration data. The PK Population will be the population used for the PK analyses. 
Subjects will be included in the treatment group to which they are randomized for the PK 
analyses.
CCI
g
s. 


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
25
6.
SUBJECT DISPOSITION
The number of subjects screened, the number and percentage of subjects randomized (as 
recorded in the IVRS database), the number and percentage of subjects not randomized among 
all subjects screened, and the eligibility criteria failed will be summarized. The failed 
inclusion/exclusion criteria of subjects who were screened and not randomized will be included 
in the summary. The above percentages will be based on the number of subjects screened.
The number and percentage of subjects included in each analysis population will be summarized 
by treatment group. The percentages will be based on the number of subjects randomized. A 
listing of subjects excluded from the analysis populations, with the reasons for exclusions, will 
be provided.
The number and percentage of subjects who entered, completed, and discontinued each study 
phase (Treatment Phase and Observational Follow-up Phase), and the number and percentage of 
primary reasons for discontinuation for subjects who early discontinued will be summarized. The 
percentages will be based on the number of subjects randomized. 
The primary reason for discontinuation is collected in the study disposition electronic case report 
form (eCRF) and will be summarized with the following categories:
!
Screen Failure
!
Death
!
Adverse event
!
Withdrawal by subject
!
Lost to follow-up
!
Protocol violation
!
Other
Listings will be provided for subjects randomized but not treated, and for discontinued subjects 
with reason for treatment discontinuation.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
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7.
PROTOCOL DEVIATIONS/VIOLATIONS
The protocol deviations/violations will be identified and assessed by the study team in 
accordance with Celgene’s standard operating procedure. The protocol deviations/violations for 
a particular analysis will be defined prior to unblinding of the database. The protocol 
deviations/violations will be summarized by treatment group for the ITT analysis set. A by-
subject listing of subjects with protocol deviations/violations will be provided. 


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Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
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Confidential and Proprietary
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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
The demographics and baseline characteristics will be summarized descriptively by treatment 
group for the ITT analysis set. Individual subject listings will be provided to support the 
summary tables.
8.1.
Demographics
Demographic variables include:
!
Age (years)
!
Age category (< 40, 40 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, Other)
!
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
!
Weight (kg)
!
Weight category (< 70, ≥ 70 to < 85, ≥ 85 to < 100, ≥ 100 kg)
!
Height (cm) at Screening
!
Body mass index (BMI; kg/m2)
!
BMI category (< 25, ≥ 25 to < 30, ≥ 30 to < 35, ≥ 35 to < 40, ≥ 40 kg/m2) 
!
Alcohol use (never, current, former user)
!
Tobacco use (never, current, former user)
!
Caffeine use (never, current, former user)
8.2.
Baseline Characteristics
Baseline characteristics include:
!
Duration of SLE (years)
 
 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
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Confidential and Proprietary
28
8.3.
Medical History
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA; Version 17.0 or higher). A frequency summary of medical history will be presented 
by treatment group, system organ class (SOC), and preferred term (PT) for the ITT analysis set. 
A data listing including the verbatim and coded terms will be presented.
A frequency summary of SLE medical history will also be presented by treatment group for the 
ITT analysis set.
8.4.
Prior and Concomitant Medications
Medications that were initiated prior to the start of study treatment and which continued after the 
start of study treatment will be counted as both prior and concomitant medications. The 
Anatomical Therapeutical Chemical (ATC) coding scheme of the World Health Organization 
Drug Dictionary (WHODD; Version March 2014 or higher) will be used to group medications 
into relevant categories. A data listing including the verbatim and coded terms will be presented.
8.4.1.
Prior Medications
Prior medications are defined as medications that were started before the start of study treatment
and either ended before the start of study treatment or continued after study treatment. A 
frequency summary of prior medications will be provided by treatment group, ATC1 level, and 
standardized medication name for the ITT analysis set.
8.4.2.
Concomitant Medications
Concomitant medications are defined as medications that were initiated before the first dose of 
IP and continued during the study treatment, or initiated on/after the date of the first dose of IP 
and on/before the date of treatment discontinuation. A frequency summary of concomitant 
medications will be provided by treatment group, ATC1 level and standardized medication name
for the Safety Population.
8.5.
Prior and Concomitant Procedures
Procedures will be coded according to MedDRA, Version 17.0 or higher.
8.5.1.
Prior Procedures
Prior procedures are defined as procedures or surgeries that occurred before the first dose of IP. 
A frequency summary of prior procedures will be presented by treatment group, SOC, and PT 
for the ITT analysis set.
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5.1.1.
P
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or pro
freq
f


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
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8.5.2.
Concomitant Procedures
Concomitant procedures will be identified similar to the criteria in Section 8.4.2. A frequency 
summary of concomitant procedures will be provided by treatment group, SOC, and PT for the 
Safety Population.
&(/*(1(35235,(7$5<,1)250$7,21


CC-220
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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
9.1.
Treatment Duration
Treatment duration (in weeks) is calculated as (the date of the last dose of IP – the date of the 
first dose of IP + 1) / 7 and rounded to one decimal place. 
Treatment duration will be summarized by treatment group for the Safety Population. 
Frequency summaries of treatment duration will also be presented for the following categories: 
< 1, ≥1 to < 2, ≥ 2 to < 4, ≥ 4 to < 8, ≥ 8 to < 12, and ≥ 12 weeks.
A subject data listing of study drug records will be provided.
9.2.
Treatment Compliance 
As part of the routine recording of the amount of IP taken by each subject, the number of tablets 
dispensed and returned will be recorded at each visit after Visit 1. These records will be used to 
calculate treatment compliance. A subject data listing of drug accountability records will be 
provided.
The compliance rate (%) for each subject for a period will be computed as 100 times the total 
number of tablets taken (the total number of tablets dispensed minus the total number of tablets 
returned) over the period divided by the intended total number of tablets that should have been 
taken over the same period. 
The intended total number of tablets is calculated as follows. First chronologically order the first 
dose date, the second dispense date, the third dispense date, etc., up to the last dose date. The 
first and last dose dates are defined in the same way as those defined for treatment duration
calculations (see Section 9.1). The intended number of tablets between any two consecutive 
dates is calculated as 2 × n, where n denotes the number of days between the 2 consecutive dates 
(ie, the second date minus the first date for all pairs of consecutive dates, and the second date 
minus the first date plus 1 for the last pair). Then the intended total number of tablets is the sum 
of all intended numbers of tablets as calculated above from the first dose date through the last 
dose date. Of note, compliance rate will not be calculated for subjects (if existent) who have only 
the dispense record at Day 1/Visit 2 and no other drug accountability records.
Treatment compliance will be summarized by treatment group for the Safety Population. 
Frequency summaries of compliance rate will also be presented with the following categories: 
< 75%, ≥75% to ≤ 120%, and > 120%.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
31
 
 
 
 
 
 
 
 
 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
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32
11.
SAFETY ANALYSIS
The purpose of this section is to define the safety parameters for the study. All summaries of 
safety data will be performed for the Safety Population.
For the analyses of TEAEs and marked abnormalities, subject incidence will be provided, unless 
otherwise specified. Subject incidence (ie, percentage [%] used in a frequency summary) is 
defined as 100 times the number of subjects with the specific event divided by the number of 
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.
Summaries of safety parameters over time (eg, summary statistics over time and shifts from 
Baseline to postbaseline time points in terms of normal/abnormal) will include data collected at 
scheduled, unscheduled, and discontinuation visits up to 28 days after the last dose of study drug 
in the study and data collected at observational follow-up visits. Summaries of marked 
abnormalities and shifts from Baseline to worst postbaseline value will include all data up to 28 
days after the last dose of study drug in the study, irrespective of the visits from which these data 
are collected.  The “worst” lab results will be defined using the worst of all post-baseline 
reference range indicators and grouped into “LOW” or “HIGH” or “Both L and H” or 
“NORMAL”.
In summaries of continuous variables with summary statistics by time point, values for Baseline, 
time point, and change from Baseline will be summarized at each time point for subjects who 
have both values at Baseline and at the time point. Similarly, in frequency summaries of shifts 
from Baseline, only subjects who have both values at Baseline and at the time point will be 
included in the summaries of shifts to the scheduled study days per protocol and only subjects 
who have a Baseline value and at least one postbaseline value will be included in the summaries 
of shifts to the end of period and to the worst postbaseline value.
11.1.
Adverse Events
Adverse events will be analyzed in terms of treatment-emergent adverse events (TEAE) which 
are defined as any AEs that begin or worsen on or after the start of study drug through 28 days 
after the last dose of study drug or study treatment discontinuation date, whichever is later. All 
AEs will be coded using MedDRA Version 17.0 or higher. A subject data listing of all AEs, 
including the verbatim and coded terms, will be presented.
Unless otherwise specified, AEs will be summarized by SOC and PT, with SOCs presented in 
the standard international order and PTs within each SOC in descending order of subject 
incidence (and then alphabetically if needed).
An overall summary of the following AE categories will be provided:
!
Any TEAE
!
Any drug-related TEAE
!
Any severe TEAE
!
Any serious TEAE
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!


CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
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Confidential and Proprietary
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!
Any serious drug-related TEAE
!
Any TEAE leading to drug interruption
!
Any TEAE leading to drug withdrawal
!
Any TEAE leading to death
Specific TEAEs under each of the above categories will be summarized.
A drug-related TEAE is defined as a TEAE which is considered to be of suspected relationship 
to study drug. Adverse events with missing relationship to study drug will be assessed as drug-
related.
If a subject reports multiple occurrences of a specific event within a specific analysis period, the 
subject will be counted only once by the maximum severity (mild, moderate, severe, and, if 
needed, missing). If the severity is missing for one or more of the occurrences, the maximum 
severity of the remaining occurrences will be used. If the severity is missing for all of the 
occurrences, the subject will be counted only once in the “missing” category of severity.
11.1.1.
All Treatment-emergent Adverse Events
All TEAEs will be summarized by SOC and PT as well as by PT only (in descending order of 
subject incidence). 
All TEAEs will be summarized by age category (< 40, ≥ 40 years) and sex (Male, Female).
All TEAEs occurring after the date of the last dose of IP and up to 28 days after the last dose 
of IP will also be summarized by SOC and PT for subjects who enter the observational follow-up 
phase.
11.1.2.
Drug-related Treatment-emergent Adverse Events
Drug-related TEAEs will be summarized.
11.1.3.
Treatment-emergent Adverse Events by Maximum Severity
All TEAEs will be summarized by maximum severity (mild, moderate, severe, and, if needed, 
missing). If a subject reports multiple occurrences of a specific event within a specific analysis 
period, the subject will be counted only once by the maximum severity. If the severity is missing 
for one or more of the occurrences, the maximum severity of the remaining occurrences will be 
used. If the severity is missing for all of the occurrences, the subject will be counted only once in 
the “missing” category of severity.
11.1.4.
Serious Treatment-emergent Adverse Events
Serious TEAEs will be summarized by SOC and PT as well as by PT only (in descending order 
of subject incidence).
Serious drug-related TEAEs will be summarized.
A subject data listing of all serious AEs (both TEAEs and non-TEAEs) will be provided.
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CC-220
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Celgene Corporation
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34
11.1.5.
Treatment-emergent Adverse Events Leading to Drug Interruption and Leading 
to Drug Withdrawal
Treatment-emergent AEs leading to drug interruption will be summarized. 
Treatment-emergent AEs leading to drug withdrawal will also be summarized. A subject data 
listing of TEAEs leading to drug withdrawal will be provided.
11.1.6.
Treatment-emergent Adverse Events Leading to Deaths
Treatment-emergent AEs leading to death will be summarized. A subject data listing of all 
deaths will be provided.
11.2.
Clinical Laboratory Evaluations
Summary statistics of observed values and changes from Baseline in hematology and serum 
chemistry laboratory parameters will be provided over time. Frequency summaries (shift tables) 
of shifts from Baseline to postbaseline time points and to the worst postbaseline value in terms of 
CCI
&(/*(1(35235,(7$5<,1)250$7,21
11.2.
11.2
mm
/*(1(35235,(7$5<,1)25


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Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
35
normal/abnormal will be provided for hematology and serum chemistry. The urinalysis results 
will be provided only in a listing.
Laboratory marked abnormalities (see Table 7) will be summarized; subject incidence for each 
abnormality will be calculated based on subjects with a baseline value and at least one 
postbaseline value for criteria requiring baseline or subjects with at least one postbaseline value 
for criteria not requiring baseline. A subject data listing of laboratory marked abnormalities will 
be provided.
A subject data listing of all laboratory data will be provided.
11.3.
Vital Sign Measurements
Summary statistics of observed values and changes from Baseline in vital signs will be provided 
over time. Frequency summaries (shift tables) of shifts from Baseline to postbaseline time points 
and to the worst postbaseline value in terms of normal/abnormal will be provided for pulse and 
blood pressure. The normal ranges are defined as: 60 to 100 beats/minute for pulse, 90 to 
140 mm Hg for systolic blood pressure, and 60 to 90 mm Hg for diastolic blood pressure.
A subject data listing of all vital signs and weight data will be provided.
11.4.
Electrocardiograms
Summary statistics of observed values and changes from Baseline in ECG findings will be 
provided over time. For each parameter, triplicate ECG readings will be averaged and this 
average used as the result in summary statistics. The overall ECG interpretation will be 
summarized by presenting the number and percentage of subjects with ‘Normal’, ‘Abnormal, not 
clinically significant’, and ‘Abnormal, clinically significant’ by treatment. The shift from 
Baseline to worst during the treatment in the overall ECG interpretation will be displayed for 
each treatment.
11.5.
Ophthalmological Examination
The overall interpretation will be summarized by presenting the number and percentage of 
subjects with ‘Normal’, ‘Abnormal, not clinically significant’, and ‘Abnormal, clinically 
significant’ by treatment. The shift from Baseline to Day 85/Early Termination in the overall 
interpretation will be displayed for each treatment.
11.6.
Physical Examination
No summary of physical examination findings will be provided. Clinically significant changes in 
physical examination findings will be captured as AEs.
11.7.
Tetanus Toxoid
Summary statistics of observed values and change from Baseline will be provided over time.
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11.7.
11.7
mm


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&(/*(1(35235,(7$5<,1)250$7,21


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13.
PHARMACOKINETIC ANALYSIS
All PK analyses will be conducted using the PK Population. 
Plasma concentration data will be presented in descriptive summary tables, individual listings, 
mean profile plots, and individual profile plots. Descriptive statistics for plasma concentrations 
will include n, arithmetic mean, SD, coefficient of variation (CV%), median, minimum,
maximum, geometric mean and geometric CV% (GeoCV%). Plasma concentrations below the 
quantifiable limit will be treated as zero (0) for the computation of arithmetic mean and a 
concentration value of 50% of the low limit of quantification for the computation of geometric 
mean.
Descriptive statistics for PK parameters will include n, arithmetic mean, SD, CV%, median, 
minimum, maximum, geometric mean and GeoCV%. 
CV% will be calculated as 100*(SD/arithmetic mean).
GeoCV% will be calculated as 100*sqrt[exp(SDlog^2)-1], where SDlog is the SD of the natural 
log transformed values.
&(/*(1(35235,(7$5<,1)250$7,21
metetrir c
%, median,
, median,
og is the SD
og is the S


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CCI
&(/*(1(35235,(7$5<,1)250$7,21
0$7
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Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
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39
15.
INTERIM ANALYSIS
Following completion of the first 28 days of the Treatment Phase by 8 subjects of each dose 
group, assessments of safety and tolerability will be conducted. Data for disposition, exposure, 
demographics, 
, TEAE, laboratory values, and vital signs will be reviewed. 
The treatment will be kept blinded.
Results will be used to assess safety and to determine if the next dose group will be enrolled.
After all Part 1 subjects have completed Day 85/Visit 10 with 12 weeks of observational follow-
up or have discontinued early, and the database has been locked, treatment will be unblinded.  
 
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Celgene Corporation
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16.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
No changes to the statistical analyses section of the protocol are made in this SAP.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
41
17.
REFERENCES
 
 
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
42
18.
APPENDICES
18.1.
Handling of Dates
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie, the Date9. datetime format in SAS). Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedure are 
performed. They include the dates of laboratory testing, physical examinations, tumor 
scans, etc. They should be present whenever data for a protocol-specified procedure 
are present and should only be missing when a procedure is marked as NOT DONE 
in the database. Procedure dates will not be imputed.
!
Log Dates are dates recorded in CRF data logs. Specifically, they are the start and 
end dates for AEs and concomitant medications/procedures. They should not be 
missing unless an event or medication is marked as ongoing in the database. 
Otherwise, incomplete log dates will be imputed according to the rules in Appendix 
18.2 (eg, for duration or cycle assignment, etc). However, in listings, log dates will be 
shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study drug termination date, study closure date, etc. They should not be 
missing if the milestone occurs for a subject. They will not be imputed.
!
Special Dates cannot be classified in any of the above categories and they include the 
date of birth. They may be subject to variable-specific censoring and imputation rules. 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
18.1.1.
Calculations Using Dates
Calculations using dates (eg, subject’s age or relative day after the first dose of study drug) will 
adhere to the following conventions: 
18.1.1.1.
Study Day
Study days after the start day of study drug (first dose date) will be calculated as follows:
!
For dates of interest on or after the first dose date: The study days will be 
calculated as the difference between the date of interest and the first dose date of 
study medication plus 1 day.
     STUDY DAY= (TARGET DATE – DSTART) + 1;
     where DSTART = the first dose date. 
!
For dates of interest prior to the first dose date: The study days will be calculated 
as the difference between the date of interest and the first dose date of study 
medication only.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
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STUDY DAY= TARGET DATE – DSTART; 
where DSTART = the first dose date. 
!
Study Day 1 is the first day of treatment of study drug. Negative study days are 
reflective of observations obtained during the baseline/screening period. 
!
Partial dates for the first study drug are not imputed in general. All effort should be 
made to avoid incomplete study drug start dates. Some analyses may exclude subjects 
without study drug start date. The SAP may be amended on a case-by-case basis, 
including guideline and suggestion such as imputing Day 1 by consent date of treated 
patient.
18.1.1.2.
Age
Age (expressed in years) is calculated as the difference between the date of birth and the 
informed consent date plus 1 day. Age will be transformed to years by dividing the difference by 
365.25 days, then truncating.
     AGE = Integer portion of (DATE of CONSENT – DATE of BIRTH + 1) /365.25
!
Preference is for using calculated age from clinical database. When not available, 
calculated age from CRF or IVRS may be used
!
Partial birth date: impute missing day as 15th of the month; impute missing month as 
July; set missing age for missing year
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
     WEEKS = DAYS /7
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
     MONTHS = DAYS /30.4167
18.1.1.3.
Duration of Systemic Lupus Erythema
Duration of SLE (expressed in years) is calculated as the difference between the date of 
diagnosis of SLE and the informed consent date plus 1 day divided by 365.25 days, then rounded
to 1 decimal.
     Duration of SLE = (DATE of CONSENT – DATE of SLE DIAGNOSIS + 1) /365.25
Partially missing SLE diagnosis dates will be imputed as specified in Section 18.2.3.
18.2.
Date Imputation Guideline
18.2.1.
Adverse Events
Partially missing AE start dates will be imputed in the analysis dataset model (ADaM) dataset 
for AEs, but partially missing AE end dates will not be imputed in the same dataset. If the AE 
end date is complete with no missing year, month, or day, and the partially missing start date 
imputed by the rules below is after the AE end date, then the start date will be imputed by the AE 
end date.
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
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The principle of the imputation rules is to treat the AE as treatment-emergent, ie, occurring on or 
after the date of the first dose of IP, if possible.
Let an AE start date be represented as “DEvent/MEvent/YEvent”, and the date of the first dose of IP as 
“DIP/MIP/YIP”. The imputation rules for partially missing AE start dates are stated in Table 3.
Table 3:
Imputation Rules for Partially Missing Adverse Event Start Date
Scenario
Condition
Imputation Rule
A. Partially missing date includes year only (both month and day are missing)
1
YEvent < YIP
31/12/YEvent
2
Otherwise, ie, YIP ≤ YEvent
Max (date of first dose of IP, 
01/01/YEvent)
B. Partially missing date includes both year and month (only day is missing)
1
YEvent < YIP, or 
(YEvent = YIP and MEvent < MIP)
Last date of MEvent/YEvent
2
Otherwise, ie, YIP < YEvent, or 
(YIP = YEvent and MIP ≤ MEvent) 
Max (date of first dose of IP,
01/MEvent/YEvent)
18.2.2.
Prior/Concomitant Medications/Procedures
Partially missing start/stop dates for prior/concomitant medications and partially missing start 
dates for prior/concomitant procedures will be imputed in the ADaM dataset. For 
prior/concomitant medications, if the stop date is complete with no missing year, month, or day, 
and the partially missing start date imputed by the rule below is after the stop date, then the start 
date will be imputed by the stop date.
Partially missing prior/concomitant medication/procedure start dates will be imputed by the 
earliest possible date given the non-missing field(s) of the date.
Partially missing prior/concomitant medication stop dates will be imputed by the latest possible 
date given the non-missing field(s) of the date.
Let a prior/concomitant medication/procedure start/stop date be represented as 
“DEvent/MEvent/YEvent”. The imputation rules for partially missing prior/concomitant medication 
start dates are stated in Table 4. The imputation rules for partially missing prior/concomitant 
medication stop dates are stated in Table 5.
Table 4:
Imputation Rules for Partially Missing Prior/Concomitant 
Medication/Procedure Start Dates
Scenario
Condition
Imputation Rule
1
Partially missing date includes year only (both 
month and day are missing)
01/01/YEvent
2
Partially missing date includes both year and month 
(only day is missing)
01/MEvent/YEvent
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
45
Table 5:
Imputation Rules for Partially Missing Prior/Concomitant Medication Stop 
Dates
Scenario
Condition
Imputation Rule
1
Partially missing date includes year only (both 
month and day are missing)
31/12/YEvent
2
Partially missing date includes both year and month 
(only day is missing)
Last date of MEvent/YEvent
18.2.3.
Medical History
Partially missing medical history start dates will be imputed in the ADaM dataset for medical 
history (for the purposes of calculating duration of SLE). The 16th of the month will be used to 
impute a partially missing start date that has only the day missing, and July 1st will be used to 
impute a partially missing start date that has both the month and day missing.
Let a medical history start date be represented as “DEvent/MEvent/YEvent”. The imputation rules for 
partially missing medical history start dates are stated in Table 6 . 
Table 6:
Imputation Rules for Partially Missing Medical History Start Dates
Scenario
Condition
Imputation Rule
1
Partially missing date includes year only (both 
month and day are missing)
01/07/YEvent
2
Partially missing date includes both year and month 
(only day is missing)
16/MEvent/YEvent
18.3.
Marked Abnormalities Criteria
The laboratory marked abnormality criteria is presented in Table 7.
Table 7:
Laboratory Marked Abnormality Criteria
Category / Analyte
SI Units 
Criteria 
Chemistry
Alanine Aminotransferase (SGPT)
U/L
> 3 xULN  
   Albumin
Kg/m3
< 25
   Alkaline Phosphatase
U/L
> 400  
   Aspartate Aminotransferase (SGOT)
U/L
> 3 x ULN  
   Total Bilirubin
μmol/L
> 1.8 x ULN  
   Blood Urea Nitrogen
mmol/L
> 15
   Calcium 
mmol/L
< 1.8
> 3.0
   Creatinine 
μmol/L 
> 1.7 x ULN 
   Glucose
mmol/L
< 2.8
> 13.9
   Hemoglobin A1C
%
> 9
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CC-220
Statistical Analysis Plan. Protocol CC-220-SLE-001 – Part 1
Celgene Corporation
Confidential and Proprietary
46
Category / Analyte
SI Units 
Criteria 
   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
   Triglycerides
mmol/L
> 3.4
   Urate
umol/L
Male: > 590; Female: > 480
   Alanine Aminotransferase (SGPT)
   Aspartate Aminotransferase (SGOT)
   Total Bilirubin
U/L
U/L
μmol/L
(ALT > 3xULN or 
AST > 3xULN) and 
Total Bilirubin > 1.5x ULN
Hematology
   Hemoglobin
g/L
Male: < 10.5, Female: < 8.5 
Male: > 18.5, Female: > 17 
  Leukocytes
10^9/L
< 1.5
  Lymphocytes
10^9/L
< 0.8
  Neutrophils
10^9/L
< 1.0
  Platelets
10^9/L
< 75
> 600
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