Clinical trial NCT04947579
Conditions: Spondylitis, Ankylosing
Keywords: Ankylosing Spondylitis CC-99677 MK2inhibitor Spinal Diseases Bone Diseases Musculoskeletal Diseases Arthritis Joint Diseases
Sponsor: Celgene
Start date: 2021-08-25; Completion date: 2023-02-21
Enrollment: 167 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to learn about response to CC-99677 treatment by measuring signs and symptoms of Ankylosing Spondylitis (AS), objective measures of disease activity, quality of life assessments, pharmacokinetics, safety, and tolerability over a 12-week double-blind period.

Detailed description:

Arms: arm 1: 49 participants will be randomized to CC-99677 150 mg in biologic naive main study arm 2: 49 participants will be randomized to CC-99677 60 mg in biologic naive main study arm 3: 49 participants will be randomized to placebo in biologic naive main study arm 4: 20 participants will be randomized to CC-99677 150 mg in biologic-failure substudy arm 5: 20 participants will be randomized to CC-99677 60 mg in biologic-failure substudy arm 6: 10 participants will be randomized to placebo in biologic-failure substudy
Interventions: intervention 1: CC-99677 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral intervention 2: Oral

Protocol documents:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Phase 2 Multicenter, Randomized, Double-Blinded, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Efficacy and Safety of CC-99677 in Subjects With Active Ankylosing Spondylitis 
 
NCT Number: NCT04947579 
Document Date (Date in which document was last revised): Sep 21, 2022 


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
1
A PHASE 2 MULTICENTER, RANDOMIZED, DOUBLE-BLINDED, PLACEBO-
CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND
SAFETY OF CC-99677 IN SUBJECTS WITH ACTIVE ANKYLOSING SPONDYLITIS
PROTOCOL NUMBER:
CC-99677-AS-001
COMPOUND NUMBER:
DATE FINAL:
CC-99677 (BMS-986371)
14 FEB 2020
DATE AMENDMENT 1.0 FINAL
06 NOV 2020
DATE AMENDMENT 2.0
16 Jun 2021
DATE AMENDMENT 3.0
21 Sep 2022
EudraCT NUMBER:
2019-004108-37
IND NUMBER:
146368
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.
1.0
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930191603
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Approved
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
2
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:  Medical Monitor
Name:  
Title:  Medical Director
Address:  
 
Phone:
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: 
 (global 
reachable number)
provides a list of country-specific contact numbers. 
Countries not listed here need to dial the global reachable number as indicated above. There may be 
restrictions when dialling a country-specific number from a mobile phone.
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
3
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
4
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, International Council for
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations governing 
the conduct of clinical studies.
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
5
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 3.0:
The primary purpose of this protocol amendment is to provide updated results from drug-drug 
interaction studies resulting in changes to permitted and prohibited concomitant medications, 
including allowance of hormonal contraceptives.
Additional revisions, including to sections of the Protocol Summary, have been made to align the 
protocol with respect to these changes.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 3.0
Section Number 
& Title
Description of Change
Brief Rationale
Medical 
Monitor/
Emergency 
Contact 
Information

Updated
contact 
information.

Updated 
due
to 
administrative 
changes.
Section 1.4:
Clinical 
Experience

Results
of 
drug-drug 
interaction studies have been 
included.

To provide context for the permission 
of 
the 
following 
concomitant 
medications: metformin, statins, and 
oral contraceptives. 

To provide context for the continued 
prohibition of moderate to strong
cytochrome P450 (CYP) 3A4/5 and
P-glycoprotein (P-gp) inhibitors and 
exclusion of moderate to strong 
CYP3A4/5 and P-gp inducers.
Section 2: Study 
Objectives and 
Endpoints

Removed tender joints from 
the exploratory endpoint of 
peripheral arthritis.

For alignment with established 
guidelines for evaluating peripheral 
joint disease in ankylosing 
spondylitis (AS).
Section 2.1:
Study Endpoints
Exploratory 
pharmacokinetic 
(PK) endpoints modified as 
follows:

AUC(TAU) for CC-99677 
and CC-0782951 included 
as PK parameters. 

MR_Cmax, 
MR_AUC(TAU), 
and 
MR_AUC(0-T) 
for 
CC-
0782951 included as PK 
parameters.

PK parameters modified to accurately 
reflect the those that can be calculated 
or reported based on the PK 
sampling, observed PK properties of 
CC-99677 and CC-0782951, and 
Bristol-Myers 
Squibb 
Company 
(BMS) standards for reporting PK 
parameters.

CL/F modified to CLT/F to correct a 
typographical error.
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
6
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 3.0
Section Number 
& Title
Description of Change
Brief Rationale

AUC(0-∞), t1/2z, and Vz/F 
removed as PK parameters.

Ctrough removed as a PK 
parameter for sparse PK 
collection.

CL/F corrected to CLT/F.
Section 3.1.5:
Primary 
Analysis

Clarified that following 
primary analysis of both the 
biologic-naive main study 
and the biologic failure 
substudy, the remainder of 
the Long-term Extension 
Period will be performed in 
a Sponsor-unblinded 
fashion.

No need to continue Sponsor 
blinding following primary analysis.
Section 4.2:
Inclusion 
Criteria for the 
Biologic-naive 
Main Study

Inclusion of hormonal 
contraceptives as an 
acceptable method of 
contraception.

Removal of requirement to 
have statins dose modified.

Oral contraceptives are now 
permitted following oral 
contraceptive drug-drug interaction
(DDI) study.

Statins are now permitted following 
results from completed DDI studies.
Section 4.3: 
Exclusion 
Criteria for 
Biologic-naive
Main Study

Revision to exclusion 
criterion 8 to add Janus 
kinase (JAK) inhibitors to 
list of prohibited 
medications.

JAK inhibitors are now approved for 
treatment of AS and therefore are 
included as a prohibited medication.

Revised exclusion criterion 
14 to include use of any 
medications known to be 
either a moderate or strong 
inhibitor or a moderate or 
strong inducer of 
CYP3A4/5.

Added strong inducers of CYP3A4/5 
due to availability of DDI data.

Revised exclusion criterion 
15 to include use of any 
medication known to be 
either a moderate or strong 
inhibitor or a moderate or 
strong inducer of P-gp.

Added strong inducers of P-gp to 
exclusion criterion due to 
availability of DDI data.
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
7
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 3.0
Section Number 
& Title
Description of Change
Brief Rationale

Separated use of any 
medication known to be 
either a moderate or strong 
P-gp or a strong breast 
cancer resistance protein 
inhibitor into 2 standalone 
criteria (exclusion criteria 
16 and 17).

Revised for ease of understanding.

Clarified exclusion criterion 
22 to indicate that 
hemoglobin A1C (HbA1c) 
should only be drawn in
subjects with a known 
history of diabetes.

To avoid the unnecessary or 
inappropriate collection of HbA1c in 
subjects without a known history of 
diabetes.
Section 7.2.2: 
Dose 
Modifications/
Interruptions

Clarified that dose 
interruptions are allowed in 
the context of an adverse 
event.

Added that temporary 
interruption of IP is allowed 
in the context of clinical 
suspicion for SARS-CoV-2 
or a positive diagnostic test 
for SARS-CoV-2.

Updated to allow dose interruptions 
in the context of adverse events
including suspicion for SARS-CoV-
2 or a positive diagnostic test for 
SARS-CoV-2.
Section 8.1:
Permitted 
Concomitant 
Medications and 
Procedures

Removal of statement that 
statin dose will require 
adjustment during the study.

Dose adjustment and associated 
monitoring of statins are no longer 
required following rosuvastatin 
drug-drug interaction studies.
Section 8.2:
Permitted 
Medications 
That Require 
Careful 
Monitoring

Updated section to reflect 
results of completed DDI 
studies involving CC-99677.

A clinically significant interaction is 
unlikely with drugs that are substrates 
of 
BCRP, 
P-gp, 
OATP1B1, 
OATP1B3 and OCT1 transporters 
AND that have a wide therapeutic 
index.

Removal of mention of 
medications 
that 
are 
substrates of CYP3A4/5 (eg, 
midazolam).

CYP3A4/5 substrates no longer 
require careful monitoring following 
the drug-drug interaction study with 
midazolam.
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
8
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 3.0
Section Number 
& Title
Description of Change
Brief Rationale

Removal of mention of 
statins and metformin.

Routine monitoring of statins and 
metformin are now permitted based 
on drug-drug interaction studies.
Section 9.0: 
Statistical 
Considerations

Clarified 
that 
following 
primary analysis of both the 
biologic-naive main study 
and the biologic failure 
substudy, the remainder of 
the Long-term Extension 
Period will be performed in 
a 
Sponsor-unblinded 
fashion.

No need to continue Sponsor blinding 
following primary analysis.
Section 9.2:
Study Population 
Definitions

PK population definition 
modified and PK Evaluable 
population definition added.

To accurately capture the BMS 
process for reporting listings, 
summaries, and statistical analyses 
of PK data.
Section 9.9.3:
Pharmacokinetic 
Analyses

PK parameters modified.

PK parameters modified to 
accurately reflect those that can be 
calculated or reported based on PK 
sampling, observed PK properties of 
CC-99677 and CC-0782951, and 
BMS standards for reporting PK 
parameters.
Appendix C:
Examples of 
Drugs That Are 
Excluded Based 
on Potential 
Drug-Drug 
Interactions

Expansion of the list of 
moderate or strong 
inhibitors and moderate or 
strong inducers of 
CYP3A4/5 (Table 7).

Expansion of the list of 
moderate or strong 
inhibitors or moderate or 
strong inducers of P-gp 
(Table 8).

To provide clarity for investigators 
as to which medications should be 
avoided.
Appendix D: 
Examples of 
Drugs That Are 
Substrates for 
Selected 

Combined Tables 10 and 
11.

Combined for ease of readability.

Removed mention of statins 
and metformin.

Statins and metformin are now 
permitted following DDI studies.
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
9
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 3.0
Section Number 
& Title
Description of Change
Brief Rationale
Transporters and 
Should Be Used 
with Caution

Removed Table 12.

CYP3A4/5 substrates now permitted 
following DDI studies.
All

Minor formatting and 
typographical corrections.

Minor, therefore, these have not 
been summarized.
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
10
PROTOCOL SUMMARY
Study Title
A Phase 2 Multicenter, Randomized, Double-Blinded, Placebo-Controlled, Parallel-Group Study 
to Evaluate the Efficacy and Safety of CC-99677 in Subjects with Active Ankylosing Spondylitis
Indication
Ankylosing Spondylitis (AS)
Objectives
Primary Objective
To evaluate the dose dependent efficacy of oral CC-99677 (also known as BMS-986371), 
administered every day (QD) compared to placebo, as determined by the attainment of the 
Assessment in SpondyloArthritis International Society Response Criteria (ASAS20) after 12 
weeks of treatment, in subjects with radiologically confirmed AS and inadequate response to 
nonsteroidal anti-inflammatory drugs (NSAIDs).
Secondary Objectives
To evaluate the effects of oral CC-99677, administered QD, compared to placebo, after 12 weeks 
of treatment in subjects with AS, on:

The signs and symptoms of AS, as assessed by attainment of Assessment in SpondyloArthritis 
International Society 40% Response Criteria (ASAS40), a composite measure of clinical 
improvement in axial spondyloarthritis, Ankylosing Spondylitis Disease Activity Score 
(ASDAS) with C-reactive protein (CRP) as the acute-phase reactant (ASDAS-CRP), and Bath 
Ankylosing Spondylitis Disease Activity Index (BASDAI)

Measures of physical function, as assessed by Bath Ankylosing Spondylitis Functional Index 
(BASFI)

Spinal and sacroiliac joint inflammation as measured by Spondyloarthritis Research 
Consortium of Canada (SPARCC) magnetic resonance imaging (MRI) score of sacroiliac 
joints and spine

Percent change from baseline in high-sensitivity C-reactive protein (hsCRP)

Safety and tolerability 
Exploratory Objectives
To evaluate the effects of oral CC-99677, administered QD in subjects with AS, on:

The signs and symptoms of AS, as assessed by the attainment of ASAS20 and ASAS40
(excluding Week 12)

The signs and symptoms of AS, as assessed by ASDAS-CRP (excluding Week 12), 
achievement of a clinically important improvement (ASDAS-CRP ≥ 1.1), a major 
improvement (ASDAS-CRP ≥ 2.0) and attainment of inactive disease (ASDAS-CRP < 1.3)

The signs and symptoms of AS, as assessed by BASDAI (excluding Week 12)

Measures of physical function, as assessed by BASFI (excluding Week 12)
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Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
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
Spinal mobility, as assessed by Bath Ankylosing Spondylitis Metrology Index-Linear 
(BASMI-Linear), Chest expansion, and Occiput to wall distance at Weeks 4 through Week 64

High-sensitivity C-reactive protein (hsCRP) level at Weeks 2 through 64

Enthesitis as assessed by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at 
Weeks 4 through 64

Peripheral arthritis, as determined by swollen joint count at Weeks 4 through 64

Quality of life, as assessed by Ankylosing Spondylitis Quality of Life (ASQoL), Short Form-
36 (SF-36), and ASAS Health Index (ASAS HI) at Weeks 12, 24 and 64

Pharmacokinetics (PK) of CC-99677 at Weeks 4 through 12

Target Engagement of CC-99677 at Weeks 4 through 12

Relationship between CC-99677 exposure and serum pharmacodynamic (PD) biomarkers at 
Weeks 4 through 64

Whole blood messenger ribonucleic acid (mRNA) gene expression profiling in relationship to 
treatment response at Weeks 4 through 64

Relationship between CC-99677 exposure and osteoclast precursors with ex vivo 
osteoclastogenesis at Week 12

Bone turnover markers at Weeks 12, 24 and 64

Pharmacogenetic (PG) markers and their relationship to treatment response at Baseline Visit

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology (anti-SARS-CoV-
2) total or immunoglobulin-G [IgG], Immunoglobulin-M [IgM]) at Week 64
Biologic-Naïve Main Study Design
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
efficacy and safety study.  This study is designed to assess response to CC-99677 treatment by 
measuring signs and symptoms of AS, objective measures of disease activity, quality of life 
assessments, safety, and tolerability over a 12-week double-blind period.  This study will also 
assess the efficacy and long-term safety of CC-99677 in a 52-Week Long-term Extension Period.
In the biologic-naïve main study, approximately 147 adult male and female subjects with a 
diagnosis of AS (Sieper, 2009) fulfilling the modified New York criteria for AS (van der Linden, 
1984) (APPENDIX B) and no prior exposure to biologic treatments for AS will be randomized 
with equal allocation to receive either CC-99677 150 mg PO QD, CC-99677 60 mg PO QD, or 
matching placebo for a duration of 12 weeks. Randomization to treatment groups will be stratified 
by Screening hsCRP concentration (≤upper limit of normal/ > upper limit of normal of the 
reference lab).  
At Week 12 subjects originally randomized to receive placebo will be re-randomized 1:1 to blinded 
CC-99677 (150 mg or 60 mg PO QD) through Week 64. Subjects originally randomized to CC-
99677 (150 mg or 60 mg PO QD) will continue to receive the same dose through Week 64.  At 
Week 16 subjects who do not achieve an ASAS20 will be discontinued from CC-99677 and the 
study.
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
12
An interim analysis (IA) will be conducted when approximately 30 subjects in the biologic-naïve 
main study complete 12 weeks of treatment.  A Steering Committee comprised of unblinded 
Bristol Myers Squibb (BMS) committee members independent of the Study Team and external AS 
expert(s) will review the data from the IA and will convey one of the following decisions to the 
blinded study team:

Continue the study without modification

Terminate the study for futility

Discontinue a treatment group based on preliminary assessment of dose-dependent risk-benefit 

Add an additional dose cohort (dose not to exceed 150 mg) 
If the Steering Committee determines that an additional dose cohort is needed, then the additional 
dose cohort will be initiated as part of the biologic-naïve main study, only, as described in 
Section 3.1.2.
The study team responsible for managing the study will remain blinded. Details and timing of the 
interim analysis will be described in a Steering Committee charter. The Steering Committee
charter will further describe any potential future interim analyses.
The primary analysis will be performed when all subjects in the biologic-naïve cohort have 
completed 12 weeks of treatment or have discontinued early, and all expected data are collected. 
Following the database lock, the remainder of the Long-term Extension Period will be conducted 
in a Sponsor-unblinded fashion. All subjects and site personnel will remain blinded throughout the 
duration of the trial.
The exposure-response analyses, along with observed efficacy and safety results from the primary 
analysis may support the selection of a single efficacious dose of CC-99677 or dropping a dose 
due to insufficient benefit-risk.  In either of these events, subjects in the Long-term Extension may 
be reallocated to the selected CC-99677 dose(s) through Week 64.
Assessments for efficacy, safety, tolerability, quality of life, PK, PD and PG will be performed at 
specified timepoints as outlined in Table of Events, Table 3 and Table 4. Subjects who discontinue 
prematurely from the study at any time will be required to enter the 4-week Post-treatment 
Observational Follow-up Period.
The study will be conducted in compliance with the International Council for Harmonisation (ICH) 
Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical 
Practice (GCP) and applicable regulatory requirements.
Biologic-failure Substudy
Approximately 50 subjects with AS who have failed not more than 1 biologic agent taken for AS 
due to inadequate efficacy response to an approved dose for at least 12 weeks and/or unacceptable 
safety/tolerability of a biologic agent (in the opinion of the Investigator) will be recruited into a 
substudy, conducted concurrently with the biologic-naïve main study.  Subjects will be 
randomized 2:2:1 to receive treatment with CC-99677 150 mg PO QD, CC-99677 60 mg PO QD, 
or matching placebo respectively and will enter into 12-Week Placebo-controlled period.  At Week 
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
13
12 subjects originally randomized to receive placebo will be re-randomized 1:1 to blinded CC-
99677 (150 mg or 60 mg PO QD) through Week 64.  Subjects originally randomized to CC-99677
(150 mg or 60 mg PO QD) will continue to receive the same dose through Week 64.
Internal Safety Monitoring Team
In addition to daily safety monitoring conducted by Investigators and individual study personnel, 
cumulative and interval blinded adverse events (AEs), serious adverse events (SAEs), 
discontinuations and laboratory findings will be reviewed by a Safety Management Team (SMT) 
internally at Celgene.
The SMT is comprised of lead representatives from multiple Celgene 
functions. The scope, conduct, processes, and accountabilities of the SMT are specified by 
Celgene Standard Operating Procedure (SOP).
Independent External Data Monitoring Committee
Although the Celgene study staff will monitor safety on an ongoing basis throughout the study, 
formal unblinded safety and efficacy assessments of the study data will be performed by an 
independent external Data Monitoring Committee (DMC). The DMC will include physician 
experts with experience in treating subjects with AS and a statistician, all of whom are not 
otherwise involved in the study conduct and in whom there is no identified conflict of interest. The 
external DMC may make a recommendation to stop the study at any time based on an assessment 
of the overall Benefit/Risk of clinical data.  Operational details for the DMC will be detailed in a 
separate DMC charter.
Steering Committee
A Steering Committee (SC), comprised of both unblinded BMS committee members independent 
of the study team and external AS expert(s) will review the data from the IA and will convey 
decisions to the blinded study team.  The SC may oversee additional IAs.  Operational details for 
the SC will be detailed in a separate SC charter.
Study Population
Adult male and female subjects ≥18 years of age with a diagnosis of AS fulfilling the modified 
New York criteria for AS (van der Linden, 1984) (APPENDIX B), symptoms of active disease 
based on a BASDAI score ≥ 4, and a Total Back Pain Numerical Rating Scales (NRS) score ≥ 4 
will be recruited.  Subjects can receive NSAID therapies, or low-dose corticosteroids, provided 
they are in accordance with eligibility criteria and permitted concomitant medications.  Subjects 
in the biologic-naïve main study must not have had prior treatment with a biologic therapy (eg,
tumor necrosis factor (TNF) blocker or anti-IL-17 agent) for AS.  Subjects with AS who have 
failed not more than one biologic agent taken for AS due to inadequate response to an approved 
dose for at least 12 weeks and/or unacceptable safety/tolerability with at least one dose of a 
biologic agent (in the opinion of the Investigator) will be recruited into a separate biologic-failure 
substudy.
Length of Study
The study consists of multiple periods:
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CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
14

Screening Period (up to 6 weeks)

Double-blind, Placebo-controlled Treatment Period (12 weeks)

Long-term Extension Period (52 Weeks)

Post-treatment Observational Follow-Up Period (4 weeks)
Subjects will remain in the study for a maximum of 74 weeks and will be requested to attend a 
total of 16 study visits (from Screening Visit to Observational Follow-up Visit).  Subjects who 
discontinue treatment early (after randomization) are required to have an Early Termination Visit 
and will be requested to enter the Observational Follow-up Period.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
Study Treatments
Subjects will be randomized (1:1:1 in the biologic-naïve main study, 2:2:1 in the biologic-failure 
substudy) to one of the following 3 treatment groups at Baseline (Day 1; Week 0):
1) CC-99677 150 mg PO QD
2) CC-99677 60 mg PO QD
3) Placebo PO QD
If the additional dose cohort is initiated (Section 3.1.4) in the biologic-naïve main study, then 
subjects will be randomized in a 5:1 ratio to receive either CC-99677 (additional dose) or matching 
placebo at Baseline (Day 1, Week 0):
4) Additional dose cohort (dose not to exceed 150 mg), (Section 3.1.2) 
5) Placebo PO QD
Randomization and treatment assignment will be managed by an Interactive Web Response 
System (IWRS).
Overview of Key Efficacy Assessments

ASAS20

ASAS40

ASDAS-CRP 

BASDAI 

BASFI-Linear

SPARCC MRI assessments of the spine and sacroiliac joints
Overview of Key Pharmacodynamic Assessments

hsCRP

Serum levels of other proinflammatory cytokines relevant to AS pathophysiology and disease 
evolution may include, but are not limited to, TNF-α, IL-6, IL-17A, and IL-23

mRNA expression will be analyzed. This is set to explore the relationship between clinical 
response and change in gene expression with CC-99677
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
Markers of bone turnover (including but not limited to serum carboxy terminal cross-linked 
telopeptide of type 1 collagen [CTX] and procollagen Type I N-terminal pro-peptide [P1NP])

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) target engagement in 
peripheral blood mononuclear cells (PBMCs)

Osteoclast precursors in PBMCs
Overview of Key Safety Assessments

Adverse Events (type, frequency, severity, seriousness, and relationship of AEs to 
Investigational Product [IP])

Number of subjects who discontinue IP due to any AE

Clinically significant changes in laboratory findings

Physical examination, vital signs, and weight

Pregnancy testing and pregnancy education 

12-lead electrocardiogram
Statistical Methods
With 147 total subjects and an equal allocation ratio, the study will randomize 49 subjects to each 
treatment group.  This sample size will provide 80% power, calculated by nQuery Advisor version 
7 and without accounting for multiplicity, to detect a treatment difference of 25% in ASAS20
response rate at Week 12 between either active treatment group and placebo, using a chi-square 
test at a two-sided significance level of 0.10, and assuming the response rates of 59% for both CC-
99677 treatment groups and 34% for placebo (the latter based on historical studies), with dropouts 
considered as nonresponders in these assumed response rates. Applying the Hochberg procedure 
to adjust for the multiplicity of the comparisons of two active treatment groups with placebo, the 
study will provide 81% power to achieve statistical significance at the two-sided significance level 
of 0.10 for at least 1 treatment group, with the same response rate assumptions stated above.
An additional 50 subjects will be enrolled in the biologic-failure substudy.  Primary analysis of 
efficacy of subjects enrolled in the biologic-failure substudy will be separate from that of the
biologic-naive main study although an exploratory pooled analysis of efficacy will also be 
performed.
The full analysis set (FAS) will be the primary population for the efficacy analysis.  The FAS will 
consist of all subjects who are randomized and receive at least 1 dose of IP.
Binary endpoints will be analyzed by the Cochran-Mantel-Haenszel (CMH) test stratified by the 
randomization stratification factor hsCRP concentration (≤ upper limit of normal/ > upper limit of 
normal) obtained at Screening Visit 1. The primary missing data handling approach for binary 
endpoints will be nonresponder imputation (NRI), by which a subject will be considered a 
nonresponder at a given time point if the subject does not have sufficient data (including the 
baseline data for the endpoints assessing the change from baseline) assessed within the analysis 
window of the time point for response determination.  The Hochberg procedure will be applied to 
the primary efficacy endpoint analysis to adjust for multiplicity.  
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The continuous endpoints will be analyzed by an adaptive approach (Mehrotra, 2012) that uses 
either a longitudinal data analysis (LDA) model (Liu, 2009) (in the absence of severe departures 
from normality) or robust regression model/nonparametric methods (in the presence of severe 
departures from normality).  The LDA model assumes a common mean across treatment groups 
at baseline and a different mean for each treatment group at each of the postbaseline time points.
In this model, the response vector consists of the baseline and postbaseline values. Time is treated 
as a categorical variable so that no restriction is imposed on the trajectory of the means over time. 
The model will also adjust for the randomization stratification factor hsCRP concentration (≤ upper 
limit of normal/ > upper limit of normal) and its interaction with time.
Summary statistics will be provided over time for the Long-term Extension Period.
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 3.0:............................................5
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 3.0 ................................5
PROTOCOL SUMMARY ........................................................................................................10
TABLE OF CONTENTS..........................................................................................................17
LIST OF TABLES....................................................................................................................21
LIST OF FIGURES ..................................................................................................................22
1
INTRODUCTION..................................................................................................23
1.1
Disease Background ...............................................................................................23
1.2
Compound Background ..........................................................................................24
1.3
Nonclinical Experience...........................................................................................24
1.3.1
Nonclinical Toxicology...........................................................................................25
1.4
Clinical Experience.................................................................................................27
1.4.1
Efficacy and Safety .................................................................................................27
1.4.2
Pharmacokinetics ...................................................................................................29
1.4.3
Pharmacodynamics ................................................................................................31
1.5
Rationale ................................................................................................................31
1.5.1
Rationale for the Study Design................................................................................31
1.5.1.1
COVID-19 Pandemic-related Risk Assessment........................................................32
1.5.2
Rationale for Dose, Schedule and Regimen Selection..............................................32
1.5.3
Rationale for Placebo Comparator.........................................................................33
1.5.4
Rationale for Pharmacodynamics and Potential Predictive Biomarkers..................34
2
STUDY OBJECTIVES AND ENDPOINTS...........................................................36
2.1
Study Endpoints .....................................................................................................37
3
OVERALL STUDY DESIGN ................................................................................41
3.1
Study Design ..........................................................................................................41
3.1.1
Biologic-Naïve Main Study.....................................................................................41
3.1.2
Additional Dose Cohort..........................................................................................42
3.1.3
Biologic-Failure Substudy ......................................................................................42
3.1.4
Interim Analysis......................................................................................................43
3.1.5
Primary Analysis ....................................................................................................43
3.1.6
Safety Monitoring Team..........................................................................................44
3.1.7
Independent External Data Monitoring Committee.................................................44
3.1.7.1
Study Stopping Criteria (Criteria for Urgent Review of Clinical Data by the 
DMC) .....................................................................................................................44
3.1.8
Steering Committee.................................................................................................44
3.2
Study Duration for Subjects....................................................................................45
3.3
End of Trial ............................................................................................................46
4
STUDY POPULATION.........................................................................................47
4.1
Number of Subjects ................................................................................................47
4.2
Inclusion Criteria for the Biologic-naïve Main Study..............................................47
4.3
Exclusion Criteria for Biologic-naïve Main Study...................................................48
4.4
Inclusion Criteria for Biologic-Failure Substudy.....................................................52
4.5
Exclusion Criteria for Biologic-Failure Substudy....................................................52
5
TABLE OF EVENTS.............................................................................................53
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6
PROCEDURES......................................................................................................63
6.1
Screening Period.....................................................................................................63
6.2
Treatment Period ....................................................................................................66
6.3
Early Termination...................................................................................................67
6.4
Post-treatment Observational Follow-up Period......................................................68
6.5
Safety Assessments.................................................................................................69
6.5.1
Physical Examination .............................................................................................69
6.5.2
Electrocardiogram..................................................................................................69
6.5.3
Clinical Laboratory Assessments ............................................................................69
6.6
Efficacy Assessment...............................................................................................71
6.6.1
Assessment of SpondyloArthritis International Society Response Criteria ...............71
6.6.2
Ankylosing Spondylitis Disease Activity Score with CRP ........................................72
6.6.3
Bath Ankylosing Spondylitis Disease Activity Index ................................................72
6.6.4
Bath Ankylosing Spondylitis Functional Index ........................................................72
6.6.5
Patient Global Assessment of Disease Activity........................................................72
6.6.6
Total Back Pain......................................................................................................72
6.6.7
Nighttime Back Pain...............................................................................................73
6.6.8
Bath Ankylosing Spondylitis Metrology Index - Linear............................................73
6.6.9
Occiput to Wall Measurement.................................................................................73
6.6.10
Chest Expansion Measurement ...............................................................................73
6.6.11
Enthesitis Evaluation..............................................................................................73
6.6.12
Peripheral Joint Count ...........................................................................................73
6.6.13
MRI of Sacroiliac Joint and Spine (SPARCC Method) ............................................74
6.7
Pharmacokinetics....................................................................................................74
6.7.1
Sparse Pharmacokinetics Blood Draw....................................................................75
6.7.2
Intense Pharmacokinetics Blood Draw ...................................................................75
6.8
Biomarkers, Pharmacodynamics, Pharmacogenomics.............................................75
6.8.1
Biomarkers/Pharmacodynamics .............................................................................75
6.8.2
Pharmacogenomics ................................................................................................77
6.9
Patient Reported Outcomes.....................................................................................77
6.9.1
Ankylosing Spondylitis Quality of Life ....................................................................77
6.9.2
Medical Outcome Study Short Form 36-Item Health Survey, Version 2...................77
6.9.3
ASAS Health Index..................................................................................................77
7
DESCRIPTION OF STUDY TREATMENTS........................................................78
7.1
Description of Investigational Product ....................................................................78
7.2
Treatment Administration and Schedule .................................................................78
7.2.1
Overdose ................................................................................................................79
7.2.2
Dose Modification/Interruptions.............................................................................79
7.3
Method of Treatment Assignment...........................................................................80
7.4
Packaging and Labeling..........................................................................................80
7.5
Investigational Product Accountability and Disposal ..............................................80
7.6
Investigational Product Compliance........................................................................81
8
CONCOMITANT MEDICATIONS AND PROCEDURES....................................82
8.1
Permitted Concomitant Medications and Procedures...............................................82
8.2
Permitted Medications That Require Careful Monitoring........................................83
8.3
Prohibited Concomitant Medications ......................................................................83
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8.4
Vaccination Guidelines...........................................................................................84
8.5
Required Concomitant Medications and Procedures................................................85
9
STATISTICAL CONSIDERATIONS ....................................................................86
9.1
Overview................................................................................................................86
9.2
Study Population Definitions ..................................................................................86
9.3
Sample Size and Power Considerations...................................................................86
9.4
Background and Demographic Characteristics........................................................87
9.5
Subject Disposition.................................................................................................87
9.6
Efficacy Analysis....................................................................................................87
9.6.1
Statistical Methods .................................................................................................87
9.6.2
Multiplicity.............................................................................................................88
9.6.3
Subgroup Analyses .................................................................................................88
9.7
Safety Analysis.......................................................................................................88
9.8
Interim Analysis .....................................................................................................88
9.9
Other Topics...........................................................................................................89
9.9.1
Internal Safety Management Team..........................................................................89
9.9.2
Independent External Data Monitoring Committee.................................................89
9.9.3
Pharmacokinetic Analyses......................................................................................89
10
ADVERSE EVENTS..............................................................................................91
10.1
Monitoring, Recording and Reporting of Adverse Events .......................................91
10.2
Evaluation of Adverse Events.................................................................................91
10.2.1
Seriousness.............................................................................................................92
10.2.2
Severity/Intensity ....................................................................................................93
10.2.3
Causality ................................................................................................................93
10.2.4
Duration.................................................................................................................94
10.2.5
Action Taken...........................................................................................................94
10.2.6
Outcome .................................................................................................................94
10.3
Abnormal Laboratory Values..................................................................................94
10.4
Pregnancy...............................................................................................................94
10.4.1
Females of Childbearing Potential .........................................................................95
10.4.2
Male Subjects .........................................................................................................95
10.5
Adverse Events of Special Interest..........................................................................95
10.5.1
Photosensitivity Reactions ......................................................................................95
10.5.2
Hepatic Enzyme Elevations.....................................................................................96
10.5.3
Monitoring, Recording and Reporting of Adverse Events of Special Interest...........96
10.6
Reporting of Serious Adverse Events......................................................................96
10.7
Expedited Reporting of Adverse Events..................................................................96
11
DISCONTINUATIONS .........................................................................................98
11.1
Individual Stopping Criteria....................................................................................98
11.2
Treatment Discontinuation......................................................................................98
11.3
Study Discontinuation ............................................................................................98
12
EMERGENCY PROCEDURES.............................................................................99
12.1
Emergency Contact.................................................................................................99
12.2
Emergency Identification of Investigational Products .............................................99
13
REGULATORY CONSIDERATIONS.................................................................100
13.1
Good Clinical Practice..........................................................................................100
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13.2
Investigator Responsibilities .................................................................................100
13.3
Subject Information and Informed Consent...........................................................101
13.4
Confidentiality......................................................................................................101
13.5
Protocol Amendments...........................................................................................101
13.6
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................101
13.7
Ongoing Information for Institutional Review Board/ Ethics Committee ..............102
13.8
Termination of the Study ......................................................................................102
14
DATA HANDLING AND RECORDKEEPING...................................................103
14.1
Data/Documents ...................................................................................................103
14.2
Data Management.................................................................................................103
14.3
Record Retention..................................................................................................103
15
QUALITY CONTROL AND QUALITY ASSURANCE......................................105
15.1
Study Monitoring and Source Data Verification....................................................105
15.2
Audits and Inspections..........................................................................................105
15.3
Product Quality Complaint ...................................................................................105
16
PUBLICATIONS .................................................................................................107
17
REFERENCES.....................................................................................................108
18
APPENDICES......................................................................................................114
APPENDIX A
TABLE OF ABBREVIATIONS...........................................................115
APPENDIX B
MODIFIED NEW YORK CRITERIA FOR ANKYLOSING 
SPONDYLITIS (1984).........................................................................120
APPENDIX C
EXAMPLES OF DRUGS THAT ARE EXCLUDED BASED ON 
POTENTIAL DRUG-DRUG INTERACTIONS...................................121
APPENDIX D
EXAMPLES OF DRUGS THAT ARE SUBSTRATES FOR 
SELECTED TRANSPORTERS AND SHOULD BE USED WITH 
CAUTION............................................................................................123
APPENDIX E
TUBERCULOSIS HIGH BURDEN COUNTRY LIST ........................124
APPENDIX F
MULTI-DRUG RESISTANT TUBERCULOSIS HIGH BURDEN 
COUNTRY LIST .................................................................................125
APPENDIX G
HEPATOTOXICITY MONITORING CRITERIA FOR 
INTERRUPTION AND DISCONTINUATION OF 
INVESTIGATIONAL PRODUCT* .....................................................126
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LIST OF TABLES
Table 1:
Study Objectives ....................................................................................36
Table 2:
Study Endpoints .....................................................................................37
Table 3:
Table of Events, Screening, Baseline and 12-Week Placebo-
Controlled Treatment Period...................................................................53
Table 4:
Table of Events, Long-term Extension Period (52- Weeks).....................58
Table 5:
Study Treatment Administration (Number of Capsules)..........................79
Table 6:
Abbreviations and Specialist Terms......................................................115
Table 7:
Examples of Moderate or Strong Inhibitors and Moderate or 
Strong Inducers of CYP3A4/5 That are Excluded.................................121
Table 8:
Examples of Moderate or Strong Inhibitors of P-gp, Moderate or 
Strong Inducers of P-gp, and Strong Inhibitors of BCRP That are 
Excluded ..............................................................................................122
Table 9:
Examples of Substrates of One or More Potentially Affected 
Transporters with a Narrow Therapeutic Index and Should be 
Excluded ..............................................................................................122
Table 10:
Examples of Drugs That Are Substrates for BCRP, P-gp, 
OATP1B1/3, and OCT1 With a Narrow Therapeutic Index and 
Should be Used With Caution...............................................................123
Table 11:
Hepatotoxicity Monitoring Criteria**...................................................126
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LIST OF FIGURES
Figure 1:
Biologic-naïve Main Study Design .........................................................45
Figure 2:
Biologic-failure Substudy Design ...........................................................45
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1
INTRODUCTION
1.1
Disease Background
Ankylosing spondylitis (AS) is a chronic, systemic inflammatory disease of indeterminate etiology 
that affects the axial spine (spondylitis), with sacroiliitis as its hallmark. Other manifestations 
include involvement of peripheral joints, digits, and entheses. The most common presenting 
symptom is chronic back pain and progressive spinal stiffness, a result of inflammation affecting 
the spine and sacroiliac joints (Feld, 2018).  The most common extraarticular manifestations of 
AS include uveitis (~33%) (Zeboulon, 2008), inflammatory bowel disease (~7%), and psoriasis 
(~9%) (Stolwijk, 2015).  Ankylosing spondylitis is typically diagnosed in people younger than 40 
years and about 80% of patients develop first symptoms when they are younger than 30 years 
(Hanson, 2017).  It is estimated that approximately 70% of patients with AS are males (de Winter, 
2016).
Recent studies reported the prevalence of AS to range from 9 to 30 per 10,000 in the general 
population, depending on geographic area, study population or data source, case definition, and 
ascertainment methods (Wang, 2018).  In general, there is a clear correlation between the 
prevalence of AS in a given population and the prevalence of HLA-B27 in that group, with the 
prevalence of AS being approximately 5 to 6 percent among people who are HLA-B27-positive 
(Reveille, 2013).  Approximately 94% of individuals with AS are HLA-B27-positive 
(Brown, 1996). 
Although HLA-B27 is the largest single genetic contributor to disease pathophysiology, many 
other genetic loci, including those associated with the interleukin (IL)-17A pathway, have been 
associated with AS (Brown, 2016; Costantino, 2018).  Chronic inflammation in AS is thought to 
be driven by CD4+ and/or CD8+ T lymphocytes, including innate-like lymphocytes, and cytokines 
such as tumor necrosis factor (TNF)-α and IL-17A (Ranganathan, 2017). Classification criteria 
for AS were proposed based on clinical grounds in the 1960s and later modified to include 
radiological criteria, known as the modified New York criteria for diagnosis of AS (van der 
Linden, 1984) (APPENDIX B).  More recently, the Assessment of SpondyloArthritis international 
Society (ASAS) formulated classification criteria for axial spondyloarthritis (axSpA), of which 
AS is considered the prototype disease, based on imaging, clinical, and laboratory criteria 
(Rudwaleit, 2009a; Rudwaleit 2009b). Disease classification of axSpA is established in persons 
with a history of back pain for 3 or more consecutive months before reaching 45 years of age, the 
presence of sacroiliitis confirmed on magnetic resonance imaging (MRI) or plain radiography, and 
with at least one clinical or laboratory finding that is characteristic of spondyloarthritis (SpA).  
Alternatively, persons with this history who have a positive test result for HLA-B27 and ≥2 
clinical or laboratory features of SpA also fulfill the classification criteria for axSpA.  Individuals 
with axSpA who have established radiographic evidence of sacroiliitis are considered to have met 
the definition for AS (Rudwaleit, 2009a; Rudwaleit 2009b). 
The treatment goal in patients with AS is to optimize long-term health-related quality of life and 
social participation through control of signs and symptoms, prevention of structural damage, 
normalization or preservation of function, avoidance of toxicities and minimization of 
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comorbidities (Smolen, 2018).  Current treatment guidelines for active AS (Bath Ankylosing 
Spondylitis Disease Activity Index [BASDAI] of at least 4 or Ankylosing Spondylitis Disease 
Activity Score – C-reactive protein [ASDAS-CRP] of at least 2.1) strongly recommend the use of 
nonsteroidal anti-inflammatory drugs (NSAIDs) and conditionally recommend their continuous 
use, based on very low-quality evidence (van der Heijde D, 2017a).  Tumor necrosis factor (TNF) 
blockers and anti-IL-17A monoclonal antibody (mAb) agents have become standard of care for 
patients who are unresponsive or intolerant to NSAIDs.  Based on results of pivotal trials of 
currently approved biologics in AS, about 30% to 40% of patients treated with biologics do not 
achieve an Assessment of SpondyloArthritis International Society Response Criteria with an 
improvement of at least 20% (ASAS20) and up to 64% of patients do not achieve an Assessment 
of SpondyloArthritis International Society Response Criteria with an improvement of at least 40% 
(ASAS40) (Sieper 2017; Deodhar 2019).  Although biologics can reduce inflammation and 
improve symptoms, there is only indirect evidence that currently available biologic TNF blockers 
influence spinal radiographic progression (Haroon, 2014; Maas, 2017; Molnar, 2018), which 
continues to occur in spite of treatment (Poddubnyy, 2016).  Biologics require parenteral 
administration and are associated with development of auto-antibodies, which may be neutralizing 
and limit drug effectiveness.  In addition, profound TNF inhibition by currently available TNF-
directed biologics is associated with increased risks of serious infections and malignancies.
In summary, AS patients who fail or cannot tolerate NSAIDs, and those who have also failed 
therapy with biologic agents, represent a patient population with high unmet medical need and 
there are currently no approved oral medications available to treat the underlying disease.
1.2
Compound Background 
CC-99677 (also known as BMS-986371) is a novel, orally bioavailable, small-molecule covalent 
inhibitor of mitogen-activated protein (MAP) kinase-activated protein kinase 2 (MK2).  The MK2 
enzyme is a serine/threonine protein kinase that is regulated through direct phosphorylation by p38 
MAP kinase.  Inflammation mediated by MK2 is a consequence of an increase in the stability and 
translation of messenger ribonucleic acid (mRNA) of proinflammatory cytokines, such as TNF-α, 
IL-17 and IL-6. This is accomplished by phosphorylation and inhibition of the mRNA 
destabilizing function of tristetraprolin, which leads to cytokine translation (Hitti, 2006; Ronkina, 
2010).
CC-99677 is a potent and selective covalent inhibitor of MK2 in biochemical and cellular assays.  
The mean (standard deviation) half maximal effective concentration (EC50) in cellular assays was 
89 (2.6) nM.  Please refer to the Investigator’s Brochure for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and known adverse event 
profile.
1.3
Nonclinical Experience
CC-99677 inhibited production of proinflammatory cytokines, including TNF-α, IL-6, monocyte 
chemoattractant protein-1 (MCP-1), and IL-17A in vitro.  CC-99677 showed pharmacologic 
activity in a human leukocyte antigen (HLA)-B27 transgenic rat model of AS; this model is 
considered to be relevant to the study of human HLA-B27-associated diseases (O’Neill 1997; 
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Turner, 2005).  A dose of CC-99677 corresponding to MK2 engagement (target engagement [TE]) 
of approximately 70% was associated with greater decrease in paw swelling than etanercept, 
tofacitinib, or a lower (approximately 40%) level of TE.  The benefit of CC-99677 (mean 65% 
inhibition of paw swelling compared to vehicle control) was highly statistically significant.
Following oral doses, CC-99677 formed an active metabolite, CC-0782951, by O-deethylation 
which also formed a covalent bond with MK2.
Based on in vitro studies, cytochrome P450 (CYP) 3A4/5 is the major isozyme involved in 
oxidative metabolism of CC-99677.  CC-99677 is a weak to moderate inhibitor of multiple CYPs 
and a weak inducer of CYP2B6.  Given the expected exposures at the planned doses, CC-99677 
is unlikely to alter the levels of coadministered drugs due to inhibition or induction of hepatic CYP 
enzymes; however, there is potential for inhibition of gut CYP3A4/5 as CC-99677 concentrations 
may be higher in the intestinal lumen.
In vitro transporter studies indicate that at clinical doses CC-99677 has the potential to inhibit 
multiple drug transporters (p-glycoprotein [P-gp], breast cancer resistance protein [BCRP], 
organic cation transporter [OCT] 1, organic anion transporting polypeptide [OATP] 1B1, and 
OATP1B3), in addition, CC-99677 and its metabolite, CC-0782951, are substrates of P-gp and 
BCRP.  Compared to CC-99677, the major metabolite CC-0782951 has lower in vitro inhibitory 
potencies toward CYP enzymes and drug transporters. With a lower maximum plasma 
concentration (Cmax) than CC-99677 in humans, CC-0782951 is not expected to increase the 
potential in vivo CYP and drug transporter inhibition profile and therefore is not expected to alter 
the clinical drug-drug interaction (DDI) profile of CC-99677.  Based on the pharmacokinetic (PK) 
properties in animal models, CC-99677 is predicted to have an acceptable pharmacokinetic profile 
in humans (CC-99677 IB). 
1.3.1
Nonclinical Toxicology
CC-99677 has been evaluated in a battery of oral repeat-dose toxicity studies with up to 26-weeks
of dosing in mice and 39- weeks of dosing in the monkey. In addition, dose range-finding prenatal 
development studies (rabbits and mice), a fertility and early embryonic development study in mice, 
and genetic toxicity studies (in vitro and in vivo) were conducted. The phototoxic potential of 
CC-99677 was evaluated in vitro, and in vivo using mice. The oral route of administration was 
used for all in vivo toxicity studies as it is the route of clinical administration. The main circulating 
components in animal plasma were CC-99677 and its active metabolite CC-0782951. 
In the Good Laboratory Practice (GLP)-compliant repeat-dose toxicity studies, heart muscle, 
skeletal muscle, liver, duodenum, stomach, adrenal gland, bone marrow, spleen and thymus were 
identified as target organs for CC-99677.
In mice, adverse effects noted in 28- and 91-day studies were minimal to mild myofiber 
degeneration or cardiomyopathy at 750 mg/kg/day. No microscopic findings were noted in the 
hearts of recovery mice in the 91-day study. In a 26-week study in mice, there was mortality at 
750 mg/kg/day that was associated with adverse clinical observations. Some of these animals had
microscopic changes where stress may be a contributing factor, including decreased hematopoietic 
cellularity in the bone marrow and decreased lymphocytes and/or lymphoid necrosis in the spleen 
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and thymus.  Surviving animals exhibited similar clinical observation that were less severe.  In 
contrast to the shorter term studies, there were no effects noted in the hearts of early decedents or 
surviving mice in the 26-week study.  Based upon adverse findings and mortality at 
750 mg/kg/day, the no observed adverse effect level (NOAEL) in mice after 26 weeks of dosing 
was 100 mg/kg/day, corresponding to a mean area under the concentration-time curve from time 
zero to the last measurable time point (AUCLST) of 23,500 and 30,600 ng∙hr/mL for CC-99677 in 
males and females, respectively and a mean AUCLST of 2,030 and 4,620 ng∙hr/mL for CC-0782951
in males and females, respectively.
In monkeys, administration of CC-99677 once daily for up to 39-weeks to male and female 
monkeys was well tolerated at doses up to 375 mg/kg/day. No adverse findings were noted in any 
study.  Test article-related but nonadverse microscopic findings were limited to degenerative 
changes in the skeletal muscle at > 150 mg/kg/day in the 28-day study; no findings in skeletal 
muscle were noted after 91 days or 39 weeks using the same dose levels. There were no associated 
changes in clinical pathology parameters for the findings in skeletal muscle in the 28-day study. 
In the 39-week study, minimal to mild increases in platelets were noted at ≥50 mg/kg/day, which 
were most pronounced on Day 181, and were partially or fully resolved at the terminal collection 
on Day 272, despite continued dosing.
Based upon the lack of adverse changes in any parameter evaluated at up to 39-weeks of dosing, 
the NOAEL for CC-99677 was 375 mg/kg/day, the highest dose tested corresponding to an 
exposure (AUCLST) of 10,800 ng∙hr/mL for males and 6,350 ng∙hr/mL for females and for the 
metabolite CC-0782951 was 7,470 ng∙hr/mL for males and 5,650 ng∙hr/mL for females.  The 
lowest NOAEL exposures were achieved in female monkeys in the 39-week study.  These 
exposures are approximately 4.7- and 8.4-fold higher for parent and metabolite, respectively, than 
the expected exposures in humans at 150 mg.
CC-99677 was negative in the bacterial mutagenicity assay, the in vitro micronucleus assay in 
human peripheral blood lymphocytes (HPBL), and the in vivo micronucleus assay in mice. In 
prenatal development studies in mated female mice, all mice given 750 mg/kg/day, the highest 
dose tested, were euthanized due to poor clinical condition.  In mice given 15 and 100 mg/kg/day, 
no developmental toxicity or adverse maternal effects were observed. In prenatal development 
studies in time-mated female rabbits, severe maternal toxicity was observed at 375 mg/kg/day, the 
highest dose tested. Heart malformations and Tetralogy of Fallot were noted in rabbit fetuses at ≥ 
15 mg/kg/day, the lowest dose tested. The NOAEL for developmental toxicity in rabbits was 
determined to be < 15 mg/kg/day.
CC-99677 reduced fertility and fecundity indices in male and female mice and adverse ovarian 
and uterine parameters in females at 750 mg/kg/day. The NOAEL for reproductive performance 
and fertility was 100 mg/kg/day in mice.
There was no evidence of cutaneous phototoxicity in hairless mice administered 15 mg/kg/day and 
subsequently exposed to light; however, cutaneous phototoxicity (erythema, edema, and/or skin
flaking) was observed in mice administered doses ≥ 100 mg/kg/day.
Please refer to the Investigator’s Brochure for detailed information toxicity studies.
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1.4
Clinical Experience
As of May 17, 2021, CC-99677 has been administered to 162 healthy subjects in 3 completed 
clinical pharmacology studies (CC-99677-CP-001, CC-99677-CP-002, and CC-99677-CP-003).
In the clinical pharmacology study CC-99677-CP-002, CC-99677 was administered to healthy 
volunteers (N = 16) in an open-label study to evaluate effects of cytochrome P450 inhibition and 
induction of the pharmacokinetics of CC-99677 and effects of CC-99677 on the pharmacokinetics 
of digoxin, metformin, methotrexate, midazolam, rosuvastatin, and sulfasalazine (Data on file
from Celgene Corporation; Section 1.4.1 and Section 1.4.2).
Study CC-99677-CP-003 was designed to investigate whether the coadministration of CC-99677
would affect the PK of combined oral contraceptives Ortho Tri-Cyclen containing 0.035 mg 
ethinyl estradiol and 0.180 mg/0.215 mg/0.250 mg norgestimate (Data on file from Celgene 
Corporation; Section 1.4.1 and Section 1.4.2).
Study CC-99677-CP-004 is an additional ongoing clinical pharmacology study to evaluate the 
safety, tolerability, PK, pharmacodynamics (PD) and pharmacogenomics of CC-99677 in healthy 
adult Japanese volunteers. The data will be used to support the inclusion of Japanese subjects in 
future CC-99677 Phase 2 and 3 clinical trials. No clinical data are available yet for CC-99677-CP-
004 to inform the clinical experience with CC-99677.
1.4.1
Efficacy and Safety
CC-99677-CP-001 was a Phase 1, three-part study with a double-blind, placebo-controlled, single 
ascending dose (SAD) phase, a double-blind multiple ascending dose (MAD) phase, and an open-
label cross-over food effect phase. The study enrolled a total of 97 healthy adult subjects.
Part 1 (SAD phase) evaluated the safety, tolerability, and PK of CC-99677 following single oral 
doses of 3 mg to 400 mg. In Part 1, 48 subjects were randomized and enrolled into 6 cohorts. Each 
cohort consisted of 8 subjects: 6 subjects received CC-99677, and 2 subjects received placebo.  
The most common treatment-emergent adverse events (TEAEs) in this part were in the categories 
of musculoskeletal and connective tissue disorders, skin and subcutaneous tissue disorders, and 
infections and infestations. In Part 1, 5 of the 22 total TEAEs were suspected to be related to CC-
99677. The most common TEAEs suspected of being related to CC-99677 were in the skin and 
subcutaneous tissue disorder category with 2 TEAEs in 2 subjects who had a mild, transient, 
pruritic, erythematous rash without other organ involvement at the 400-mg dose level.  The 
majority of TEAEs were mild in nature. Only one TEAE was moderate in nature (gastroenteritis
lasting less than 24 hours in the 30 mg cohort).  There were no severe TEAEs or serious adverse 
events (SAEs).
Part 2 (MAD phase) evaluated the safety, tolerability, and PK of CC-99677 following multiple 
daily oral doses of 10, 30, 60, 120, and 150 mg. In Part 2, 37 subjects were randomized and 
enrolled and received 14 days of dosing. The most common TEAEs in Part 2 were categorized 
under nervous system disorders (headache and dizziness) and gastrointestinal disorders (nausea, 
constipation, diarrhea, abdominal pain, dyspepsia, and rectal bleeding). In Part 2, 9 of the 42 total 
TEAEs were suspected to be related to CC-99677. The most common TEAEs suspected of being 
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related to CC-99677 in Part 2 were in the vascular disorders class with 2 TEAEs in 2 subjects (skin 
flushing in 1 subject and hot flush in 1 subject). In the 120-mg dose cohort there was an 
observation in 3 of 6 subjects on active treatment with an increase in serum transaminase levels 
(alanine aminotransferase [ALT] in particular) above the upper limit of the normal reference range
(ULN). The ALT elevation in one of these subjects, which peaked at 2.3 X ULN at Day 17, was 
judged by the Investigator to be a TEAE suspected to be related to CC-99677. This adverse event 
(AE) resolved without intervention when the ALT returned toward the normal reference range by
day 28. The other 2 subjects had ALT elevations less than 2x above the upper limit of normal. 
All subjects in the 120-mg cohort with ALT values crossing above the ULN were asymptomatic, 
and on follow-up laboratory testing after completion of dosing, all transaminase levels began to 
return toward the baseline values without intervention. No other liver chemistry abnormalities 
were noted. In the subsequent 150-mg dose cohort, no transaminase level changes were observed 
in any subject during the 14-day dosing period. One subject in the 150-mg dose cohort was found 
to have an elevated aspartate transaminase (AST) level on outpatient follow up 14 days after the 
end of dosing (Day 28). This was determined to be the result of increased exercise undertaken by 
the normally sedentary subject after leaving the site at the end of the confinement period. There 
was no apparent trend towards increasing liver transaminase concentrations (ALT and AST) in 
any subject in that dose cohort.
The PK of CC-99677 was assessed in 48 healthy human subjects in Study CC-99677-CP-002. 
Study CC-99677-CP-002 was a Phase 1, three-part, open-label, DDI study to assess the safety, 
tolerability, and PK of BMS-986371 administered alone or in combination with methotrexate and 
sulfasalazine; itraconazole; rifampin; midazolam; or a cocktail of digoxin, metformin, and 
rosuvastatin in healthy subjects. CC-99677, administered alone; coadministered with methotrexate 
and sulfasalazine; or coadministered with itraconazole, rifampin, midazolam, or a cocktail of 
digoxin, metformin, and rosuvastatin, was generally safe and well tolerated by the healthy adult 
subjects in this study. Overall, 13 of 48 subjects (27.1%) experienced at least 1 TEAE. With the 
exception of 1 severe TEAE of increased transaminases experienced by 1 subject, all other TEAEs 
were considered mild in severity. No TEAEs were suspected of being related to any study drug. 
No deaths or other serious TEAEs were reported, and no subjects discontinued due to a TEAE
(CC-99677 IB).
Study CC-99677-CP-003 was a Phase 1, open-label, fixed-sequence, cross-over study on the 
effects of BMS-986371 on the PK of an oral contraceptive (OC) in healthy female subjects. There 
were no deaths or SAEs in the study. Overall, 13 of 28 subjects (46.4%) experienced at least 1 
TEAE (total of 26 TEAEs). With the exception of 3 moderate TEAEs and 1 severe TEAE, all other 
TEAEs were considered mild in severity. Overall, 7 subjects (25.0%) reported TEAEs that were 
suspected of being related to the study drug: 6 subjects (21.4%) after receiving the OC and prior 
to CC-99677 dosing on Cycle 2 Day 15, and 3 subjects (12.5%) after receiving the OC and/or CC-
99677 on or after Cycle 2 Day 15 and throughout the 28-day follow-up. After receiving the OC, 4 
subjects (14.3%) reported TEAEs that led to discontinuation from the study. In this study, of note, 
asymptomatic
self-limited
elevations of
alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) were reported as TEAEs in 2 subjects per the study protocol based on the 
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degree of elevation above the laboratory reference range. Both increased hepatic enzyme TEAEs 
occurred after the last day of OC+CC-99677 dosing and during the 28-day follow-up period, when 
only OC was being dosed. In the first subject, this was noted 29 days after the last CC-99677 dose 
(ALT: 1.78× above the upper limit of the reference range; AST: 1.05× above the upper limit of the 
reference range), and the investigator did not suspect a relationship, as there was no clear temporal 
relationship. In the second subject, elevation in levels began during the OC-only treatment phase 
and peaked 27 days after the last dose of CC-99677 (ALT: 9.94× above the upper limit of normal;
AST: 2.73× above the upper limit of normal). The investigator felt there was a reasonable 
possibility that the study drug was the cause of the event. However, this subject had additional risk 
factors of prior biliary disease, fatty liver, and an overweight body mass index of 29.8. Therefore, 
the Sponsor deemed the precise etiology of these abnormal hepatobiliary laboratory results to be 
unknown. Bilirubin levels remained within normal limits for both subjects (please refer to CC-
99677 IB for additional details). 
Based upon review of the safety data, including physical examinations, vital sign measurements, 
clinical laboratory assessments, electrocardiograms (ECGs), and TEAEs, CC-99677 appears to be 
well tolerated when administered as a single dose up to 400 mg and when administered for 14 days 
up to 150 mg.
1.4.2
Pharmacokinetics
The PK of CC-99677 in healthy human volunteers was assessed in study CC-99677-CP-001. This 
clinical pharmacology study evaluated single doses of CC-99677 ranging from 3 to 400 mg and 
also repeat daily doses (QD x 14 days) of CC-99677 ranging from 10 mg to 150 mg. 
Following single oral dosing, CC-99677 was rapidly absorbed with a median time to observed 
maximum plasma concentration (Tmax) of 1 to 3 hours across the dose range of 3 mg to 400 mg.
The systemic exposure (maximum plasma concentration [Cmax] and area under the curve [AUC]) 
of CC-99677 increased in an approximately dose proportional manner across this range. The 
terminal elimination half-life (t½) ranged from (geometric mean) 1.66 to 6.95 hours.  
After multiple daily doses, CC-99677 was absorbed rapidly with a Tmax of 1 to 2.5 hours across 
the dose range of 10 mg to 150 mg. The systemic exposures (Cmax and AUC) on Day 14 of 
CC-99677 increased in an approximately dose-proportional manner. The t½ on Day 14 was similar 
across studied doses, ranging from (geometric mean) 1.96 to 4.39 hours. There was limited 
accumulation of CC-99677 (range of accumulation ratio for AUC0-t was 1.1 to 1.2 from 10 to 150 
mg, respectively) upon repeated daily doses.
CC-99677 forms a pharmacologically active metabolite, CC-0782951 (formed by O-deethylation). 
Following single oral doses of CC-99677, CC-0782951 was formed with a Tmax of approximately
1 to 3 hours across the dose range of 3 mg to 400 mg. With increasing dose, Cmax and AUC0-t 
increased in an approximately dose-proportional manner from 3 mg to 400 mg of single doses. 
The geometric mean t½ of CC-0782951 ranged from 1.60 to 6.59 hours. 
After multiple daily doses of CC-99677, CC-0782951 formed rapidly at a median Tmax of
approximately 1 to 3 hours across the dose range of 10 mg to 150 mg. The t½ of CC-0782951 was 
similar after multiple daily doses (QD x 14 days), ranging from 2.13 to 4.4 hours across the studied 
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dose groups. There was limited accumulation of CC-0782951 (range of accumulation ratio for 
AUC0-t was 0.9 to 1.2 from 10 to 150 mg, respectively) upon repeated daily doses.
Food has limited effect on the PK of the current formulation of CC-99677. Therefore, CC-99677 
can be taken with or without food.
In Part 1 of Study CC-99677-CP-002, the effect of CC-99677 as a potential perpetrator of BCRP 
transporter based DDI was evaluated. To achieve this objective, methotrexate and sulfasalazine, 
both BCRP substrates and important concomitant medications in the rheumatologic indications for 
which CC-99677 is being studied, were administered in a cocktail approach to adult healthy male 
volunteers. The cocktail consisted of 7.5 mg of methotrexate and 1000 mg of sulfasalazine; CC-
99677 was administered at a dose of 150 mg between Day 3 to Day 8. Serial PK samples were 
collected to characterize PK of methotrexate and sulfasalazine when administered without and 
with CC-99677. Pharmacokinetics of CC-99677 and its metabolite CC-0782951 was also collected 
during the combination phase with methotrexate and sulfasalazine.
The effect of CC-99677 on the plasma exposure of methotrexate and sulfasalazine was minimal 
with an approximate 50% increase in exposures in the presence of CC-99677 between the 
respective single administration of methotrexate or sulfasalazine and co-administered with CC-
99677. The minimal change in PK exposure suggests a limited clinically relevant drug-drug 
interaction with BCRP.  For narrow therapeutic index drugs, BCRP substrates should be used with 
caution.  Concomitant dosing of methotrexate and sulfasalazine did not impact the PK exposures 
of CC-99677 and CC-0782951 based on comparison of historical PK data from PK data of CP-
001, and consistent with a minimal extent of biliary secretion of CC-99677.  These data indicate 
that coadministration of methotrexate or sulfasalazine would have limited impact on exposures of 
CC-99677 and CC-0782951.
In Part 2 of Study CC-99677-CP-002, coadministration of CC-99677 with itraconazole increased 
CC-99677 exposure by 150%. Coadministration of CC-99677 with rifampin reduced CC-99677
exposure by 92.4%. Therefore, concomitant use of strong or moderate CYP3A4/5 and/or P-gp 
inhibitors or inducers is prohibited.
In Part 3 of Study CC-99677-CP-002, coadministration of CC-99677 did not have a clinically 
meaningful effect on midazolam or metformin exposure. Therefore, concomitant use of CC-99677 
with either CYP3A4/5 or OCT2 substrates is permitted. Coadministration of CC-99677 with 
rosuvastatin increased rosuvastatin exposure modestly by 41%. Based on this result with 
rosuvastatin and the lack of effect on the CYP3A4/5 substrate midazolam, coadministration of CC-
99677 with statins is allowed with routine monitoring (eg, hepatic enzyme elevations and muscle 
soreness) of statin-associated adverse events (AEs). 
In Study CC-99677-CP-003, coadministration of CC-99677 and Ortho Tri-Cyclen did not have a 
clinically meaningful effect on ethinyl estradiol, norgestrel, or 17-desacetyl norgestimate 
exposure. Therefore, concomitant administration of CC-99677 and oral contraceptives is allowed.
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1.4.3
Pharmacodynamics
The pharmacodynamics (PD) of CC-99677 were assessed during Parts 1 and 2 of Study CC-99677 
CP-001 by evaluating the effect of ascending dose levels of CC-99677 on target engagement (TE)
with MK2 protein and on levels of proinflammatory cytokines using a whole-blood ex vivo assay 
in which blood isolated from subjects treated with CC-99677 or placebo was incubated with 
lipopolysaccharide stimulation (LPS) for 24 hours.  A dose dependent increase in TE and TNF 
inhibition in the ex vivo assay was observed by 4 hours with single oral doses ranging from 10 mg 
to 400 mg in Part 1 of Study CC-99677-CP-001.  Daily dosing of CC-99677 in Part 2 of the study 
resulted in a dose-dependent increases in TE following doses between 10 mg and 120 mg and 
plateauing at the 120 mg and 150 mg dose levels.  This was accompanied by sustained reductions 
in TNF-α over 14 days of dosing, at doses greater than 10 mg, with maximal inhibition at 150 mg.
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, drug metabolism, clinical studies, and known adverse event profile.
1.5
Rationale
1.5.1
Rationale for the Study Design
CC-99677-AS-001 is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study 
to evaluate the efficacy and safety of 2 dose groups of CC-99677 in subjects with active AS.  The 
main study population comprises AS subjects who have failed therapy with at least 2 NSAIDs; an 
additional substudy will recruit AS subjects who have failed therapy with 2 NSAIDs and who have 
also failed 1 biologic agent.  These patient populations were chosen to represent AS patients most 
likely to derive clinical benefit from CC-99677.  Since biologic-failure subjects are expected to be 
less responsive to anti-inflammatory treatments, in general, the benefit-risk profile of CC-99677 
will be evaluated separately for the main study population and the substudy population.
Efficacy assessment in this study will be based on patient and physician-reported outcomes, and 
objective measures of inflammation and disease activity. The ASAS Response Criteria are based 
on a disease assessment tool that utilizes results from a subject self-administered survey.  The 
ASAS20 and ASAS40 criteria have been widely validated as tools to measure symptomatic 
improvement in the context of AS clinical trials (Anderson, 2001; Brandt, 2004).  The ASAS20 is 
the primary endpoint in this study and has been used extensively in most Phase 2 and 3 clinical 
trials in AS.  Several other disease activity measures will be assessed to corroborate the efficacy 
evaluation of CC-99677 during the study. These include ASAS40, ASDAS-CRP (van der Heijde, 
2009), BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing 
Spondylitis Metrology Index-Linear (BASMI-Linear) (Sieper, 2009).
Magnetic resonance imaging of the spine and sacroiliac joints using the Spondyloarthritis Research 
Consortium of Canada (SPARCC) scoring system (Maksymowych, 2005; Maksymowych, 2010)
will be performed to assess the effect of CC-99677 on spinal and sacroiliac joint inflammation.  
Magnetic resonance imaging provides an objective assessment of inflammation and evidence of 
sacroiliitis and predicts radiographic progression of disease (reviewed in Schwartzman, 2019). In 
clinical trials of AS, clinical improvements are accompanied by rapid (within 12 weeks) reduction 
in bone marrow edema, as measured by MRI (Lambert, 2007; Braun, 2017; van der Heijde, 2017b; 
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van der Heijde, 2018).  Therefore, MRI provides a rapid, responsive PD measure of inflammation 
and will yield supportive evidence of efficacy of CC-99677.
The 12 weeks treatment duration of this trial is considered adequate to assess potential clinical 
benefits and improvements in spinal and sacroiliac joint inflammation, as assessed by MRI.  This 
duration is consistent with other trials of biological agents in AS (Mease, 2019).  In 24-week, 
placebo-controlled trials of biologics in AS, maximal clinical benefits were already apparent after 
12 weeks of treatment (Davis, 2003; Inman, 2008; Landewé, 2014), suggesting that 12 weeks of 
treatment is the optimal duration to demonstrate the maximal benefit of an anti-inflammatory agent 
while minimizing the duration of treatment with placebo.
The 52-week Long-term Extension Period following Week 12 will provide additional exploratory 
long-term safety and efficacy information and enable those subjects randomized to placebo in the 
placebo-controlled period the opportunity to receive CC-99677 during the extension period. The 
16-week timepoint to assess subject eligibility to continue in the Long-term Extension provides
the shortest duration to reasonably assess efficacy of CC-99677 in those subjects receiving placebo
through Week 12.  In other trials of AS, attainment of ASAS20 was observed in a high proportion 
of subjects as early as 4 weeks following onset of treatment (Landewé, 2014; van der Heijde, 
2018). Therefore, it is anticipated that clinical benefits of CC-99677 should already be apparent
following 4 weeks of treatment. Discontinuing treatment in nonresponders ensures that subjects 
who are unlikely to derive benefits from CC-99677 do not remain in the study beyond 16 weeks.
The planned Interim Analysis (IA) (see Section 3.1.4) will provide additional information on 
observed safety and efficacy of CC-99677. A Steering Committee (see Section 3.1.8) will review 
the Interim Analysis data and determine whether to add an additional dose.  For example, if 60 mg 
and 150 mg dose groups demonstrate similar robust efficacy an additional low-dose cohort will be 
added to potentially define a lower efficacious dose.
1.5.1.1
COVID-19 Pandemic-related Risk Assessment
While the global coronavirus disease 2019 (COVID-19) pandemic has been identified as a 
potential risk to clinical trial subjects in general, and it may particularly affect individuals with 
underlying chronic diseases, the overall benefit-risk for participation in this AS study with CC-
99677 is considered favorable.  The individual benefit-risk considerations regarding COVID-19 
infection remains the responsibility of the Investigator.  Testing to exclude COVID-19 infection 
prior to enrollment and to inform decisions about subject care during the study should follow local 
standard practice and requirements.  Based on the mechanism of action, pharmacological 
modulation of the MK2 pathway by CC-99677 may alter the host response to infection and 
potentially predispose to infections, including COVID-19.
1.5.2
Rationale for Dose, Schedule and Regimen Selection
Daily doses of 60 mg and 150 mg CC-99677 were selected for this trial based on preclinical and 
clinical data in addition to simulation that supports adequate target engagement at clinically 
tolerated doses.
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In the CC-99677-CP-001 study of healthy volunteers, daily doses between 60 mg and 150 mg were 
associated with exposures of CC-99677 that were sufficient to achieve levels of the TE in humans 
that correlate with efficacy in multiple preclinical animal models.  In multiple animal models of 
arthritis and skin inflammation, TE of 40% and above were associated with efficacy, and greater 
levels of TE were associated with greater improvements in disease activity. In the human 
leukocyte antigen - B27 transgenic (HLA-B27Tg) model of AS in rats, TE of approximately 70% 
was associated with a greater decrease in paw swelling as compared to therapeutic doses of 
etanercept, a biologic TNF-α inhibitor, and tofacitinib, a Janus kinase (JAK) inhibitor (CC-99677 
IB). In ex vivo studies of peripheral blood mononuclear cells (PBMCs) from healthy volunteers, 
TE of 60% achieved approximately 70% inhibition of TNF-α secretion.  The relationship between 
CC-99677 exposure and TE was explored using a maximum effect (Emax) model with clinical 
data from study CC-99677-CP-001.  The 60 mg and 150 mg doses correspond to exposures with 
a predicted median TEs of approximately 67% and 79%, respectively.  These two doses represent 
a distribution across a range of target engagement levels that can be expected to lead to clinical 
benefits in AS.
In a 91-day repeat-dose toxicology study with mice, the NOAEL was determined to be 
100 mg/kg/day, corresponding to a mean AUCLST of 28800 and 3590 ng·hr/mL for CC-99677 and 
CC-0782951, respectively. In humans, the highest dose tested in this study will be 150 mg, which 
corresponds to an observed AUCLST of 1361 ng·hr/mL and 670.3 ng·hr/mL for CC-99677 and CC-
0782951, respectively. These represent 21-fold and 5.4-fold margins below the mouse NOAEL 
for CC-99677 and CC-0782951, respectively.  The NOAEL in mice was based on microscopic 
findings in the heart at a dose of 750 mg/kg/day (mean AUCLST of 144000 ng·hr/mL and 39900
ng·hr/mL for CC-99677 and CC-0782951, respectively).  This adverse finding was not observed 
in the 28- and 91-day studies in cynomolgus monkeys, which resulted in AUCLST at the NOAEL 
corresponding to the highest dose tested, 375 mg/kg/day, of 9115 and 6470 ng·hr/mL for CC-
99677 and CC-0782951, respectively. The exposures in monkeys represent 6.7-fold and 9.7-fold 
margins for CC-99677 and CC-0782951, respectively, based on the 150-mg dose.
Safety and tolerability data from study CC-99677-CP-001, which included single-dose and 
multiple-dose testing in healthy volunteers, support the proposed doses.  In addition, there was 
limited to no observed accumulation of CC-99677 and limited accumulation of the major 
metabolite, CC-0782951, with daily dosing for 14 days (CC-99677 IB).  In summary, the 
nonclinical and clinical safety, tolerability, exposure, PD, and preclinical efficacy data indicate 
that the proposed doses are appropriate for this study.
1.5.3
Rationale for Placebo Comparator
A placebo arm is needed in this Phase 2 trial to accurately determine the benefit-risk profile of 
CC-99677.  Placebo ASAS20 response rates in AS clinical trials have been highly variable, 
ranging from 28.3% (van der Heijde, 2018) to 41.2% (van der Heijde, 2017b). The relatively high 
and variable placebo response rate has a significant impact on interpretation of efficacy in 
therapeutic AS trials and justifies the need to determine the placebo-adjusted response rate to 
adequately assess the treatment benefit of CC-99677 in AS.  The use of placebo for 12 weeks is 
deemed acceptable by the AS research community as evidenced by multiple recently published 
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AS studies with other compounds.  In addition, the European Union guidance on the clinical 
investigation of medicinal products for the treatment of axial spondyloarthritis also recommends 
placebo-controlled studies (European Medicines Agency [EMA], 2017).
1.5.4
Rationale for Pharmacodynamics and Potential Predictive Biomarkers
CC-99677 is a potent and selective inhibitor of MK2 in biochemical and cellular assays; moreover, 
it is an effective inhibitor of inflammation in vivo in animal models and of pro-inflammatory 
cytokines in vitro in patient-derived cells. These pro-inflammatory cytokines and chemokines 
include TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-17A and have been shown 
to be increased in AS patients (Braun, 2002; West, 2017; Romero-Sanchez, 2011). Additionally, 
increased serum levels of TNF-α have been correlated with increased CRP levels in AS patients 
(Wagner, 2012). Thus, endogenous levels of TNF-α, IL-17A, and MCP-1 (among other soluble 
factors) in serum, as well as CRP, will serve as PD biomarkers. Reduction in CRP will provide 
evidence of modulation of a disease-relevant biomarker and establish a link to a clinical endpoint,
as measured by ASDAS-CRP. The effect of CC-99677 administration on endogenous TNF-α and 
other circulating inflammatory factors will provide additional evidence of pathway modulation 
and proof of mechanism. 
MK2 target engagement will be measured at each dose level and will allow for determination of 
PK/TE/PD/efficacy correlations and comparisons to previous studies and support dose selection 
in future studies. 
In AS, several bone remodeling processes take place simultaneously: pathologic new bone 
formation in the form of syndesmophytes and bone loss in the form of bone erosion, osteolysis, 
and bone mineral density (BMD) loss leading to osteoporosis (Klingberg, 2012). CC-99677 has 
been shown to reduce bone resorption activity in vitro. Bone formation markers, such as 
procollagen type 1 N-terminal propeptide (P1NP) and bone resorption markers, such as carboxy 
terminal cross-linked telopeptide of type 1 collagen (CTX-1), are released from osteoblasts and 
osteoclasts, respectively (Arends, 2014).  These biomarkers will be assessed in the study, providing 
an early evaluation of CC-99677 effect on bone remodeling.
Bone destruction is mediated by the recruitment of osteoclast precursors (OCPs) into the inflamed 
tissue and their differentiation into mature osteoclasts. TNF inhibition has resulted in sustained 
loss of circulating OCPs that can differentiate into osteoclasts (Lam, 2000; Li, 2004). CC-99677 
was found to inhibit osteoclast differentiation in vitro, suggesting that MK2 inhibition may result 
in a similar reduction in osteoclast precursors in AS subjects. 
Although TNF and IL-17 blockers as well as other emerging therapies are efficacious in patients 
with AS, not all patients derive benefits from these treatments. To identify biomarkers that 
potentially stratify subjects based on disease characteristics and response to CC-99677 treatment, 
pharmacogenetic and PD analyses will be incorporated in this study.
The analysis of variations or mutations in genes thought to be relevant to the drug’s target pathway, 
and/or to the pathogenesis of the disease, may provide information relevant to differential 
responses of subjects to CC-99677. Genetic markers to be assessed include, but are not limited to, 
those involved in MK2 signaling, such as regulatory variants associated with circulating protein 
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levels of MK2 and other members of the MK2 pathway (Sun, 2018), CC-99677 metabolism 
(functional variants in CYP3A4, CYP3A5, CYP3A7, CYP2C8, and CYP2C9), and those shown 
to be associated with AS, including individual genetic variants such as HLA-B27 as well as 
polygenic risk scores built using public AS data (Rostami, 2019).
Whole genome ribonucleic acid (RNA) sequencing will be used to examine the quantity and 
sequences of RNA in blood, and to explore pharmacodynamics and opportunities for AS patient 
stratification with respect to response to CC-99677 special attention will be given to previously 
reported markers of AS in whole blood transcriptomics (Pimentel-Santos, 2011) and sexual 
dimorphism in AS (Gracey, 2016). Additionally, experiments are in progress to establish the 
signature of CC-99677 treatment on immune cells; such signatures, if identified, may be explored 
in the RNA sequencing data. Protein expression of cytokines and chemokines that we have shown 
to be modulated by CC-99677, including but not limited to TNF-α, IL-17A and MCP-1, will be 
monitored for stratification purposes as well.  It is anticipated that the above biomarkers will be 
useful in monitoring disease course, predicting therapeutic response, and guiding population 
selection for future studies.  In addition, serum samples will be biobanked at specified timepoints 
(Table 3 and Table 4) for SARS COV-2 serology.
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2
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate the dose dependent efficacy of oral CC-
99677, administered every day (QD), compared to placebo, as determined by the attainment of 
ASAS20 response after 12 weeks of treatment, in subjects with radiologically confirmed 
ankylosing spondylitis (AS) and inadequate response to nonsteroidal anti-inflammatory drugs 
(NSAIDs).
Secondary Objectives
To evaluate the effects of oral CC-99677, administered QD, compared to placebo, after 12 
weeks of treatment in subjects with AS, on:

The signs and symptoms of AS, as assessed by attainment of ASAS40 response, 
ASDAS-CRP, and BASDAI

Measures of physical function, as assessed by BASFI

Spinal and sacroiliac joint inflammation as measured by Spondyloarthritis Research 
Consortium of Canada (SPARCC) MRI score of sacroiliac joints and spine

Percent change from baseline in C-reactive protein (hsCRP)

Safety and tolerability
Exploratory Objectives
To evaluate the effects of oral CC-99677, administered QD in subjects with AS, on:

The signs and symptoms of AS, as assessed by the attainment of ASAS20 and ASAS40
(excluding Week 12)

The signs and symptoms of AS, as assessed by ASDAS-CRP (excluding Week 12),
achievement of a clinically important improvement (ASDAS-CRP ≥ 1.1), a major 
improvement (ASDAS-CRP ≥ 2.0) and attainment of inactive disease (ASDAS-CRP < 
1.3)

The signs and symptoms of AS, as assessed by BASDAI (excluding Week 12)

Measures of physical function, as assessed by BASFI (excluding Week 12)

Spinal mobility, as assessed by BASMI-Linear, Chest expansion, and Occiput to wall 
distance at Weeks 4 through Week 64

High-sensitivity C-reactive protein (hsCRP) level at Weeks 2 through 64

Enthesitis, as assessed by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)
at Weeks 4 through 64

Peripheral arthritis, as determined by swollen joint count at Weeks 4 through 64

Quality of life, as assessed by Ankylosing Spondylitis Quality of Life (ASQoL), Short 
Form-36 (SF-36), and ASAS Health Index (ASAS HI) at Weeks 12, 24 and 64

Pharmacokinetics (PK) of CC-99677 at Weeks 4 through 12

Target Engagement of CC-99677 at Weeks 4 through 12
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Table 1:
Study Objectives

Relationship between CC-99677 exposure and serum pharmacodynamic (PD) 
biomarkers (including but not limited to TNF-α, IL-6, IL-17A, IL-23) at Weeks 4 
through 64

Whole blood mRNA gene expression profiling in relationship to treatment response at 
Weeks 4 through 64

Relationship between CC-99677 exposure and osteoclast precursors with ex vivo 
osteoclastogenesis at Week 12

Bone turnover markers (including but not limited to P1NP and CTX-1 in serum) at 
Weeks 12, 24 and 64

Pharmacogenetic (PG) markers and their relationship to treatment response at Baseline 
Visit

SARS-CoV-2 serology (anti-SARS-CoV-2 total or IgG, IgM)a at Baseline and Week 64
a Study objectives are the same for the biologic-naive main study and for the biologic-failure substudy. 
2.1
Study Endpoints
Table 2:
Study Endpoints
Endpoint
Name
Description
Time-frame
Primary 
ASAS20
Proportion of subjects who achieve an improvement 
in disease activity from baseline of ≥ 20% and ≥ 1 
unit in at least 3 of the 4 ASAS domains on a scale 
of 0 to 10, and no worsening from baseline of ≥ 
20% and ≥ 1 unit in the remaining domain on a 
scale of 0 to 10
Four ASAS Domains:
–
Patient Global Assessment of Disease (0 to 10 
unit Numerical Rating Scale [NRS]);
–
Total Back Pain NRS;
–
Function (the Bath Ankylosing Spondylitis 
Functional Index [BASFI] score NRS);
–
Inflammation (mean of Bath Ankylosing 
Spondylitis Disease Activity Index [BASDAI] 
NRS Questions #5 and #6 for morning 
stiffness).
Week 12
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Table 2:
Study Endpoints
Endpoint
Name
Description
Time-frame
Secondary 
ASAS40
Proportion of subjects who achieve an improvement 
in disease activity from baseline of ≥40% and ≥ 2 
unit in at least 3 of the 4 ASAS domains on a scale 
of 0 to 10, and no worsening at all from baseline in 
the remaining domain
Week 12
ASDAS-CRP
Change from baseline in ASDAS-CRP.
ASDAS is score of disease activity comprising 3 
items from BASDAI: 1. Back pain (question 2); 
2. Peripheral pain/swelling (question 3); and 
3. Duration of morning stiffness (question 6).
ASDAS-CRP Formula:
0.12 x Back Pain + 0.06 x Duration of Morning 
Stiffness + 0.11 x Patient Global + 0.07 x 
Peripheral Pain/Swelling + 0.58 x ln (CRP+1)
Week 12
BASDAI
Change from baseline in BASDAI
Week 12
BASFI
Change from baseline in BASFI
Week 12
SPARCC score for 
the total spine and 
sacroiliac joints
Change from baseline in the SPARCC scores of the 
total spine and of the sacroiliac joints
Week 12
hsCRP
Percent change from baseline in high-sensitivity C-
reactive protein (hsCRP)
Week 12
Exploratory
Safety and 
tolerability
AE Type
Signing of 
informed consent 
form through 4-
week post-
treatment 
observational 
follow-up period
AE Frequency
AE Severity
Relationships of treatment emergent AEs to IP
Number of subjects who discontinue IP due to any 
treatment emergent AE
Clinically significant changes in vital signs, ECGs 
and/or laboratory findings
ASAS20
Proportion of subjects who achieve an improvement 
in disease activity from baseline of ≥20% and ≥ 1 
unit in at least three ASAS domains on a scale of 
10, and no worsening from baseline of ≥ 20% and ≥ 
1 unit in the remaining domain on a scale of 0 to 10
Week 4 through 
Week 8 and Week 
16 through Week 
64
ASAS40
Proportion of subjects who achieve an improvement 
in disease activity from baseline of ≥40% and ≥ 2 
unit in at least three ASAS domains on a scale of 0 
to 10, and no worsening at all from baseline in the 
remaining domain
Week 4 through 
Week 8 and Week 
16 through Week 
64
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Table 2:
Study Endpoints
Endpoint
Name
Description
Time-frame
ASDAS-CRP
Change from baseline in ASDAS-CRP
Week 4 through 
Week 8 and Week 
16 through Week 
64
BASDAI
Proportion of subjects achieving a ≥ 50% 
improvement from baseline in BASDAI
Week 4 through 
Week 8 and Week 
16 through Week 
64
BASFI
Change from baseline in BASFI
Week 4 through 
Week 8 and Week 
16 through Week 
64
BASMI - Linear 
Change from baseline in spinal mobility
Week 4 through 
Week 64
Chest expansion
Change from baseline in spinal mobility
Week 4 through 
Week 64
Occiput to wall 
distance
Change from baseline in spinal mobility
Week 4 through 
Week 64
Exploratory
MASES Score
Change from baseline in MASES score in subjects 
with pre-existing enthesopathy 
Week 4 through 
Week 64
Peripheral Joint 
Count (44 swollen 
joint count) 
Change from baseline in subject’s swollen joint 
counts
Week 4 through 
Week 64
Ankylosing 
Spondylitis Quality 
of Life (ASQoL)
Change from baseline in the ASQoL Questionnaire
Week 12, Week 
24, and Week 64
Short Form-36 (SF-
36) v2
Change from baseline in SF-36 quality of life 
questionnaire
Week 12, Week 
24, and Week 64
ASAS Health Index 
(HI)
Change from baseline in ASAS Health Index 
quality of life questionnaire
Week 12, Week 
24, and Week 64
Exploratory Pharmacokinetic/Pharmacodynamic Endpoints
PK
Plasma PK parameters, such as Cmax, Tmax, 
AUC(0-T), AUC(TAU), and CLT/F for CC-99677 
and Cmax, Tmax, AUC(0-T), AUC(TAU), 
MR_Cmax, MR_AUC(0-T), and MR_AUC(TAU) 
for CC-0782951, will be calculated for intense PK 
sampling at Week 4 if data permit.
For sparse PK at Weeks 0, 4, 8, 12, 16, 20, and 24, 
concentrations of CC-99677 and CC-0782951 will 
be reported.
Intense PK: Week 
4
Sparse PK: 
Baseline, Weeks  
4, 8, 12, 16, 20,
and 24
Pharmacodynamics 
(PD)
Absolute change from baseline in high-sensitivity 
C-reactive protein (hsCRP)
Week 2 through 
Week 64
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Table 2:
Study Endpoints
Endpoint
Name
Description
Time-frame
Percent change from baseline in high-sensitivity C-
reactive protein (hsCRP)
Weeks 2 through 
8 and Weeks 16 
through 64
Change from baseline in serum bone turnover 
markers, including but not limited to carboxy 
terminal cross-linked telopeptide of type 1 collagen
(CTX) and procollagen type 1 N-terminal 
propeptide (P1NP) 
Week 4 through 
Week 64
Exploratory
Pharmacodynamics 
(PD)
Change from baseline in target engagement 
measured by percent of MK2 bound to CC-99677 
vs percent of free MK2 in peripheral blood 
mononuclear cells (PBMCs)
Weeks 4, 8, and 
12
Change from baseline in serum cytokines and other 
proteins by proteomics
Week 4 through 
Week 64
Change from baseline in serum TNF-α and IL-17A
Week 4 through 
Week 64
Change from baseline in osteoclast precursor 
frequency with ex vivo osteoclastogenesis in 
PBMCs
Week 12
Change from baseline in whole blood RNA gene 
expression 
Week 4 through 
Week 64
Pharmacogenetics 
(PG)
Deoxyribonucleic acid (DNA) single nucleotide 
polymorphism (SNP) chip to detect AS associated 
polymorphisms and polymorphisms in the MK2 
pathway
Baseline
Biobanking for 
SARS-CoV-2 
serologic status 
SARS-CoV-2 serology (anti-SARS-CoV-2 total or 
IgG, IgM)
Baseline and 
Week 64
Abbreviations: Tmax = time to peak (maximum) serum concentration; AUC(0-T) = area under the plasma 
concentration-time curve from time zero to last measurable concentration; AUC(TAU) = area under the plasma 
concentration-time curve within a dosing interval; CLT/F = apparent total clearance; Cmax = maximum serum 
concentration of drug; Tmax = time to peak (maximum) serum concentration.
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3
OVERALL STUDY DESIGN
3.1
Study Design
This is a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
efficacy and safety study in subjects with active AS.  This study is designed to assess response to 
CC-99677 treatment by measuring signs and symptoms of AS, objective measures of disease
activity, quality of life assessments, safety, and tolerability over a 12-week Double-blind Period.  
This study will also assess the efficacy and long-term safety of CC-99677 in a 52-week Long-term 
Extension Period.
The study consists of multiple periods (Figure 1):

Screening Period (up to 6 weeks)

Double-blind, Placebo-controlled Treatment Period (12 weeks)

Long-term Extension Period (52 weeks)

Post-treatment Observational Follow-up Period (4 weeks)
3.1.1
Biologic-Naïve Main Study
Approximately 147 adult male and female subjects with a diagnosis of AS fulfilling the modified 
New York criteria for AS (van der Linden, 1984) (APPENDIX B), symptoms of active disease 
based on a BASDAI score ≥4, a Total Back Pain Numerical Rating Scales (NRS) score ≥4, and 
no prior exposure to biologic treatment of AS, will be randomized 1:1:1 (49 subjects per arm) to 
receive either CC-99677 150 mg PO QD, CC-99677 60 mg PO QD, or matching placebo for a 
duration of 12 weeks (Figure 1). Randomization and treatment assignment will be managed by an 
Interactive Web Response System (IWRS).  Randomization to treatment groups will be stratified 
by hsCRP concentration, (≤upper limit of normal/ > upper limit of normal) obtained at initial 
Screening Visit 1. 
Subjects will be treated for 12 Weeks in a Double-blind, Placebo-controlled Treatment Period, 
followed by a 52-week Long-term Extension Period and a 4-Week Post-treatment Observational 
Follow-up Period.  At Week 12, subjects originally randomized to receive placebo will be re-
randomized 1:1 to blinded CC-99677 (150 mg or 60 mg PO QD) through Week 64 or until early 
discontinuation. Subjects originally randomized to CC-99677 (150 mg or 60 mg PO QD) will 
continue to receive the same dose through Week 64 or until early discontinuation. Subjects who 
do not achieve an ASAS20 at Week 16 will be discontinued from the study.
An additional dose cohort may be added (Section 3.1.2) on the basis of the outcome of a planned 
Interim Analysis (IA) (Section 3.1.4).
The primary analysis (Section 3.1.5) for the biologic-naive cohort will be performed when all 
subjects in this cohort have completed 12 weeks of treatment, or have discontinued early, and all 
expected data are collected (Section 9). Following the database lock, the remainder of the Long-
term Extension Period will be conducted in a Sponsor-unblinded fashion. All subjects and site 
personnel will remain blinded throughout the duration of the trial. The results may support the 
selection of a single efficacious dose of CC-99677 or dropping a dose due to insufficient benefit-
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risk.  In either of these events, subjects in the Long-term Extension may be reallocated to the 
selected CC-99677 dose(s) through Week 64.
Subjects will remain in the study for a maximum of 74 weeks and will be required to attend a total 
of 16 study visits (from Screening Visit to Observational Follow-up Visit).  Assessments for 
efficacy, safety, tolerability, quality of life, PK and PD will be performed at specified timepoints 
as outlined in Table of Events, Table 3.  Subjects who discontinue prematurely from the study at 
any time will be required to complete an Early Termination Visit (ET) and enter the 4-week Post-
treatment Observational Follow-up Period.
The blind will be maintained for persons responsible for the ongoing conduct of the study. Blinded 
persons may include but are not limited to subjects, site personnel, Clinical Research Physician, 
Clinical Research Scientist, Clinical Trial Manager, Study Statistician, Data Manager, 
Programmers, and Clinical Research Associates.
The study will be conducted in compliance with the International Council for Harmonisation (ICH) 
Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical 
Practice (GCP) and applicable regulatory requirements.
3.1.2
Additional Dose Cohort
Approximately 59 eligible subjects will be randomized in a ~5:1 ratio (49 subjects in the CC-
99677 dose cohort and 10 subjects in the placebo arm).  Refer to Section 4 for specific inclusion 
and exclusion criteria.  Randomized subjects will be treated for 12 Weeks in a Double-blind, 
Placebo-controlled Treatment period, followed by a 52-week long-term extension period and a 4-
week Post-treatment Observational Follow-up Period (Figure 1).  
At Week 12, all subjects originally randomized to receive placebo will be re-allocated to receive 
CC-99677 through Week 64 or until early discontinuation. All subjects originally randomized to 
CC-99677 will continue to receive the same dose through Week 64 or until early discontinuation.  
Subjects who do not achieve an ASAS20 at Week 16 will be discontinued from the study.
3.1.3
Biologic-Failure Substudy
Approximately 50 subjects with AS who have failed not more than 1 biologic agent taken for AS 
due to inadequate efficacy response to an approved dose for at least 12 weeks and/or unacceptable 
safety/tolerability of a biologic agent (in the opinion of the Investigator) will be recruited into a 
separate substudy, conducted concurrently with the biologic-naïve main study (Section 3.1.1).  A 
minimum of 50% of biologic failure subjects will be recruited due to inadequate efficacy response. 
Subjects will be randomized with 2:2:1 ratio to have 20 subjects each to receive either treatment 
with CC-99677 150 mg PO QD, CC-99677 60 mg PO QD, and 10 subjects to receive matching 
placebo, for 12 weeks in a Double-blind, Placebo-controlled Treatment Period followed by a 52-
week Long-term Extension Period, and a 4-week Post-treatment Observational Follow-up Period
(Figure 2).
At Week 12, subjects originally randomized to receive placebo will be re-randomized 1:1 to 
blinded CC-99677 (150 mg or 60 mg PO QD) through Week 64 or until early discontinuation. 
Subjects originally randomized to CC-99677 (150 mg or 60 mg PO QD) will continue their current 
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dose through Week 64) or until early discontinuation.  Subjects who do not achieve an ASAS20
at Week 16 will be discontinued from the study.
Subjects will remain in the study for a maximum of 74 weeks and will be required to attend a total 
of 16 study visits (from Screening Visit to Observational Follow-up Visit).  Subjects who 
discontinue prematurely from the study at any time will be required to complete an Early 
Termination Visit and enter the 4-week Post-treatment Observational Follow-up Period.  Other 
aspects of the substudy will be carried out as described in Section 6 for subjects recruited into the 
biologic-naïve main study.
3.1.4
Interim Analysis
An interim analysis (IA) will be conducted when approximately 30 subjects in the biologic-naïve 
main study complete 12 weeks of treatment.  A Steering Committee (SC) comprised of both 
unblinded BMS committee members independent of the Study Team and external AS expert(s)
will review the data from the IA and will convey one of the following decisions to the blinded 
study team:

Continue the study without modification

Terminate the study for futility

Discontinue a treatment group based on preliminary assessment of dose-dependent risk-benefit 

Add an additional dose cohort (dose not to exceed 150 mg)
If the SC determines that an additional dose cohort is needed, then the additional dose cohort will 
be initiated in the biologic-naïve main study only as described in Section 3.1.2.
The SC will not play a role in the study conduct and the blind will be maintained for persons 
responsible for the ongoing conduct and management of the study.  The SC may oversee additional 
IAs.  Operational details for the SC will be detailed in a separate SC charter. Additional interim 
analyses may be conducted.
3.1.5
Primary Analysis
The primary analysis for the biologic-naive cohort will be performed when all subjects in this
cohort have completed 12 weeks of treatment, or have discontinued early, and all expected data 
are collected (Section 9). The primary analysis for the biologic-failure cohort will be performed 
when all subjects in this cohort have completed 12 weeks of treatment, or have discontinued early, 
and all expected data are collected (Section 9). Following the database lock, the remainder of the 
Long-term Extension Period will be conducted in a Sponsor-unblinded fashion. All subjects and 
site personnel will remain blinded throughout the duration of the trial.
The primary analysis may support the selection of a single efficacious dose of CC-99677 or 
dropping a dose due to insufficient benefit-risk.  In either of these events, subjects in the Long-
term Extension may be reallocated to the selected CC-99677 dose(s) through Week 64.
Primary analysis of efficacy of subjects enrolled in the biologic-failure substudy will be separate 
from that of the biologic-naive main study.
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3.1.6
Safety Monitoring Team
In addition to daily safety monitoring conducted by Investigators and individual study personnel,
cumulative and interval blinded AEs, SAEs, discontinuations and laboratory findings will be 
reviewed by a Safety Management Team (SMT) internally at Celgene. The SMT is comprised of 
lead representatives from multiple Celgene functions.
The scope, conduct, processes, and 
accountabilities are specified by Celgene Standard Operating Procedure (SOP).
3.1.7
Independent External Data Monitoring Committee
Although the Celgene study staff will monitor safety on an ongoing basis throughout the study, 
formal unblinded safety and efficacy assessments of the study data will be performed by an 
independent external Data Monitoring Committee (DMC). The DMC will include physician 
experts with experience in treating subjects with AS and a statistician, all of whom are not 
otherwise involved in the study conduct and in whom there is no identified conflict of interest. The 
external DMC may make a recommendation to stop the study at any time based on an assessment 
of the overall Benefit/Risk based on clinical data.  Operational details for the DMC will be detailed 
in a separate DMC charter.
3.1.7.1
Study Stopping Criteria (Criteria for Urgent Review of Clinical Data by 
the DMC)
The study enrollment will be stopped, and the clinical data will be reviewed by the DMC if any of 
the following occur:

If 1 subject experiences a drug-related Grade 5 AE by Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0 grading system

If 2 subjects develop drug-related Grade 4 AEs by CTCAE Version 5.0 grading system

If 3 subjects develop the same drug-related Grade 3 AEs by CTCAE Version 5.0 grading 
system
Following urgent review by the DMC, the overall risk-benefit of continuing the trial will be 
assessed and a decision on whether to terminate the trial will be made.
Note: In the case of Grade 3 or 4 safety laboratory AEs that are considered at least possibly drug-
related, repeat all abnormal safety laboratory assessments within 48 to 72 hours to refute or 
confirm the findings. The decision to temporarily interrupt the IP will be based on the 
Investigator’s clinical judgment.
3.1.8
Steering Committee
A SC, comprised of both unblinded BMS committee members independent of the Study Team and 
external AS expert(s) who are not member(s) of the DMC, will review the data from the IA and 
will convey decisions to the blinded study team, as described in Section 3.1.4.  The SC may 
oversee additional IAs.  Operational details for the SC will be detailed in a separate SC charter.
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Final: 21 Sep 2022
45
Figure 1:
Biologic-naïve Main Study Design
Figure 2:
Biologic-failure Substudy Design
3.2
Study Duration for Subjects
The study will have a total duration of up to 74 weeks.  The study will consist of up to a 6-week 
Screening Period; 12-Week Double-blind Placebo-controlled Treatment Period; a 52-Week Long-
term Extension; and a 4-Week Post-treatment Observational Follow-up Period.
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3.3
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
Post-treatment Follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
1.0
Approved
930191603
11.0
v
Approved
1.0
v


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
47
4
STUDY POPULATION
4.1
Number of Subjects 
Approximately 147 subjects diagnosed with AS will be recruited for the biologic-naïve main study.  
If an additional dose cohort is initiated after the interim analysis, an additional 59 subjects will be 
recruited for the biologic-naïve main study, yielding a total of approximately 206 subjects for the 
biologic-naïve main study. Approximately 50 subjects will be recruited for the biologic-failure 
substudy.
4.2
Inclusion Criteria for the Biologic-naïve Main Study
Subjects must satisfy the following criteria to be enrolled in the study:
General Patient Population:
1) Subject is ≥ 18 and ≤ 65 years of age at the time of signing the informed consent form (ICF)
2) Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted
3) Subject is willing and able to adhere to the study visit schedule and other protocol requirements
4) Females of childbearing potential (FCBP) must either commit to true abstinence* from 
heterosexual contact (which must be reviewed on a monthly basis and source documented) or 
agree to use one highly effective method of contraception and be able to comply with highly 
effective contraception without interruption, 28 days prior to starting IP, during the study 
therapy (including dose interruptions), and for 28 days after discontinuation of IP. Highly 
effective methods of contraception are those that alone or in combination result in a failure rate 
based on a Pearl index of less than 1% per year when used consistently and correctly.  
Approved options for birth control are:

Any one of the following highly effective methods: combined (estrogen- and progestogen-
containing) hormonal contraceptives;
progestogen-only hormonal contraceptives 
associated with inhibition of ovulation; intrauterine device (IUD); tubal ligation (tying your 
tubes); or a partner with a vasectomy
Note:  A female of childbearing potential (FCBP) is a female who: 1) has achieved 
menarche, 2) has not undergone a hysterectomy or bilateral oophorectomy or 
salpingectomy, or 3) has not been naturally postmenopausal for at least 24 consecutive 
months (ie, has had menses at any time in the preceding 24 consecutive months), 
amenorrhea following cancer therapy does not rule out childbearing potential.
5) Females of childbearing potential (FCBP) must not be pregnant and must have two negative 
pregnancy tests as verified by the Investigator prior to starting investigational product (IP). She 
must agree to ongoing pregnancy testing during the course of the study, and after end of study 
treatment. This applies even if the subject practices true abstinence* from heterosexual contact
6) Male subjects must:
a) Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use 
condoms not made out of natural [animal] membrane during sexual contact with a pregnant 
female or a female of childbearing potential while participating in the study, during dose 
interruptions and for 28 days after the last dose of IP, even if he has undergone a vasectomy. 
Any nonpregnant FCBP partner of a male subject must use an approved method of effective 
1.0
Approved
930191603
11.0
v
Approved
1.0
v


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
48
contraception, without interruption, during the study (including any dose interruptions) and 
for at least 28 days after the last dose of IP
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle 
of the subject and is accepted as a contraceptive method per local guidelines or practice. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable methods of contraception
7) Subjects agrees to limit ultraviolet (UV) exposure during the study and for at least 3 days after 
final dose of IP by adhering to the photoprotection guidelines below:
a) Avoid being outdoors when the sun is at maximal intensity
b) Avoid tanning beds or sunbathing 
c) Wear clothing that would protect from the sun such as long-sleeves, sunglasses, and a hat
d) Use sunscreen lotion in accordance with local guidance
Disease Specific Parameters:
8) Subject has a diagnosis of AS fulfilling the modified New York criteria for AS (van der Linden,
1984) (APPENDIX B) with radiologic entry criteria documented by central reading (historical 
radiographs up to 12 months old are considered acceptable)
9) Subject has active axial disease at Screening and Baseline defined by a BASDAI score ≥4 (0
to 10 scale) and Total Back Pain, as measured by a NRS ≥ 4 (0 to 10 scale)
Prior and Current Treatment:
10) Subject must have failed prior treatment with at least 2 NSAIDs (at the maximum tolerated
dose) for at least 4 weeks each, with documented inadequate response
Note: Concomitant use of one NSAID or cyclooxygenase 2 inhibitor for AS is permitted 
provided that the subject is receiving a stable dose 2 weeks prior to Baseline and subject agrees 
to maintaining this dose until Week 64, unless dose is reduced, or treatment is discontinued 
due to safety and/or tolerability concerns.
11) Subject has never received a biologic therapy (eg, TNF antagonist or monoclonal antibody 
[mAb] against IL-17A) for the treatment of AS
12) Concomitant use of sulfasalazine is permitted provided it is used at a stable dose for at least 4 
weeks prior to Baseline (Day 1 of study)
4.3
Exclusion Criteria for Biologic-naïve Main Study
Disease Specific Requirements:
1) Subject has radiographic evidence of total ankylosis of the spine
2) Subject has uncontrolled severe psoriasis (defined as Body Surface Area > 10%)
3) Subject has active inflammatory bowel disease (eg, ulcerative colitis, Crohn’s disease) within 
6 months of Screening Visit based on clinical assessment
4) Presence of acute anterior uveitis within 4 weeks prior to Screening Visit
5) Autoimmune diseases such as, but not limited to: systemic lupus erythematous, mixed 
connective tissue disease, multiple sclerosis, rheumatoid arthritis, gout, reactive arthritis,
vasculitis
1.0
Approved
930191603
11.0
v
Approved
1.0
v


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
49
6) Subject has concomitant fibromyalgia, which symptoms or therapy for, in the opinion of the 
Investigator, will significantly impact the assessment of AS disease manifestations and activity
7) Subject has clinically significant back pain caused by diseases other than AS (eg, degenerative 
disc disease, osteoarthritis) which symptoms or therapy for, in the opinion of the Investigator, 
will significantly impact the assessment of AS disease manifestations and activity
Prior and/or Current Medications/Therapies:
8) Concurrent treatment or treatment within the 6 months prior to Baseline with JAK inhibitors, 
cell depleting biologic agents (eg, anti-CD20 [eg, rituximab], anti-CD4, anti-CD3), 
denosumab, anti-IL-6 [eg, tocilizumab, sarilumab], and anti-IL-23 (eg, ustekinumab)
9) Use of oral corticosteroids (prednisone or equivalent) > 10 mg/day for ≥ 2 weeks prior to 
Baseline Visit
Note:  Concomitant use of prednisone ≤10 mg is permitted provided it is taken at a stable dose 
within 4 weeks of Baseline Visit.
10) Use of any intramuscular, intravenous or intraarticular corticosteroid treatment within 4 weeks 
of the Baseline Visit
11) Use of vitamin K antagonists (eg, warfarin)
12) Use of diclofenac or sulindac
13) Treatment with isoniazid within 4 weeks of the Baseline Visit and at any time during the 
Screening Period, up through the first dose of IP
14) Use of any medication known to be either a moderate or strong inhibitor or a moderate or 
strong inducer of CYP3A4/5 (see APPENDIX C, Table 7) until study completion. There must 
be a washout period of 5 PK half-lives of any such drug used by the subject prior to Baseline 
Visit. The Medical Monitor or designee should be queried in case of uncertainty.
15) Use of any medication known to be either moderate or strong inhibitor or moderate or strong 
inducer of P-gp until study completion (see APPENDIX C, Table 8). There must be a washout 
period of 5 PK half-lives of any such drug used by the subject prior to Baseline Visit. The 
Medical Monitor or designee should be queried in case of uncertainty.
16) Use of any medication known to be a strong BCRP inhibitor until study completion (see 
APPENDIX C, Table 8). There must be a washout period of 5 PK half-lives of any such drug 
used by the subject prior to Baseline Visit. The Medical Monitor or designee should be queried 
in case of uncertainty.
17) Use of any medications that are substrates of one or more of the transporters P-gp, OCT1, 
OATP1B1, and OATP1B3 and have a narrow therapeutic index (eg, methotrexate, digoxin, 
cyclosporine, mycophenolic acid, and leflunomide). Additional examples can be found in
APPENDIX C, Table 9.
Note:

BCRP substrates with a narrow therapeutic index (eg, prazosin) should be used with 
caution (APPENDIX D Table 10).  Sulfasalazine is not excluded based on results from CC-
99677-CP-002 (see Section 1.4.2).  

At least 1-month washout period prior to randomization is required for the conventional 
synthetic disease-modifying antirheumatic drugs (DMARDs), except for leflunomide, 
which has to be discontinued for 15 weeks prior to randomization unless a cholestyramine 
1.0
Approved
930191603
11.0
v
Approved
1.0
v


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
50
washout has been performed.  Subjects should not discontinue any of the above synthetic 
DMARDS for the sole purpose of participating in this trial.
18) Participation in any study of an investigational drug, including those for COVID-19, may not 
participate in BMS clinical trials until the protocol specific washout period is achieved (one 
month or 5 PK or PD [if known] half-lives of the investigational drug, whichever is longer 
prior to Screening Visit), or have participated in more than one study with an investigational 
agent for AS within one year prior to Screening Visit
19) If a study participant has received a COVID-19 vaccine prior to screening, enrollment must be 
delayed until the biologic impact of the vaccine is stabilized, as determined by discussion 
between the investigator and the BMS clinical trial physician, (See Section Section 8.4)
20) Any botanical preparations (eg, herbal supplements or traditional Chinese medicines derived 
from plants, minerals, or animals) intended to treat AS or other immunological diseases within 
4 weeks prior to Study Day 1
General Health:
21) Major surgery performed within 8 weeks prior to Screening Visit or planned within 64 weeks 
after Screening Visit
22) Evidence of significant cardiac, renal, neurologic, psychiatric, endocrinologic (including 
uncontrolled diabetes, defined as hemoglobin A1c (HbA1c) ≥ 9.5%), metabolic, hepatic 
disease or gastrointestinal disease
Note: HbA1c should only be collected in subjects with a known history of diabetes.
23) History or evidence of congenital and/or acquired immunodeficiencies (eg, common variable 
immunodeficiency, human immunodeficiency virus [HIV], etc.)
24) The subject has serologic tests during Screening (Table 3) consistent with infection with either 
hepatitis B or hepatitis C, and/or confirmed history of hepatitis B or hepatitis C infection. 
Subjects with isolated positive hepatitis B surface antibody are not excluded.
25) The subject has evidence on chest X-ray of lung pathology that, in the opinion of the 
Investigator, would pose an unacceptable safety risk in the event of further participation in the 
trial
Note: Examples of X-ray findings that would preclude further trial participation include active 
lower tract respiratory infection or suspected malignancy.  If comparison with prior X-rays 
demonstrates unchanged findings, subject may be eligible for further participation following 
discussion with medical monitor.
26) History of active or latent tuberculosis (TB) infection, unless there is medical record 
documentation of successful completion of a standard course of treatment considered 
appropriate
Note: Documentation of adequate treatment for TB must be obtained and reviewed by the 
Medical Monitor prior to randomization. In such subjects, the QuantiFERON-TB Gold test is 
not needed.  Instead, a chest radiograph, obtained within the 12 weeks prior to Screening or 
during Screening, without changes suggestive of active TB infection as determined by a 
qualified radiologist, is sufficient to permit further participation in the study for these subjects.
If the subject lives in, or has emigrated from, a TB high burden country (APPENDIX E, then 
further study participation requires documentation of adequate treatment for either active or 
1.0
Approved
930191603
11.0
v
Approved
1.0
v


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
51
latent TB infection within 2 years of the Screening Visit. For subjects residing in, or emigrating 
from, a TB high burden country and treated for TB more than 2 years prior to the Screening 
Visit, further trial participation requires a negative QuantiFERON-TB Gold test during 
screening.
27) History of active or latent TB infection, and subject lives in, or has emigrated from, a 
multidrug-resistant (MDR) TB high burden country (APPENDIX F)
28) Subject has had a household contact with a person with active TB and subject did not receive 
appropriate and documented prophylaxis for TB
Note: Household contact is a person who shared the same enclosed living space as the index 
case for one or more nights or for frequent or extended daytime periods during the 3 months 
before the start of current treatment
29) Active or history of recurrent bacterial, viral, fungal, mycobacterial or other infections 
(including, but not limited to, atypical mycobacterial disease and herpes zoster), or any major 
episode of infection requiring hospitalization or treatment with intravenous or oral antibiotics 
within 4 weeks of the Screening Visit and at any time during the Screening Period, up through 
the first dose of IP. 
Note:  Additionally, in the case of prior SARS-CoV-2 infection, symptoms must have completely 
resolved and based on investigator assessment in consultation with the clinical trial physician, 
there are no sequelae that would place the participant at a higher risk of receiving 
investigational treatment.  In addition, subject may not participate in the trial if participation 
is deemed inconsistent with local guidelines related to SARS-CoV-2.
30) Administration of a live or attenuated vaccine within 4 weeks prior to Baseline
31) History of malignancy (exceptions: excised and cured basal/squamous cell skin carcinomas, 
and cervical carcinoma in situ with no recurrence in 5 years)
32) Subject has any other significant medical/psychiatric condition or laboratory abnormality that 
would prevent the subject from participating in the study or places him/her at unacceptable risk 
for participation in the study
33) Subject with any of the following laboratory criteria:

White blood cell count (WBC) < 3500/mm3 (< 3.5 X 109/L) or > 14,000/mm3
(> 14 X 109/L)

Neutrophil count < 1500/mm3 (< 1.5 X 109/L)

Platelet count < 100,000/mm3or > 500,000/mm3

Serum creatinine > 1.5 mg/dL (> 132.6 μmol/L)

Aspartate aminotransferase (AST) > 1.5 X upper limit of normal (ULN)

Alanine aminotransferase (ALT) > 1.5 X ULN

Total bilirubin > 2 X ULN 

Hemoglobin < 8.5 g/dL (< 85 g/L)
34) Subject engages in or has a history of systemic use (eg, smoking, ingestion) of marijuana, 
tetrahydrocannabinol (THC), cannabidiol (CBD oil), or cannabinoids within 4 weeks of 
randomization; or has a history of recreational drug abuse or significant alcohol consumption 
1.0
Approved
930191603
11.0
v
Approved
1.0
v


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
52
for a period of more than 3 consecutive months within 1 year prior to Screening. Significant 
alcohol consumption is defined as more than 14 oz (420 mL) per week in females and more 
than 21 oz (630 mL) per week in males, on average (1 oz/30 mL of alcohol is present in one 
12 oz/360 mL beer, one 4 oz/120 mL glass of wine, or a 1 oz/30 mL measure of 40% proof 
alcohol)
Subjects must also agree not to engage in recreational drug abuse, significant alcohol 
consumption as described above, or systemic use of marijuana, THC, CBD oil, or cannabinoids 
for the duration of the study.
35) Subject has history of drug-related photosensitivity
36) Subject has a known hypersensitivity to CC-99677 or any ingredient in the IP
37) Females of childbearing potential (FCBP) must not be lactating or breastfeeding during the 
study period.
38) Females of childbearing potential (FCBP) must not donate eggs during the study or within 28 
days of the last dose of study drug
39) Males must not donate sperm or semen during the study or within 28 days of the last dose of 
study drug
4.4
Inclusion Criteria for Biologic-Failure Substudy
Subjects participating in the biologic-failure substudy must:
1) Meet all the inclusion criteria for subjects in the biologic-naïve main study except Inclusion 
Criterion 11
2) Have discontinued one and only one biologic (eg, TNF antagonist or monoclonal antibody 
[mAb] against IL-17A) for AS, either due to inadequate response to an approved biologic dose 
for at least 12 weeks and/or unacceptable safety/tolerability with at least one dose of a biologic 
agent (in the opinion of the Investigator).  The following minimum washout periods prior to 
Baseline must be adhered to for the biologics or their corresponding biosimilars:

etanercept: 4 weeks

infliximab: 8 weeks

adalimumab, certolizumab pegol, golimumab, ixekizumab: 12 weeks

secukinumab: 24 weeks
Note: Any questions regarding washout periods prior to Baseline should be directed to 
the Medical Monitor.  Subjects should not discontinue any of the above biologics for the 
sole purpose of participating in this trial
4.5
Exclusion Criteria for Biologic-Failure Substudy
1) Subjects participating in the biologic-failure substudy must not meet any of the exclusion 
criteria listed for subjects in the biologic-naïve main study
1.0
Approved
930191603
11.0
v
Approved
1.0
v


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
53
5
TABLE OF EVENTS
Table 3:
Table of Events, Screening, Baseline and 12-Week Placebo-Controlled Treatment Period
Screening
Placebo-controlled Treatment Period
Early 
Termination 
(ET)
Visit Number
1
2 (Baseline)
3
4
5
6
ETa
Week
-6 to -1
0 (Day 1)
2 (± 3 days)
4 (± 3 days)
8 (± 3 days)
12 (± 5 days)
NA
General Assessments
Informed Consent
X
-
-
-
-
-
-
Optional informed consent for PG
X
-
-
-
-
-
-
Inclusion/Exclusion criteria
X
X
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
Complete medical history and disease 
history
X
-
-
-
-
-
-
Prior/concomitant medications
Continuous, starting after the informed consent form is signed through 28 days after end of treatment
Prior AS therapies
X
-
-
-
-
-
-
Prior/concomitant procedures
Continuous, starting after the informed consent form is signed through 28 after end of treatment
QuantiFERON®-TB Gold ELISAb
X
-
-
-
-
-
-
HLA-B27 testing
-
X
-
-
-
-
-
Chest radiographc
X
-
-
-
-
-
-
Viral serologiesd
X
-
-
-
-
-
-
Postmenopausal testing: estradiol and 
follicle-stimulating hormone (for women 
50-55 years with undocumented status)
X
-
-
-
-
-
-
Hemoglobin A1c
X
-
-
-
-
-
-
Sacroiliac joint radiographse
X
-
-
-
-
-
-
1.0
Approved
930191603
11.0
v
Approved
1.0
v


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
54
Table 3:
Table of Events, Screening, Baseline and 12-Week Placebo-Controlled Treatment Period
Screening
Placebo-controlled Treatment Period
Early 
Termination 
(ET)
Visit Number
1
2 (Baseline)
3
4
5
6
ETa
Week
-6 to -1
0 (Day 1)
2 (± 3 days)
4 (± 3 days)
8 (± 3 days)
12 (± 5 days)
NA
Safety and Laboratory Assessments
Adverse eventsf
Continuous starting after the informed consent form is signed through 28 days after end of treatment
Complete physical examination
X
-
-
-
-
-
X
Limited physical examination
-
X
X
X
X
X
-
Vital signs and weight
X
X
X
X
X
X
X
Height
X
-
-
-
-
-
-
12-lead ECG
X
X
-
X
X
X
X
Hematology laboratory evaluations
X
X
X
X
X
X
X
Chemistry laboratory evaluations
X
X
X
X
X
X
X
Lipid panel
X
X
-
X
X
X
X
PT/INR
-
X
X
X
X
X
X
Pregnancy testingg
X
X
X
X
X
X
X
Pregnancy counseling for FCBP and male 
subjects with female partners of 
childbearing potential
Continuous starting after the informed consent form is signed through 28 days after end of treatment
Efficacy Assessments
BASDAI
X
X
-
X
X
X
X
BASFI
-
X
-
X
X
X
X
Patient Global Assessment of Disease
-
X
-
X
X
X
X
Total Back Pain NRS
X
X
-
X
X
X
X
1.0
Approved
930191603
11.0
v
Approved
1.0
v


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
55
Table 3:
Table of Events, Screening, Baseline and 12-Week Placebo-Controlled Treatment Period
Screening
Placebo-controlled Treatment Period
Early 
Termination 
(ET)
Visit Number
1
2 (Baseline)
3
4
5
6
ETa
Week
-6 to -1
0 (Day 1)
2 (± 3 days)
4 (± 3 days)
8 (± 3 days)
12 (± 5 days)
NA
Nighttime back pain NRS
-
X
-
X
X
X
X
BASMI Linear
-
X
-
X
X
X
X
Occiput to wall measurement
-
X
-
X
X
X
X
Chest expansion
-
X
-
X
X
X
X
Enthesitis evaluationh
-
X
-
X
X
X
X
Peripheral joint count evaluation
-
X
-
X
X
X
X
MRI of sacroiliac joints AND spine 
(SPARCC method)i
-
X
-
-
-
X
X
Sparse Pharmacokinetic Assessments
PK blood draw (sparse)j
-
X
-
X
X
X
-
Intense Pharmacokinetic, Biomarkers and Pharmacodynamic Assessments at Selected Sites
PK blood draw (intense)k
-
-
-
X
-
-
-
Blood draw for PD (target engagement)l
-
X
-
X
X
X
-
Blood draw for PD (ex vivo 
osteoclastogenesis)m
-
X
-
-
-
X
-
Biomarkers and Pharmacodynamic Assessments at All Sites
hsCRPn
X
X
X
X
X
X
X
Serum bone turnover markerso
-
X
-
X
-
Serum TNF-α and IL-17A
-
X
-
X
X
X
-
Serum cytokines and other proteins by 
proteomics
-
X
-
X
X
X
-
1.0
Approved
930191603
11.0
v
Approved
1.0
v


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
56
Table 3:
Table of Events, Screening, Baseline and 12-Week Placebo-Controlled Treatment Period
Screening
Placebo-controlled Treatment Period
Early 
Termination 
(ET)
Visit Number
1
2 (Baseline)
3
4
5
6
ETa
Week
-6 to -1
0 (Day 1)
2 (± 3 days)
4 (± 3 days)
8 (± 3 days)
12 (± 5 days)
NA
RNA gene expression analysis (whole 
blood sample)
-
X
-
X
X
X
-
SARS-CoV-2 serology for biobankingp
X
-
-
-
-
X
SARS-CoV-2 Serology for Documented or 
Suspected Infection q
Only collected approximately 4 weeks after SARS-CoV-2 infection
DNA blood draw (whole blood)r
-
X
-
-
-
-
-
Health-Related Quality of Life Assessments
ASQoL
-
X
-
-
-
X
X
SF-36
-
X
-
-
-
X
X
ASAS Health Index
-
X
-
-
-
X
X
Investigational Product
Dispense IP
-
X
-
X
X
X
-
Return and count IP capsules
-
-
X
X
X
X
X
Abbreviations: AE = adverse event; AS = ankylosing spondylitis; ASAS Health Index = Assessment of SpondyloArthritis International Society Health Index; ASQoL = Ankylosing 
Spondylitis Quality of Life questionnaire; BASDAI  = Bath Ankylosing Spondylitis Disease Activity Index; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMI linear 
= Bath Ankylosing Spondylitis Metrology Index – Linear; β-hCG = beta human chorionic gonadotropin; CRF = case report form; DNA = deoxyribonucleic acid; ECG = 
electrocardiogram; ET = early termination; EOT= end of treatment; FCBP = female of childbearing potential; HLA-B27 = human leukocyte antigen B27; hsCRP = high-sensitivity 
c-reactive protein; IL-17A = interleukin-17; IP = investigational product; MRI = magnetic resonance imaging; NA= not applicable; NRS = numerical rating scales; PD = 
pharmacodynamics; PG = pharmacogenetics; PK = pharmacokinetics; RNA = ribonucleic acid; SAE = serious adverse event; SF-36 = Short Form (36) Health Survey; SPARCC = 
Spondyloarthritis Research Consortium of Canada; TB = tuberculosis; TNF-α = tumor necrosis factor-alpha.
a. Subjects who discontinue the study prior to the Week 12 Visit will have an ET Visit.
b. QuantiFERON-TB Gold testing will be performed at Screening, only.  Documentation of adequate treatment for TB must be obtained and reviewed by the Medical Monitor prior 
to randomization.  In such subjects, the QuantiFERON-TB Gold test is not needed.  Instead, a chest radiograph, obtained within the 12 weeks prior to Screening or during 
Screening, without changes suggestive of active TB infection as determined by a qualified radiologist, is sufficient to permit further participation in the study for these subjects.  
If the subject lives in, or has emigrated from, a TB high burden country then further study participation requires documentation of adequate treatment for either active or latent 
1.0
Approved
930191603
11.0
v
Approved
1.0
v


CC-99677
Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
57
TB infection within 2 years of the Screening Visit. For subjects residing in, or emigrating from, a TB high burden country and treated for TB more than 2 years prior to the 
Screening Visit, further trial participation requires a negative QuantiFERON-TB Gold test during screening.
c. Chest radiography (posterior anterior view) will be performed at Screening visit or obtained within 12 weeks prior to Screening for all subjects to determine eligibility.
d. Serology testing will be performed at Screening to determine the subject's immune status with respect to the following viruses: human immunodeficiency virus antibodies, hepatitis 
B surface antigen and core antibody, and hepatitis C virus antibody. Subjects who received hepatitis B vaccination and who test positive for hepatitis B surface antibody and 
negative for both hepatitis B surface antigen and hepatitis B core antibody are not excluded from the study.
e. Sacroiliac joint radiographs must be performed if not obtained within 12 months prior to Screening, to determine whether subjects fulfill the modified New York classification 
criteria. Sacroiliac joint films must be submitted for central reading to confirm eligibility.  Images of the anterior-posterior lumbar spine will not be accepted for sacroiliac joint 
examination.
f. Adverse events collected from time of consent.  All AEs (SAEs or non-serious AEs) related to SARS-CoV-2 infection are collected from time of consent and continuously during
the study including at the safety follow up visit.  After the initial AE/SAE report, the investigator is required to proactively follow each participant at subsequent visits/contacts.  
All SAEs and non-serious AEs, including SARS-COV-2 will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the 
participant is lost to follow-up.  COVID-19 related AEs/SAEs will be captured in specific clinical safety program (CSP) case report form (CRF) pages
g. Females of childbearing potential must have a negative serum pregnancy test result at Screening, and negative urine and serum pregnancy test result at Baseline and all subsequent 
visits.  A negative urine pregnancy test result is required prior to IP administration.  If the urine pregnancy test is indeterminate, confirmation retesting on serum is required and 
IP must be held pending negative serum pregnancy test result.  If the urine pregnancy test is positive IP must be discontinued and confirmation retesting on serum is required (see
Section 10.4).
h. Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) should be obtained in all subjects.
i. MRI of sacroiliac joint AND spine – SPARCC methodology must be performed between Visits 1 and 2 inclusive, as well as at Visit 6 or Early Termination Visit.  If Early 
Termination Visit occurs before Week 6, then MRI of sacroiliac joint should not be done.  All images will be submitted for central reading.
j. Sparse PK samples will be collected in all subjects at pre-specified time points (See Section 6.7.1). For subjects who take IP in the evening, IP will be taken at 5 PM the day prior 
to the sparse PK collections.  On the day of sparse PK sample collection, IP must be taken in the morning and at the study site.  The actual times of drug administration and PK 
blood sample collections will be recorded in the source documents and CRF.
k. Intense PK samples will only be performed at selected sites and will be collected in subjects predose and 0.5, 1, 2, 3, 6, 8, and 12 hours postdose. IP must be taken at the study 
site after collection of the pre-dose PK blood sample.  The actual times of drug administration and PK blood sample collections will be recorded in the source documents and 
CRF.  This planned PK schedule may be modified; if modified, the total number of minimal time points per subject will not exceed 8 draws per visit.
l. Blood draw for PD (target engagement) will only be performed at selected sites and in a subset of subjects participating in the study.
m. Blood draw for PD (ex vivo osteoclastogenesis) will only be performed at selected sites and in a subset of subjects participating in the study
n. The subject’s serum CRP will be measured using hsCRP.  Post-baseline results are to be blinded.
o. Serum bone turnover marker samples will be collected under fasted conditions.  Subjects must not have received high-dose biotin supplements (multivitamins are allowable) 
within 72 hours prior to sample collection.
p.
Serum collected to be used for measurements of anti-SARS-CoV-2 serology (anti-SARS-CoV-2 total or IgG [see Section 6]) per national and local guidelines.
q.
Serum should also be collected approximately 4 weeks after a documented or suspected SARS-CoV-2 infection (Section 6).
r. Pharmacogenetic testing will only be performed when an optional informed consent is provided from the subject.
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CC-99677-AS-001 Amendment 3.0
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Table 4:
Table of Events, Long-term Extension Period (52- Weeks)
Long-Term Extension Period (1 Year)
Early 
Termination 
(ET)
Observational 
Follow-up
Visit Number
7
8
9
10
11
12
13
14
15
(EOT)
ETa
16
Week
14 (± 3 
days)
16b (± 3 
days)
20 (± 3 
days)
24 (± 3 
days)
32 (± 3 
days)
40 (± 3 
days)
48 (± 3 
days)
56 (± 3 
days)
64 (± 3 
days)
NA
4 Weeks after 
Last Dose (± 
3 days)
General Assessments
Concomitant medications
Continuous, starting after the informed consent form is signed through 28 days after end of treatment
Prior/concomitant procedures
Continuous, starting after the informed consent form is signed through 28 days after end of treatment
Safety and Laboratory Assessments
Adverse eventsc
Continuous, starting after the informed consent form is signed through 28 days after end of treatment
Complete physical 
examination
X
-
-
-
-
-
-
-
X
X
X
Limited physical examination
-
X
X
X
X
X
X
X
-
Vital signs and weight
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
-
X
X
X
X
X
X
X
X
Hematology laboratory 
evaluations
X
X
X
X
X
X
X
X
X
X
X
Chemistry laboratory 
evaluations
X
X
X
X
X
X
X
X
X
X
X
Lipid panel
-
X
X
X
X
X
X
X
X
X
X
PT/INR
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testingd
X
X
X
X
X
X
X
X
X
X
X
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Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
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Table 4:
Table of Events, Long-term Extension Period (52- Weeks)
Long-Term Extension Period (1 Year)
Early 
Termination 
(ET)
Observational 
Follow-up
Visit Number
7
8
9
10
11
12
13
14
15
(EOT)
ETa
16
Week
14 (± 3 
days)
16b (± 3 
days)
20 (± 3 
days)
24 (± 3 
days)
32 (± 3 
days)
40 (± 3 
days)
48 (± 3 
days)
56 (± 3 
days)
64 (± 3 
days)
NA
4 Weeks after 
Last Dose (± 
3 days)
Pregnancy counseling for 
FCBP and male subjects with 
female partners of 
childbearing potential
Continuous starting after the informed consent form is signed through 28 days after end of treatment
Efficacy Assessments
BASDAI
-
X
X
X
-
-
X
-
X
X
-
BASFI
-
X
X
X
-
-
X
-
X
X
-
Patient Global Assessment of 
Disease
-
X
X
X
-
-
X
-
X
X
-
Total Back Pain NRS
-
X
X
X
-
-
X
-
X
X
-
Nighttime back pain NRS
-
X
X
X
-
-
X
-
X
X
-
BASMI Linear
-
X
X
X
-
-
X
-
X
X
-
Occiput to wall measurement
-
X
X
X
-
-
X
-
X
X
-
Chest expansion
-
X
X
X
-
-
X
-
X
X
-
Enthesitis evaluatione
-
X
X
X
-
-
X
-
X
X
-
Peripheral joint count 
evaluation
-
X
X
X
-
-
X
-
X
X
-
Sparse Pharmacokinetic Assessments
PK blood draw (sparse)f
-
X
X
X
-
-
-
-
-
-
-
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Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
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Table 4:
Table of Events, Long-term Extension Period (52- Weeks)
Long-Term Extension Period (1 Year)
Early 
Termination 
(ET)
Observational 
Follow-up
Visit Number
7
8
9
10
11
12
13
14
15
(EOT)
ETa
16
Week
14 (± 3 
days)
16b (± 3 
days)
20 (± 3 
days)
24 (± 3 
days)
32 (± 3 
days)
40 (± 3 
days)
48 (± 3 
days)
56 (± 3 
days)
64 (± 3 
days)
NA
4 Weeks after 
Last Dose (± 
3 days)
Biomarkers and Pharmacodynamic Assessments at All Sites
hsCRPg
X
X
X
X
-
-
X
-
X
X
-
Serum bone turnover 
markersh
-
-
-
X
-
-
-
X
-
-
Serum TNF-α and IL-17A
-
-
-
X
-
-
X
-
X
-
-
Serum cytokines and other 
proteins by proteomics
-
-
-
X
-
-
X
-
X
-
-
RNA gene expression 
analysis (whole blood 
sample)
-
-
-
X
-
-
-
-
X
-
-
SARS-CoV-2 serologyi
-
-
-
-
-
-
-
-
X
X
-
SARS-CoV-2 serology for 
documented or suspected 
infection j
Only collected approximately 4 weeks after confirmed or suspected SARS-CoV-2 infection
Health-Related Quality of Life Assessments
ASQoL
-
-
-
X
-
-
-
-
X
X
-
SF-36
-
-
-
X
-
-
-
-
X
X
-
ASAS Health Index
-
-
-
X
-
-
-
-
X
X
-
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Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
61
Table 4:
Table of Events, Long-term Extension Period (52- Weeks)
Long-Term Extension Period (1 Year)
Early 
Termination 
(ET)
Observational 
Follow-up
Visit Number
7
8
9
10
11
12
13
14
15
(EOT)
ETa
16
Week
14 (± 3 
days)
16b (± 3 
days)
20 (± 3 
days)
24 (± 3 
days)
32 (± 3 
days)
40 (± 3 
days)
48 (± 3 
days)
56 (± 3 
days)
64 (± 3 
days)
NA
4 Weeks after 
Last Dose (± 
3 days)
Investigational Product
Dispense IP
-
X
X
X
X
X
X
X
-
-
-
Return and count IP capsules
-
X
X
X
X
X
X
X
X
X
-
Abbreviations: AE = adverse event; AS = ankylosing spondylitis; ASAS Health Index = Assessment of SpondyloArthritis International Society Health Index; ASQoL = Ankylosing 
Spondylitis Quality of Life questionnaire; BASDAI  = Bath Ankylosing Spondylitis Disease Activity Index; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMI linear 
= Bath Ankylosing Spondylitis Metrology Index – Linear; β-hCG = beta human chorionic gonadotropin; CRF = case report form; DNA = deoxyribonucleic acid; ECG = 
electrocardiogram; ET = early termination; EOT= end of treatment; FCBP = female of childbearing potential; HLA-B27 = human leukocyte antigen B27; hsCRP = high-sensitivity 
c-reactive protein; IL-17A = interleukin-17; IP = investigational product; MRI = magnetic resonance imaging; NA= not applicable; NRS = numerical rating scales; PD = 
pharmacodynamics; PG = pharmacogenetics; PK = pharmacokinetics; RNA = ribonucleic acid; SAE = serious adverse event; SF-36 = Short Form (36) Health Survey; SPARCC = 
Spondyloarthritis Research Consortium of Canada; TB = tuberculosis; TNF-α = tumor necrosis factor-alpha.
a. Subjects who discontinue the study prior to the Week 64 Visit will have an ET Visit.
b. Subjects who do not achieve an ASAS20 at Week 16 will be discontinued from the study
c. Adverse events collected from time of consent.  All AEs (SAEs or non-serious AEs) related to SARS-CoV-2 infection are collected from time of consent and continuously during
the study including at the safety follow up visit.  After the initial AE/SAE report, the investigator is required to proactively follow each participant at subsequent visits/contacts.  
All SAEs and non-serious AEs, including SARS-COV-2 will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the 
participant is lost to follow-up.  COVID-19 related AEs/SAEs will be captured in specific clinical safety program (CSP) case report form (CRF) pages.  
d. Females of childbearing potential must have a negative urine and serum pregnancy test result at all visits.  A negative urine pregnancy test result is required prior to IP 
administration.  If the urine pregnancy test is indeterminate, confirmation retesting on serum is required and IP must be held pending negative serum pregnancy test result.  If the 
urine pregnancy test is positive IP must be discontinued and confirmation retesting on serum is required (see Section 10.4). At home urine pregnancy test kits will be provided to 
maintain monthly pregnancy testing between Weeks 24 and 64.  
e. Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) should be obtained in all subjects.
f. Sparse PK samples will be collected in all subjects at pre-specified time points (See Section 6.7.1).  For subjects who take IP in the evening, IP will be taken at 5PM the day prior 
to the sparse PK collections.  On the day of sparse PK sample collection, IP must be taken in the morning and at the study site.  The actual times of drug administration and PK 
blood sample collections will be recorded in the source documents and CRF.
g. The subject’s serum CRP will be measured using hsCRP.  Post-baseline results are to be blinded.
h. Serum bone turnover marker samples will be collected under fasted conditions.  Subjects must not have received high-dose biotin supplements (multivitamins are allowable) 
within 72 hours prior to sample collection.
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Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
62
i. Serum collected to be used for measurements of anti-SARS-CoV-2 serology (anti-SARS-CoV-2 total or IgG [see Section 6]).
j. Serum should also be collected approximately 4 weeks after a documented or suspected SARS-CoV-2 infection (see Section 6).
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Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
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6
PROCEDURES
The following procedures will be conducted according to the schedule indicated in Table of 
Events, Table 3 and Table 4.
Any questions regarding the protocol should be directed to the Medical Monitor or designee.
Signed informed consent forms (ICFs) must be obtained before any study evaluations are 
performed per local regulations during the course of the study.
6.1
Screening Period
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 6 weeks of Screening (Visit 1) unless noted otherwise 
below. Subjects are permitted to be re-screened once should they fail to meet the study criteria; 
however all rescreened subjects must be re-consented for the study.
Note: Subjects who fail the entry criteria due to a positive hepatitis B, hepatitis C or TB test result 
should not be rescreened for the study. Subjects who received hepatitis B vaccination and who test 
positive for hepatitis B surface antibody and negative for both hepatitis B surface antigen and 
hepatitis B core antibody are not excluded from the study.
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
Safety laboratory analyses and all assessments will be performed centrally. Screening laboratory 
values must demonstrate subject eligibility but may be repeated within the Screening window, if 
necessary.
The following will be performed at screening as specified in Table of Events, Table 3 after 
informed consent has been obtained:

The Screening Visit should be registered in the interactive web response system (IWRS).

Pharmacogenomics:  The pharmacogenetic substudy is optional, and a separate consent will 
be signed for this assessment at Screening.

Inclusion/exclusion criteria: Subjects must meet all inclusion criteria (Section 4.2) and must 
not have any of the conditions specified in the exclusion criteria (Section 4.3) to qualify for 
participation in the study. The subject’s source documents must support his/her qualifications 
for the study.

Demographics: Including initials, date of birth, sex, race, and ethnicity if allowed by local 
regulations.

Complete medical history: All relevant medical conditions diagnosed or occurring prior to 
Screening should also be included. Specific information regarding AS diagnosis should also 
be included.

Prior and concomitant medication evaluation: Including all medication (prescription and non-
prescription, including vitamins) taken by the subject ≤ 28 days before Screening, including 
stop dates for medications prohibited in the study.  All medications taken by the subject at any 
time during the study must also be recorded. Other key medications and therapies, such as 
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Final: 21 Sep 2022
64
tuberculosis or relevant diseases, should also be recorded.  Additional instructions can be found 
in the electronic case report form (eCRF) Completion Guidelines.

Prior AS therapies: Including all previous treatment for AS.

Prior and concomitant procedures: Including surgery, systemic or any other therapy for AS.

Chest Radiograph:  A chest radiograph (posterior anterior view) will be performed at Screening 
visit or obtained within 12 weeks prior to Screening for all subjects to determine eligibility. 
Note:  Examples of X-ray findings that would preclude further trial participation include active 
lower tract respiratory infection or suspected malignancy.  If comparison with prior X-rays 
demonstrates unchanged findings, subject may be eligible for further participation following 
discussion with medical monitor.

QuantiFERON-TB Gold test: A positive test or 2 successive indeterminate tests will disqualify 
the subject from further participation in the study.  
QuantiFERON-TB Gold testing is not needed in subjects who have adequate documentation 
of successful treatment for either latent or active TB. In such subjects, a chest radiograph, 
obtained within the 12 weeks prior to Screening, without changes suggestive of active TB 
infection as determined by a qualified radiologist, will be sufficient to permit further 
participation in the study.  Documentation of adequate treatment for TB must be obtained and 
reviewed by the Medical Monitor prior to randomization.  If the subject lives in, or has 
emigrated from, a TB high burden country (APPENDIX E) then further study participation 
requires documentation of adequate treatment for either active or latent TB infection within 2 
years of the Screening Visit. For subjects residing in, or emigrating from, a TB high burden 
country and treated for TB more than 2 years prior to the Screening Visit, further trial 
participation requires a negative QuantiFERON-TB Gold test during screening.

Sacroiliac joint radiograph:  One sacroiliac (SI) joint radiograph (anterior-posterior [AP] view) 
must be obtained if not performed in the previous 12 months prior to Screening, on all study 
subjects.  This radiographic assessment needs to be carried out to ensure the diagnostic 
radiographic criterion has been met based on the modified New York criteria (van der Linden, 
1984) (APPENDIX B). The SI joint radiograph (historical or newly obtained image) will be 
sent to a central reader for centralized scoring to determine if the subject has met the 
radiographic criterion of sacroiliitis grade ≥ 2 bilaterally, or sacroiliitis grade 3 to 4 unilaterally.

Adverse Events: Adverse event assessment begins when the subject signs the informed 
consent form.

Complete Physical Examination: Complete physical examinations will include evaluation of 
the skin, nasal cavities, eyes and ears, respiratory, cardiovascular, abdominal, neurological, 
lymphatic, and musculoskeletal systems (Section 6.5.1).

Vital signs, height and weight: Vital signs, including seated blood pressure, body temperature, 
and heart rate will be taken. Height and weight (to be done in street clothes, no shoes) will 
also be measured and recorded.

12-lead electrocardiogram (ECG) (Section 6.5.2)

Clinical laboratory evaluations: Clinical laboratory evaluations will be performed by a central 
laboratory to include the following laboratory assessments below.
Subject eligibility and 
clinical laboratory criteria are provided in Section 4. One laboratory re-test is allowed after 
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obtaining Medical Monitor approval if the result is exclusionary during the Screening Period.
Details pertaining to the central laboratory assessments and panels are included in 
Section 6.5.3.

QuantiFERON-TB Gold (see details above)

Hepatitis B and C tests

Human immunodeficiency virus (HIV) test

Postmenopausal tests

Hemoglobin A1c

Hematology panel

Chemistry panel

Lipid panel

Pregnancy test (serum beta human chorionic gonadotropin [β-hCG])

Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted

Efficacy assessments (Section 6.6):

BASDAI

Total Back Pain NRS

Biomarkers/Pharmacodynamic assessment (Section 6.8):

hsCRP

SARS-CoV-2 serology is collected approximately 4 weeks after a documented or suspected 
SARS-CoV-2 infection.  Unless required by local guidelines, testing for asymptomatic 
COVID-19 infection via molecular testing is not required.  However, some subjects may 
develop suspected or confirmed symptomatic COVID-19 infection, or be discovered to have 
asymptomatic COVID-19 infection during the Screening Period.  In such cases, subjects may 
be considered eligible for the study after meeting the following criteria: 

At least 10 days (20 days for severe/critical illness) have passed since symptoms first 
appeared or positive test result, and

At least 24 hours have passed since last fever without the use of fever-reducing 
medications, and

Symptoms (eg, cough, shortness of breath) have resolved and

In the opinion of the investigator, there are no COVID-19 sequelae that may place the 
participant at a higher risk of receiving investigational treatment, and 

Negative follow-up molecular test for COVID-19 based on institutional, local or regional 
guidelines

Information to be collected on Screening Failures: At a minimum, the information to be 
collected should include the informed consent date, demographics, and reason why the subject 
did not qualify for the study will be collected for all subjects determined to be screen failures. 
Adverse events experienced by screen failure subjects will be collected from the date of signing 
consent to the day the subject is confirmed to be a screen failure. This information will be 
captured in the subject’s source documents and appropriate case report forms (CRFs).
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Final: 21 Sep 2022
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6.2
Treatment Period
The subject will begin treatment upon confirmation of eligibility. For all subsequent visits, an 
administrative window of ± 3 days is permitted.
The following evaluations will be performed at the frequency specified in Table of Events, Table 
3 and Table 4. The evaluations should be performed prior to dosing on the visit day, unless 
otherwise specified.

Inclusion/exclusion criteria:  Subjects must meet all inclusion criteria (Section 4.2 or
Section 4.4) and must not have any of the conditions specified in the exclusion criteria 
(Section 4.3 or Section 4.5) to qualify for participation in the study.  The subject’s source 
documents must support his/her qualifications for the study.

Concomitant medications evaluation (continuously)

Concomitant procedures evaluation (continuously)

Adverse event evaluation (continuously)

Limited physical examination (Section 6.5.1)

Vital signs, including seated blood pressure, body temperature, and heart rate will be taken.  
Weight (to be done in street clothes, no shoes) will also be measured and recorded

12-lead ECG (Section 6.5.2)

Clinical Laboratory Evaluations (Section 6.5.3)

Hematology panel

Chemistry panel

Lipid panel

Prothrombin time (PT) and international normalized ratio (INR)

HLA-B27

Serum and urine pregnancy test (prior to dosing)

Counseling about pregnancy precautions and the potential risks of fetal exposure 
(continuously)

Efficacy assessments (Section 6.6)

BASDAI

BASFI

Patient Global Assessment of Disease

Total Back Pain NRS

Nighttime back pain NRS

BASMI-Linear

Occiput to wall measurement

Chest expansion

Enthesitis evaluation

Peripheral joint count
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
MRI of sacroiliac joint AND spine (SPARCC method)

Pharmacokinetic (PK) assessments (Section 6.7)

Sparse pharmacokinetic assessment

Intense pharmacokinetic assessment (at selected sites)

Biomarkers and Pharmacodynamic assessments (Section 6.8)

Target engagement (at selected sites)

Ex vivo osteoclastogenesis (at selected sites)

hsCRP

Serum bone turnover markers

Serum TNF-α and IL-17A

Serum cytokines and other proteins by proteomics

Whole blood RNA gene expression profiling for genes including but not limited to TNF-
α, IL-17A, MCP-1, IL-6

SARS-CoV-2 serology for biobanking

SARS-CoV-2 serology for documented or suspected Infection  

Pharmacogenetics assessment (Section 6.8.2) at the Baseline Visit

Patient-reported Outcomes/Quality of Life Questionnaires (Section 6.9)

ASQoL

SF-36

ASAS Health Index

Investigational product (IP) dispensation: The Principal Investigator, Sub-investigator, or 
Study Coordinator should make an effort to witness subjects taking their first dose and record 
the date and time in the source document record.
6.3
Early Termination 
An early termination (ET) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made. 
The following evaluations will be performed as specified in Table of Events, Table 3 and Table 4:

Concomitant medications evaluation

Concomitant procedures evaluation

Adverse Events (monitored through 28 days after the last dose of IP, Section 10)

Complete physical examination

Vital signs, including seated blood pressure, body temperature, and heart rate will be taken.  
Weight (to be done in street clothes, no shoes) will also be measured and recorded

12-lead ECG

Clinical Laboratory Evaluations (Section 6.5.3)

Hematology panel
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
Chemistry panel

Prothrombin time (PT) and international normalized ratio (INR)

Pregnancy test (Urine and serum β-hCG) 

Counseling about pregnancy precautions and the potential risks of fetal exposure 
(continuously)

Efficacy assessment will be continued according to the schedule defined in Table of Events,
Table 3 and Table 4.

Pharmacodynamics assessment (Section 6.8)

hsCRP test

SARS-CoV-2 serology for biobanking

SARS-CoV-2 Serology for Documented or Suspected Infection  

Patient-reported Outcomes/ Quality of Life Questionnaires (Section 6.9)

Investigational product (IP) return (all used and unused pill containers) and IP compliance 
assessment (Section 7.6)
6.4
Post-treatment Observational Follow-up Period
All subjects will be followed for 28 days after the last dose of IP for AE reporting, as well as SAEs 
made known to the Investigator at any time thereafter that are suspected of being related to IP, as 
described in Section 10.

Concomitant medications evaluation (continuously)

Concomitant procedures evaluation (continuously)

Adverse event evaluation (continuously)

Complete physical examination

Vital, including seated blood pressure, body temperature, and heart rate will be taken.  Weight 
(to be done in street clothes, no shoes) will also be measured and recorded

12-lead ECG (Section 6.5.2)

Clinical Laboratory Evaluations (Section 6.5.3)

Hematology panel

Chemistry panel

Prothrombin time (PT) and international normalized ratio (INR)

Pregnancy test (Urine and serum β-hCG) 

Counseling about pregnancy precautions and the potential risks of fetal exposure 
(continuously)

Pharmacodynamics assessment (Section 6.8)

SARS-CoV-2 Serology for Documented or Suspected Infection  
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6.5
Safety Assessments
6.5.1
Physical Examination
Complete physical examinations will include evaluation of the skin, nasal cavities, eyes, ears, 
respiratory, cardiovascular, abdominal, neurological, lymphatic, and musculoskeletal systems. 
Gynecological, urogenital, and rectal examinations will not be performed unless needed. A limited 
physical examination includes evaluation of the respiratory, cardiovascular, abdominal systems. 
Gynecological, urogenital and rectal examinations will not be done unless needed. Results of the 
physical examination will be recorded only in the source documents. Clinically significant 
abnormal findings (with the exception of the disease under study [AS]) identified prior to first dose 
of IP will be recorded on the eCRF as medical history; clinically significant findings after the first 
dose of IP will be recorded as AEs.
6.5.2
Electrocardiogram
Subjects will have a 12-lead electrocardiogram (ECG) at the frequency specified in Table of 
Events, Table 3 and Table 4. The Investigator or designee will use his/her own ECG equipment.
The same ECG equipment should be used throughout the entire study. A standard 12-lead ECG 
(reporting PR interval, QRS, QT and corrected QT [QTc] intervals) will be performed by the 
Investigator or qualified designee. For safety evaluation of the subject’s ECG, the Investigator 
should utilize the QT correction method (ie, Bazett or Fridericia) routinely available at the study 
site. ECGs will be performed after the subject has been in the supine or near supine position for 
at least 10 minutes.  An ECG tracing from each prespecified visit will be reviewed by the 
Investigator or medically qualified designee and any abnormal results will be classified as 
clinically significant (CS) or not clinically significant (NCS) for real-time safety monitoring.
Clinically significant abnormal findings identified prior to first dose of IP will be recorded on the 
eCRF as medical history; clinically significant findings after the first dose of IP will be recorded 
as an AE and followed to resolution (ie, until it returns to baseline, stabilizes, or becomes NCS as 
judged by the Investigator or medically-qualified designee).
6.5.3
Clinical Laboratory Assessments
Clinical laboratory evaluations will be performed by a central laboratory to include the following 
laboratory assessments performed at the frequency specified in Table of Events, Table 3 and Table 
4. “Abnormal, clinically significant” results should be recorded in the Medical History eCRF if 
found prior to first dose of IP, or in the AE eCRF if found after the first dose of IP.  
Clinical laboratory evaluations are not required to be fasting; however, any unusual findings in 
serum glucose may be repeated with a subsequent fasting lab.  In all cases, the site will record 
whether a clinical laboratory evaluation was fasting or non-fasting on the lab requisition form.

Mycobacterium tuberculosis (TB) testing:  testing will be done at the Screening Visit via 
QuantiFERON®-TB Gold.
Note: A positive QuantiFERON-TB Gold test or 2 successive indeterminate QuantiFERON-
TB Gold tests will disqualify the subject from further participation in the study.
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If a subject has adequate documentation of successful treatment for either latent or active TB, 
the QuantiFERON-TB Gold test is not needed.  Instead, a chest radiograph, obtained within 
the 12 weeks prior to Screening, without changes suggestive of active TB infection as 
determined by a qualified radiologist, will be sufficient to permit further participation in the 
study for these subjects.  Documentation of adequate treatment for TB must be obtained and 
reviewed by the Medical Monitor prior to randomization.
If the subject lives in, or has emigrated from, a TB high burden country (APPENDIX E) then 
further study participation requires documentation of adequate treatment for either active or 
latent TB infection within 2 years of the Screening Visit. For subjects residing in, or emigrating 
from, a TB high burden country and treated for TB more than 2 years prior to the Screening 
Visit, further trial participation requires a negative QuantiFERON-TB Gold test during 
screening. 

Hepatitis B and hepatitis C testing: testing will be performed at Screening. The hepatitis 
screen includes testing for hepatitis B surface antigen (HBsAg) and antibody, hepatitis B core 
antibodies, and hepatitis C antibodies (HCV Ab). A positive result for one or more of these 
tests will disqualify the subject from further participation in the study (Section 4.3). The 
Investigator should refer the subject to his/her general practitioner or other appropriate 
healthcare provider for further follow-up. 
Note: Subjects who received hepatitis B vaccination and who test positive for hepatitis B 
surface antibody and negative for both hepatitis B surface antigen and hepatitis B core 
antibody are not excluded from the study.

Human immunodeficiency virus (HIV) test: testing will be performed at Screening.  A positive 
test result will disqualify the subject from participation in the study.  The Investigator should 
refer any subject who tests positive for HIV to the appropriate HIV counsellor or Health 
Advisor (per the Investigator’s medical practice procedure) for further follow-up.

Postmenopausal tests: estradiol and follicle-stimulating hormone (FSH) levels are required for 
all females 50 to 55 years of age who do not have documentation confirming their 
postmenopausal status.  Postmenopausal test will be performed at Screening.

Hemoglobin A1c: test will be only be performed on subjects receiving metformin treatment 
at screening as indicated in Table of Events, Table 3 and Table 4.

Hematology Panel: including complete blood count (CBC) with differential, including red 
blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, white blood cell (WBC) count (with 
differential), neutrophil count (percent and absolute), and platelet count.

Chemistry Panel: including total protein, albumin, calcium, phosphorous, glucose, uric acid, 
total bilirubin (TBL), alkaline phosphatase (ALP), AST/ serum glutamic oxaloacetic 
transaminase (SGOT), ALT/ serum glutamic pyruvic transaminase (SGPT), sodium, 
potassium, chloride, carbon dioxide, blood urea nitrogen (BUN), serum creatinine, creatine
phosphokinase (CPK), troponin-T and lactic dehydrogenase (LDH).

Lipid panel:  including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-
density lipoprotein (LDL) cholesterol, and triglycerides will be assessed as indicated in Table 
of Events, Table 3 and Table 4.  As described above, clinical laboratory evaluations are not 
required to be fasting; however, any unusual findings in lipids may be repeated with a 
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subsequent fasting lab.  In all cases, the site will record whether a clinical laboratory evaluation 
was fasting or non-fasting on the lab requisition form.

Prothrombin time (PT) and international normalized ratio (INR) will be assessed as indicated 
in Table of Events, Table 3 and Table 4.  

HLA-B27:  a DNA test for the presence of HLA-B27 gene variant will be completed at 
Baseline in all subjects for AS diagnostic purposes (Reveille, 2006).  This is the only DNA test 
that will be done on the subject’s blood, as part of the main study informed consent, and is 
different from the DNA blood draw for the pharmacogenetic substudy, which requires a 
separate informed consent.

Pregnancy testing is required for all female subjects of childbearing potential as indicated in 
Table of Events, Table 3 and Table 4:

Urine β-hCG pregnancy test will be performed at the Baseline Visit and prior to the first 
administration of IP.  A negative urine pregnancy test result is required prior to IP 
administration.  

Urine β-hCG pregnancy test will be performed at all other visits as indicated in the Table 
of Events, Table 3 and Table 4.  If the urine β-hCG pregnancy test is indeterminate IP must 
be held pending negative serum β-hCG pregnancy test result.  If the urine β-hCG pregnancy 
test is positive IP must be discontinued and confirmation retesting on serum β-hCG is 
required (refer to Section 10.4).

Serum beta human chorionic gonadotropin (β-hCG) pregnancy test will be performed at 
all visits.  
6.6
Efficacy Assessment
The following sections describe the efficacy measures and assessments obtained or completed 
directly from the subject, or efficacy evaluations completed by the Investigator (or authorized site 
staff member) on the subject. Every effort must be made to ensure the same assessor completes 
the clinical efficacy assessments for each participant at all visits at approximately the same time 
throughout the study, according to the Table of Events (Table 3 and Table 4).  The timeframes for 
all clinical efficacy measures obtained from the subject are indicated in Table of Events, Table 3
and Table 4.
6.6.1
Assessment of SpondyloArthritis International Society Response 
Criteria
The ASAS20 and ASAS40 are validated response criteria widely used in the evaluation of efficacy 
of agents used in the treatment of axSpA (Sieper, 2009).
The ASAS20 is defined as improvement ≥ 20% and ≥ 1 unit on a scale of 0 to 10 in each of the 3 
domains, with no worsening in the fourth, where the domains are physical function, total back 
pain, patient global assessment of disease, and inflammation (mean of BASDAI NRS Questions 
#5 and #6 for morning stiffness) (Anderson, 2001).
The ASAS40 is defined as improvement ≥ 40% and ≥ 2 units on a scale of 0 to 10 in each of the 3 
domains, with no worsening in the fourth, where the domains are physical function, total back 
pain, patient global assessment of disease, and inflammation (mean of BASDAI NRS Questions 
#5 and #6 for morning stiffness) (Brandt, 2004).
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6.6.2
Ankylosing Spondylitis Disease Activity Score with CRP
The ASDAS–CRP is a validated disease activity index in AS that combines patient reported 
assessments of back pain (BASDAI question 2), duration of morning stiffness (BASDAI question 
6), peripheral joint pain and/or swelling (BASDAI question 3), general wellbeing, and CRP, in a 
weighted manner (van der Heijde, 2009).  The cut-off values for disease activity states and 
improvement scores are defined as follows:  < 1.3 inactive disease, ≥1.3 and < 2.1 low disease 
activity, ≥ 2.1 and ≤ 3.5 high disease activity and, 3.5 very high disease activity.  The minimum 
clinically important difference (MCID), are defined as:  change of at least 1.1 unit for ‘clinically 
important improvement’ and change of at least 2.0 units for ‘major improvement’ (Machado, 2011; 
Machado, 2018).
6.6.3
Bath Ankylosing Spondylitis Disease Activity Index
The BASDAI is a composite score based on a subject self-administered survey of six questions 
using a 0 to 10 unit numerical rating scale (NRS) that assesses the subject’s five major symptoms 
of AS during the last week: 1) fatigue; 2) spinal pain; 3) peripheral joint pain/swelling; 4) areas of 
localized tenderness; 5a) morning stiffness severity upon wakening; 5b) morning stiffness duration 
upon wakening (Calin, 1999; Sieper, 2009). The subject will be asked to mark the box with an X 
on a 0 to 10 unit NRS for each of the 6 questions. To give each of the five symptoms equal 
weighting, the mean of the two scores relating to morning stiffness is taken. The resulting 0 to 50 
score is divided by 5 to give a final 0 to 10 BASDAI score. A BASDAI score of 4 or greater is 
considered to be indicative of active AS disease.
6.6.4
Bath Ankylosing Spondylitis Functional Index
The BASFI is a composite score based on a subject self-administered survey of ten questions using 
a 0 to 10 unit numerical rating scale (NRS) that assesses a subject’s degree of mobility and 
functional ability (Calin, 1994; Sieper, 2009) during the last week. The questionnaire consists of 
eight questions regarding function in AS and the two last questions reflecting the subject’s ability 
to cope with everyday life. The subject will be asked to mark the box with an X on a 0 to 10 unit 
NRS for each of the 10 questions, on which the left-hand box of 0 represents “easy,” and the right-
hand box represents impossible.” The resulting 0 to 100 score is divided by 10 to give a final 0 to 
10 BASFI score.  A higher BASFI score correlates to reduced functional ability.
6.6.5
Patient Global Assessment of Disease Activity
The Patient Global Assessment of Disease Activity is the subject’s assessment of how active their 
spondylitis was on average during the last week. The subject will be asked to mark the box with 
an X on a 0 to 10 unit NRS in which the left-hand box of 0 represents “not active” and the right-
hand box represents “very active” (Sieper, 2009).
6.6.6
Total Back Pain
The Total Back Pain NRS is the subject’s assessment of, on average last week, how much pain 
they have in their spine due to AS. The subject will be asked to mark the box with an X on a 0 to 
10 unit NRS in which the left-hand box of 0 represents “no pain” and the right-hand box represents 
“most severe pain” (Sieper, 2009).
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6.6.7
Nighttime Back Pain
The nighttime back pain NRS is the subject’s assessment of, on average last week, how much pain 
they have in their spine due to AS at night. The subject will be asked to mark the box with an X 
on a 0 to 10 unit NRS in which the left-hand box of 0 represents “no pain” and the righthand box 
represents “most severe pain” (Sieper, 2009).
6.6.8
Bath Ankylosing Spondylitis Metrology Index - Linear
The BASMI - Linear was designed to assess axial status (ie, cervical, dorsal and lumbar spine, 
hips, and pelvic soft tissue) and to define clinically significant changes in spinal movement 
(Jenkinson, 1994; Sieper, 2009). Five dimensions of movement (lateral lumbar flexion, tragus to 
wall, forward lumbar flexion, maximal intermalleolar distance, and cervical rotation) are measured 
and normalized on 0 to 10 unit NRS. The average of these scores is the total BASMI - Linear
score, with a higher value indicating more severe limitation in spinal mobility.
6.6.9
Occiput to Wall Measurement
Occiput to wall measurement is the distance measured between the occiput located on the back of 
the subject’s skull and the wall. The subject stands with heels and shoulder against the wall with 
the back straight. The chin is at the usual carry level. The maximal effort to touch the head against 
the wall is asked of the subject. The distance between the occiput and the wall is measured in 
centimeters (cm) (Sieper, 2009).
6.6.10
Chest Expansion Measurement
When ankylosing spondylitis affects the mid-back region (thoracic spine), normal chest expansion 
may be compromised. 
The chest expansion measurement is the difference between the 
circumference of the chest in maximal inspiration and maximal expiration. To conduct the test, 
the subject has his/her hands resting on or behind the head. The amount of chest expansion is 
measured from deep expiration to full inspiration and is measured at the level of the fourth 
intercostal space anteriorly in males and just below the breasts in females (Sieper, 2009).
6.6.11
Enthesitis Evaluation
Enthesitis, or the swelling of the sites where tendons or ligaments insert into the bone, is a 
prominent clinical manifestation in subjects with AS. The Maastricht Ankylosing Spondylitis 
Enthesitis Score (MASES) will be used in this study to measure the severity of a subject’s 
enthesitis (Heuft-Dorenbosch, 2003).
6.6.12
Peripheral Joint Count
An ASAS joint evaluation which includes the “44 tender and 44 swollen” joint counts (Sieper, 
2009) will be performed on all subjects to monitor peripheral joint involvement. Non weighted 
measures will be used to assess tender and swollen joints. In order to maintain consistency 
throughout the study, preferably the same evaluator should perform the peripheral joint 
assessments at the study site at each study visit.
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6.6.13
MRI of Sacroiliac Joint and Spine (SPARCC Method)
The MRI assessments will be conducted at all sites.  Details regarding the MRI specific procedures 
and the consistent acquisition of MRI images will be outlined in a separate image acquisition 
document.
MRI assessment will be performed on the sacroiliac joints and the entire spine (cervical, thoracic, 
and lumbar).  The Baseline MRI must be performed between Visits 1 and 2 inclusive.  Subsequent 
MRIs should be completed at Visit 6 (the final treatment visit) or at the Early Termination Visit.  
If the Early Termination Visit occurs before Week 6, then MRI of sacroiliac joint should not be 
done.
All MRI visits should be scheduled well in advance to allow for proper planning. In addition, it is 
strongly recommended to schedule two MRI visits (an initial and a repeat visit) for each MRI time 
point in order to be assured of a high-quality MRI scan at each protocol-specified time point. The 
initial and repeat MRI visits should be scheduled approximately 7 to 14 days apart to allow enough 
time for confirmation of quality scans from the initial MRI. If the initial MRI scans are of 
acceptable quality, then the scheduled repeat MRI session can be cancelled.  The scoring of the 
standardized MRIs will be conducted by well-trained, independent, central readers.
6.7
Pharmacokinetics
Blood samples will be collected at prespecified times for measurement of CC-99677 and CC-
0782951 in plasma.  Concentrations of CC-99677 and CC-0782951 in plasma will be measured 
using a validated liquid chromatography tandem mass spectrometry assay.
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 predose PK blood sample. Subjects will be 
asked to report the date and time of their last IP dose (dose from the day before visit) 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. Dosing and sample collection information 
including dosing date, dosing time, and actual PK blood sampling time should be accurately 
documented on the appropriate eCRF pages. 
Pharmacokinetic blood sampling should be performed at the nominal time(s) specified in this 
clinical protocol.  All actual PK blood sample collection times will be recorded in the source 
documents and CRF.  Explanation should be provided in the source documents and CRF for missed 
or mishandled samples and for samples collected outside the following time windows:

Predose (0 hour) sample: - 60 minutes;

Samples between 0.25 to 1 hour postdose, inclusive: ± 3 minutes;

Samples between 2 to 4 hours postdose, inclusive: ± 15 minutes; 

Samples between 6 to 12 hours postdose, inclusive: ± 20 minutes;
See the Laboratory Manual for specific sample collection, handling and processing instructions.
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6.7.1
Sparse Pharmacokinetics Blood Draw
All subjects in the study will have sparse PK samples collected (~3 ml) at the following time 
points:

Visit 2 (Week 0): 3 hours post dose

Visit 4 (Week 4): 2 hours post dose

Visit 5 (Week 8): 1 hour post dose

Visit 6 (Week 12): pre-dose and 3 hours post dose

Visit 8 (Week 16): 2 hours post dose

Visit 9 (Week 20): 1 hour post dose

Visit 10 (Week 24):  pre-dose
Note: For subjects who take IP in the evening, IP should be taken at approximately 5 PM the 
day prior to sparse PK collections.  On the day of sparse PK sample collection, IP must be taken 
and witnessed at the study site.
6.7.2
Intense Pharmacokinetics Blood Draw
A subset of sites will be selected for participation in the intensive PK study.  In addition to the 
sparse PK sampling in these subjects, intensive PK blood samples will be collected (~3 ml) at the 
following time points:

Visit 4 (Week 4):  pre-dose and 0.5, 1, 2, 3, 6, 8, and 12 hours post dose.
The actual times of drug administration and PK blood sample collections will be recorded in the 
source documents and CRF.  On the day of intense PK sample collection, IP must be taken at the 
study site after collection of the pre-dose PK blood sample.  This planned PK schedule may be 
modified; if modified, the total number of minimal time points per subject will not exceed 8 draws 
per visit and blood sample volume will remain approximately 3 mL for each nominal time point. 
6.8
Biomarkers, Pharmacodynamics, Pharmacogenomics
Blood samples will be collected as specified in Table of Events, Table 3 and Table 4 for 
measurement of various PD and PG biomarkers.  Specific details regarding the collection, 
processing, storage, and shipment of all PD and PG samples are provided in a separate Laboratory 
Manual.
For those biomarkers that require approval from national health authorities, biomarker samples 
cannot be collected in those countries until approval is received (See Section 6.8.1 and 
Section 6.8.2).  Note:  Assays for some biomarkers may not be available in all countries.
6.8.1
Biomarkers/Pharmacodynamics
All sites will be expected to participate in biomarker studies, except for pharmacodynamic 
measurement of target engagement and ex vivo osteoclastogenesis, which will be performed at 
selected sites, only.
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Biospecimen operations will ensure that all sites are qualified to handle biomarker logistic 
requirements, including sample collection, processing and shipping, and image acquisition 
procedures.  The following assessments will be explored:
High-sensitivity C-reactive protein (hsCRP)
Blood samples will be collected as specified in Table of Events, Table 3 and Table 4 to measure 
hsCRP levels since it is required for calculating the ASDAS efficacy variables, and it is also an 
important disease-relevant biomarker (Section 1.4.3).
Serum bone turnover markers
Blood samples will be collected under fasted conditions.  Subjects must not have received high-
dose biotin supplements (multivitamins are allowable) within 72 hours prior to sample collection
as specified in Table of Events, Table 3 and Table 4.  Specific serum bone turnover markers 
including but not limited to C terminal telopeptide (CTX) and procollagen I intact N terminal 
peptide (P1NP) will be measured. 
Blood Collection for Pharmacodynamic Measurement of Target Engagement, at selected 
sites only
Blood samples will be collected as specified in Table of Events, Table 3, to measure target 
engagement.  Samples will be evaluated for percent of MK2 bound to CC-99677 versus percent 
of free MK2 in PBMCs.
Blood Collection for Measurement of Serum TNF-α and IL-17A
Blood samples will be collected as specified in Table of Events, Table 3 and Table 4, to measure 
serum TNF-α and IL-17A by an ultra-sensitive enzyme-linked immunosorbent assay (ELISA)
method.
Blood Collection for Measurement of Serum Cytokines and Proteins by Proteomics
Effects of CC-99677 on serum proteins such as serum cytokines, chemokines and other 
inflammatory factors will be evaluated.  Blood samples will be collected as specified in Table of 
Events, Table 3 and Table 4.
Blood Collection for Markers of ex vivo osteoclastogenesis (at selected sites only)
Osteoclast precursors in PBMCs will be assessed as specified in Table of Events, Table 3. 
Whole blood RNA for gene expression profiling
Effects of CC-99677 on gene expression will be evaluated by RNAseq analysis as specified in 
Table of Events, Table 3 and Table 4.
SARS-CoV-2 serology
Serum will be collected at times indicated in Table 3 and Table 4 for biobanking and possible 
measurements of SARS-CoV-2 serology (anti-SARS-CoV-2 total or IgM and/or IgG antibodies), 
and documented or suspected infection.
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6.8.2
Pharmacogenomics
The pharmacogenetic substudy is optional, and a separate consent will be signed for this 
assessment at Screening.
Pharmacogenetic testing will be conducted using DNA isolated from a single blood sample at 
Baseline, as specified in Table of Events, Table 3.  DNA polymorphisms will be investigated for 
their ability to stratify patient subsets or response to CC-99677. Genetic markers to be assessed 
include, but are not limited to, those involved in MK2 signaling, CC-99677 metabolism, and those 
shown to be associated with ankylosing spondylitis.
Detailed instructions for sample preparation and handling will be provided in a separate lab 
manual.
6.9
Patient Reported Outcomes
The timeframes for all health-related quality of life measures are indicated in Table of Events,
Table 3 and Table 4.
6.9.1
Ankylosing Spondylitis Quality of Life
The ASQoL is a validated disease specific patient reported outcomes instrument to assess the 
impact of ankylosing spondylitis (AS) on the quality of life of individuals with emphasis on the 
ability of the person to fulfill his or her needs (Doward, 2003). It consists of 18 items requesting a 
yes (score=1) or no (score=0) response to questions related to the impact of pain on sleep, mood, 
motivation, ability to cope, activities of daily living (ADL), independence, relationships, and social 
life.  The summary score ranges 0–18 with higher scores indicating worse quality of life.  The 
MCID was defined as a 1.8-point change for ASQoL (van der Heijde, 2007a). 
6.9.2
Medical Outcome Study Short Form 36-Item Health Survey, Version 2 
The SF-36 (Ware, 1992) is a validated, self-administered 36-item general health status instrument 
often used in clinical trials and health services research.  It consists of 8 scales: physical function 
(PF), role limitations–physical (RP), vitality (VT), general health perceptions (GH), bodily pain 
(BP), social function (SF), role limitations–emotional (RE), and mental health (MH) (Ware, 1992).  
Scale scores range from 0 to 100, with higher scores indicating better health.  Two overall summary 
scores can also be obtained—a Physical Component Summary score (PCS) and a Mental
Component Summary score (MCS).  The PCS and MCS scores are transformed to have a mean of 
50 and standard deviation of 10, with higher scores indicating better health.  The concepts 
measured by the SF-36 are not specific to any age, disease, or treatment group, allowing 
comparison of relative burden of different diseases and the relative benefit of different treatments.  
Version 2 of the SF-36 will be used in this study.
6.9.3
ASAS Health Index
The ASAS Health Index is a validated linear composite measure and includes 17 items and is 
intended to capture relevant information on functioning and health of patients with AS 
(Kiltz, 2014).
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Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
78
7
DESCRIPTION OF STUDY TREATMENTS
CC-99677 is available for clinic use in Swedish orange, opaque, hard hydroxypropyl 
methylcellulose (HPMC) capsules.  In addition to drug substance, the formulated capsules will 
contain HPMCAS, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, and 
magnesium stearate. Refer to the Investigator’s Brochure for information regarding CC-99677.
CC-99677 will be supplied by the Sponsor and labeled appropriately as IP for this study.  
CC-99677 will be provided by the sponsor as 30 mg and 60 mg formulated capsules and will be 
labeled appropriately as investigational material.  In addition, the sponsor will provide matching 
placebo identical in appearance to CC-99677 30 mg and 60 mg formulated capsules labeled 
appropriately as investigational material.
7.1
Description of Investigational Product

Sufficient quantities of CC-99677 and equivalent placebo will be supplied by Celgene (or 
designee) and labeled appropriately as IP for this study.  Celgene as the sponsor will label the 
IP as appropriate and will include all required information following local regulations and/or 
regulatory requirements in each participating country.

CC-99677 and equivalent placebo will be provided in the relevant strength(s) as capsules for 
oral administration. The dosing schedule and dose adjustments to be followed for this study 
are described in Section 7.2.

All IP must be stored according to the package label and in a secure, limited-access location 
and may be dispensed only by the Investigator or by a member of the staff specifically 
authorized by the Investigator.
7.2
Treatment Administration and Schedule
Subjects are instructed to take 3 capsules once daily, approximately the same time of day 
(preferably in the morning), with or without food.
12-Week Double-blind, Placebo-controlled Treatment Period: Baseline to Week 12

CC-99677 150 mg QD PO

CC-99677 60 mg QD PO

Placebo QD PO
If the additional dose cohort is initiated (Section 3.1.4) in the biologic-naïve main study, then 
additional IP will be provided as follows:

Additional dose cohort (dose not to exceed 150 mg) (Section 3.1.2) 

Placebo PO QD
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Protocol CC-99677-AS-001
Celgene Corporation
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Final: 21 Sep 2022
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Table 5:
Study Treatment Administration (Number of Capsules)
Treatment 
Allocation
30 mg
60 mg
Placebo 
Matching 30 mg
Placebo Matching 
60 mg
Total Number of 
Capsules per Day
CC-99677 150 mg
1
2
0
0
3
CC-99677 60 mg
0
1
1
1
3
Placebo
0
0
1
2
3
Note:  An additional dose cohort (dose not to exceed 150 mg) may be added following results from 
the planned IA (Section 3.1.4).  In this event, this will not result in subjects receiving an increased 
number of capsules per day.
To maintain the blind at the site and subject level, the original individual subject treatment 
assignments at randomization will not be revealed to the Investigators until after the 12-Week 
database lock and after all final analyses are completed and the final results have been released.
Capsules of CC-99677 will be counted at every visit starting at Visit 3 through the completion of 
the study. If a dose of IP is missed for the entire day, the subject should not take an extra dose the 
next day or take an unscheduled dose. Subjects who take more than the prescribed dose of IP 
should be instructed to contact study staff immediately and seek emergency medical care if needed.
Any interruption in the IP will not alter the current dose or dose interval, nor will the length of the 
study be extended to account for days of missed IP.
7.2.1
Overdose
Overdose, as defined for this protocol, applies to protocol-required dosing of the IP, only.  Other 
medications are excluded from this definition.  Overdose for this protocol is defined as the 
accidental or intentional administration of any dose of IP that is considered both excessive and 
medically important.  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.  
Detailed information about any CC-99677 overdose in this study, regardless of whether the 
overdose was accidental or intentional, should be reported on the drug exposure CRF page.
7.2.2
Dose Modification/Interruptions
Because this is a dose-finding study no dose reductions will be permitted.  However, in the event 
the subject experiences an adverse event, a temporary IP interruption is permitted anytime during 
the study.  The Sponsor should be notified in advance of the dosage interruption; however, the 
decision to interrupt IP dosing will be based on the Investigator’s clinical judgment. If the subject 
misses 4 or more consecutive days of dosing, Celgene must be contacted to decide whether dosing 
should resume or whether the subject should be terminated from the study IP and enter the Post-
treatment Observational Follow-up Period.
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Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
80
If a dose of IP is missed, it should be taken as soon as possible on the same day, provided it occurs 
within 36 hours of the previous dose.  The dose should be skipped if the timing of the dose occurs 
> 36 hours of the previous dose.
Temporary interruption of IP is allowed in the context of clinical suspicion for SARS-CoV-2 or a 
positive diagnostic test for SARS-CoV-2 if deemed necessary by the investigator. Temporary 
interruption of IP may also be considered in the event of SARS-CoV-2 vaccination according to 
local guidelines. In order to facilitate reporting of SARS-CoV-2 events that occur during the study, 
all AEs and SAEs related to SARS-CoV-2 must be reported from the time of consent. In addition, 
such AEs or SAEs will trigger additional data collection through dedicated eCRF pages, which 
will allow the Sponsor to further evaluate these events. 
Note: If the dose is missed for the entire day, the subject should not take an extra dose the next day 
or take an unscheduled dose.
7.3
Method of Treatment Assignment
Randomization, stratification and treatment assignment will be managed by an Interactive Web 
Response System (IWRS).  
Designated study personnel at the investigational sites will be assigned password-protected, coded 
identification numbers, which give them authorization to access the IWRS to randomize subjects.  
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 IWRS will assign a 
randomization identification number. Confirmation of the randomization will be sent via fax to the 
investigational site, Celgene and/or its representative.
During the study visits, the pharmacy or authorized study personnel at the investigational site will 
dispense coded IP kits in accordance with the randomization number assigned by the IWRS.
7.4
Packaging and Labeling
The label(s) for IP will include, but not limited to 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.
7.5
Investigational Product Accountability and Disposal 
The Investigator(s) or a qualified designee(s) is/are responsible for taking an inventory of each 
shipment of IP received, and comparing it with the accompanying accountability form.  The 
Investigator(s) or qualified 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, where it will be 
maintained in the trial master file.
At the study site, all IP will be stored in a secure, locked area to prevent unauthorized access. IP
must be stored at the correct temperature as directed on the bottle label(s).  Any expired IP must 
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be stored separately before they are returned or destroyed to prevent them from being accidentally 
administered to study subjects.  Accurate recording of all IP administration will be made, at 
minimum, in the appropriate section of the subject’s source documents.
The Investigator(s) or qualified designee(s) is responsible for the accountability of all IP issued to 
the site during the course of the study.
Celgene (or designee) will review with the Investigator and relevant site personnel the process for 
IP return, disposal, and/or destruction including responsibilities for the site versus Celgene (or 
designee).
7.6
Investigational Product Compliance
The study staff will maintain an ongoing record of the dispensing and administration of CC-99677 
for each subject via an accountability record or equivalent document that will be verified by 
Celgene’s study monitor.
For CC-99677 dispensed to the subject for outpatient administration, study personnel will review 
the instructions printed on the package with the study subject prior to dispensing CC-99677. IP
will be dispensed as noted in Table of Events, Table 3 and Table 4. 
The subjects will be instructed to return the CC-99677 containers, including any unused 
medication, to the study site at each visit for capsule counts and reconciliation.  Subjects will be 
asked whether they have taken their CC-99677 as instructed at each study visit.  Any problems 
with CC-99677 compliance will be reviewed with the subject.  
If a subject misses 4 or more consecutive days of dosing or is taking less than 80% of the doses 
between study visits Celgene should be contacted to decide whether dosing should resume or 
whether the subject should be terminated from the treatment period of the study.
Gross compliance problems (eg, missing 4 or more consecutive days of dosing or taking less than 
80% of the doses between study visits) should be discussed with Celgene. Compliance will be 
categorized into 4 classes: < 50%, ≥ 50% to ≤ 80%, > 80% to ≤ 120%, > 120%.
Accurate recording of all CC-99677 administration (including dispensing and dosing) will be made 
in the appropriate section of the subject’s eCRF and source documents.
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Protocol CC-99677-AS-001
Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
82
8
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease progression.  
All concomitant medications (prescription and non-prescription), treatments, and therapies taken 
by the subject from Screening until 28 days after the last dose of IP, must be reported on the CRF. 
All concomitant medications (prescription and non-prescription) will be commercially sourced by 
the clinical site responsible for use in this trial and in accordance with local guidelines.  Please 
refer to local prescribing and package insert information for more details on available 
formulations, preparation, storage conditions (eg, refrigeration), approved indications, known 
precautions, warnings, and adverse reactions for these drugs (see current version of prescribing 
information).
Non-drug therapies for AS (including physical therapies) should be kept stable during the study.
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the Investigators Brochure.
8.1
Permitted Concomitant Medications and Procedures

Concomitant use of one NSAID or cyclooxygenase (COX)- 2 inhibitor on a regular basis up 
to the maximum recommended dose as per local guidelines is permitted, provided the drug is 
for treatment of AS and is used at a stable dose for at least 2 weeks prior to Baseline (Day 1 of 
study).  The dose and frequency of the medication must be maintained stable until conclusion 
of study treatment (end of Week 64), even if subject experiences improvement in disease 
activity. If the subject experiences an adverse event (eg, gastrointestinal bleed) then dose 
reduction, stopping or switching to another NSAID or COX-2 inhibitor, or discontinuation of 
the agent is allowed. 
As needed (PRN) use of NSAIDs or COX-2 inhibitors is not 
recommended during the study and is not permitted within the 24 hours prior to a study visit.

Concomitant use of sulfasalazine is permitted, provided sulfasalazine is used at a stable dose 
for at least 4 weeks prior to Baseline (Day 1 of study); dose must be stably maintained until 
conclusion of study treatment (end of Week 64) unless dose adjustments are required for safety 
and/or tolerability concerns.

In case the subject requires PRN medication for pain, acetaminophen/paracetamol and/or low-
strength opioid analgesics up to the maximum recommended doses per local guidelines may 
be used but cannot be taken within 24 hours prior to a study visit with disease activity 
assessment.

Acetylsalicylic acid at a dose of ≤325 mg /day for cardiac prophylaxis is allowed.

Bisphosphonate therapy is allowed if stable for at least 1 year prior to randomization and must 
be maintained stable until conclusion of study treatment (end of Week 64).

Concomitant use of systemic corticosteroids at or up to 10 mg/day of prednisone or equivalent 
is permitted, provided the drug is used at a stable dose for at least 4 weeks prior to Baseline.  
The dose and frequency of the medication must be maintained stable until conclusion of study 
treatment (end of Week 64).
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Celgene Corporation
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Final: 21 Sep 2022
83

Subjects may receive statins (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase [HMG-
CoA reductase] inhibitors) during the study; however, routine monitoring for statin-related 
AEs (eg, hepatic enzyme elevations and muscle soreness) is recommended.
8.2
Permitted Medications That Require Careful Monitoring
Studies examining drug-drug interactions involving CC-99677 in humans have been completed
(see Section 1.4.2). CC-99677 may potentially inhibit the transporters BCRP, P-gp, OATP1B1, 
OATP1B3 and OCT1 (Section 1.3). Based on data from these studies, there is unlikely to be a 
clinically significant interaction with drugs that are substrates of these transporters AND that have 
a wide therapeutic index. Drugs that are substrates of these transporters AND that have a narrow 
therapeutic index, however, should be used with caution, and subjects receiving such drugs should
be closely monitored for potential toxicities during participation in the study. A partial list of these 
drugs, including those that are therapeutically relevant to common comorbidities in the AS 
population, are listed in APPENDIX D, Table 10. Questions regarding potential co-administration 
of CC-99677 with drugs that are substrates of BCRP, P-gp, OATP1B1, OATP1B3 or OCT1
(APPENDIX D, Table 10) should be discussed with the medical monitor.
8.3
Prohibited Concomitant Medications
The following medications cannot be administered for the specified times prior to the initiation of 
study IP and for the duration of the study:

Use of Vitamin K antagonists (eg, warfarin) during the study

Use of diclofenac or sulindac

Use of any medication known to be either a moderate or strong inhibitor or a moderate or 
strong inducer of CYP3A4/5 until study completion (See APPENDIX C, Table 7). There must 
be a washout period of 5 PK half-lives of any such drug used by the subject prior to Baseline 
Visit. The Medical Monitor or designee should be queried in case of uncertainty.

Use of any medication known to be either a moderate or strong inhibitor or a moderate or 
strong inducer of P-gp until study completion (see APPENDIX C, Table 8). There must be a 
washout period of 5 PK half-lives of any such drug used by the subject prior to Baseline Visit. 
The Medical Monitor or designee should be queried in case of uncertainty.

Use of any medication known to be a strong BCRP inhibitor until study completion (see 
APPENDIX C, Table 8).  There must be a washout period of 5 PK half-lives of any such drug 
used by the subject prior to Baseline Visit. The Medical Monitor or designee should be queried 
in case of uncertainty.

Use of any medications that are substrates of one or more of the transporters P-gp, OATP1B1, 
OATP1B3, and OCT1 and have a narrow therapeutic index (eg, methotrexate, digoxin, 
cyclosporine, mycophenolic acid, and leflunomide). Additional examples can be found in 
APPENDIX C, Table 9.
Note: 
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BCRP substrates with a narrow therapeutic index (eg, prazosin) should be used with 
caution (APPENDIX D, Table 10). Sulfasalazine is not excluded based on results from 
CC-99677-CP-002 (see Section 1.4.2).
At least a 1-month washout period prior to randomization is required for the 
conventional synthetic disease-modifying antirheumatic drugs (DMARDs), except for 
leflunomide, which has to be discontinued for 15 weeks prior to randomization unless 
a cholestyramine washout has been performed. Subjects should not discontinue any of 
the above synthetic DMARDs for the sole purpose of participating in this trial.

Use of high potency opioid analgesics (eg, methadone, hydromorphone, morphine or 
oxycodone)

Treatment with any biologic indicated for AS (eg, anti-TNF or anti-IL-17A mAb)

Introduction of a JAK inhibitor or immunomodulating therapy including but not limited to 6-
mercaptopurine, azathioprine, cyclosporine or other calcineurin inhibitors (eg, sirolimus, 
tacrolimus), gold therapies

Treatment with any systemic, intravenous, intramuscular or intra-articular corticosteroid
within 4 weeks of the Baseline visit

Use of any other investigational drug

Any botanical preparation (eg, herbal supplements or traditional Chinese medicines derived 
from plants, minerals, or animals) intended to treat AS or other immunological diseases.
8.4
Vaccination Guidelines
Currently, there are no available data on the use of CC-99677 and its impact on immune responses 
following vaccination.  Based on the mechanism of action, pharmacological modulation of the 
MK2 pathway by CC-99677 may reduce the effectiveness of vaccines.
Administration of live and live-attenuated vaccines, such as varicella, oral polio and inhaled flu 
vaccine, is prohibited during the study and for 4 weeks after the last dose of study drug. Routine 
household contact with persons vaccinated with live vaccine components should be avoided. 
Vaccination with non-live vaccines should be performed based on local guidelines (eg, COVID-
19 vaccine, seasonal influenza vaccine).
All routine vaccinations should be administered prior to the study. If vaccination is performed 
near the expected enrollment date, it is suggested that enrollment is delayed until the vaccination 
series is completed and any symptoms related to vaccination have resolved. If vaccination becomes 
available only after enrollment, vaccination can proceed at discretion of the investigator. These 
include genetic, protein-based, replication incompetent, or inactivated vaccine as approved by 
local authorities. 
COVID-19 vaccination, when available, is recommended prior to enrollment.  If a participant 
receives a COVID-19 vaccine during the study, the Week 12 visit should not take place within 5 
days after vaccine administration so that any acute reaction to the vaccine will not potentially 
confound study assessments.  Please contact the Medical Monitor with any questions related to 
COVID-19 vaccines.
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Celgene Corporation
CC-99677-AS-001 Amendment 3.0
Final: 21 Sep 2022
85
8.5
Required Concomitant Medications and Procedures
There are no required concomitant medications for inclusion in this study.  However, subjects must 
have undergone prior treatment with at least 2 NSAIDs (at the highest dose tolerable) for at least 
4 weeks (each) with documented inadequate response.
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Protocol CC-99677-AS-001
Celgene Corporation
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Final: 21 Sep 2022
86
9
STATISTICAL CONSIDERATIONS
9.1
Overview
Key elements of the statistical analysis of this study are described in this section; details, including 
the estimands for the primary and secondary objectives, will be documented in a Statistical 
Analysis Plan (SAP). The statistical analysis of this study will be the responsibility of the 
Biostatistics department of the Sponsor or its designee. 
This study will initially be conducted as a double-blind study with in-house blinding procedures. 
Following primary analysis of both the biologic-naïve main study and the biologic-failure 
susbstudy, the remainder of the Long-term Extension Period will be conducted in a Sponsor-
unblinded fashion. For the primary data analysis, the Week 12 database will not be unblinded until 
medical/scientific review has been conducted, protocol deviations have been identified, the data 
have been declared final and complete, and an SAP has been written and approved. The 
randomization schedule will be generated and implemented by the external vendor of the study 
IWRS.
9.2
Study Population Definitions
The full analysis set (FAS) will be the primary population for the efficacy analysis.  The FAS will 
consist of all subjects who are randomized and receive at least 1 dose of IP.
Primary analysis of efficacy of subjects enrolled in the substudy will be separate from that of the 
main cohort.
A supportive analysis using the per-protocol (PP) Population will be performed for the primary 
endpoint. The PP population will consist of all subjects included in the FAS who have no protocol 
deviations that may substantially affect the efficacy results. The final determination on protocol 
deviations, and thereby the composition of the PP population, will be made prior to the unblinding 
of the database and will be separately documented.
Subjects will be included in the treatment group to which they were randomized for the analysis 
using the FAS and PP populations.
The safety analysis will be based on the safety population, which will consist of all subjects who 
are randomized and receive at least 1 dose of IP. Subjects will be included in the treatment group 
corresponding to the IP they actually received for the analysis using the safety population.
The PK Population will include all subjects who receive at least 1 dose of CC-99677 and have at 
least 1 measurable concentration datum. Subjects will be included in the treatment group 
corresponding to the IP they actually receive. The PK Population will be used for all listings.
The PK Evaluable Population will include all subjects who have at least 1 evaluable PK parameter. 
Subjects will be included in the treatment group corresponding to the IP they actually receive. The 
PK Evaluable Population will be the population used for all summaries and statistical analyses. 
9.3
Sample Size and Power Considerations
With 147 total subjects and an equal allocation ratio, the study will randomize 49 subjects to each 
treatment group.  This sample size will provide 80% power, calculated by nQuery Advisor version 
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7 and without accounting for multiplicity, to detect a treatment difference of 25% in ASAS20
response rate at Week 12 between either active treatment group and placebo, using a chi-square 
test at a two-sided significance level of 0.10, and assuming the response rates of 59% for both CC-
99677 treatment groups and 34% for placebo (the latter based on historical studies), with dropouts 
considered as nonresponders in these assumed response rates. Applying the Hochberg procedure 
to adjust for the multiplicity of the comparisons of two active treatment groups with placebo, the 
study will provide 81% power to achieve statistical significance at the two-sided significance level 
of 0.10 for at least 1 treatment group, with the same response rate assumptions stated above.
An additional 50 subjects will be enrolled in the biologic-failure substudy.  The purpose of this 
substudy is to estimate the treatment effect of CC-99677 in subjects who have received not more 
than one biologic for AS, due to inadequate efficacy response to an approved biologic dose for at 
least 12 weeks and/or unacceptable safety/tolerability of a biologic agent (in the opinion of the 
Investigator).  A minimum of 50% of biologic failure subjects will be recruited due to inadequate
efficacy response to treatment.  Subjects enrolled in the substudy will be randomized using a 2:2:1 
allocation ratio (20 subjects each to receive either CC-99677 150 mg PO QD or CC-99677 60 mg 
PO QD and 10 subjects to receive matching placebo).
9.4
Background and Demographic Characteristics
Subject’s age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while sex, race and other categorical variables will be provided using frequency 
tabulations.  Medical history data will be summarized using frequency tabulations by Medical 
Dictionary for Drug Regulatory Activities (MedDRA) system organ class and preferred term.
9.5
Subject Disposition
Subject disposition (analysis population allocation, entered, completed, discontinued, along with 
primary reason for discontinuation) will be summarized using frequency and percent. A summary 
of subjects enrolled by site will be provided. Important protocol deviations will be summarized 
using frequency tabulations.
9.6
Efficacy Analysis
The primary efficacy endpoint is the ASAS20 assessment at Week 12 (Visit 6) of the Double-
blind, Placebo-controlled Period (for the comparison between CC-99677 150 mg PO QD, 
CC-99677 60 mg PO QD and placebo.
9.6.1
Statistical Methods
Binary endpoints will be analyzed by the Cochran-Mantel-Haenszel (CMH) test stratified by the 
randomization stratification factor hsCRP concentration (≤ upper limit of normal/ > upper limit of 
normal). The primary missing data handling approach for binary endpoints will be nonresponder 
imputation (NRI), by which a subject will be considered a nonresponder at a given time point if 
the subject does not have sufficient data (including the baseline data for the endpoints assessing 
the change from baseline) are assessed within the analysis window of the time point for response 
determination. 
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The continuous endpoints will be analyzed by an adaptive approach (Mehrotra, 2012) that uses 
either a longitudinal data analysis (LDA) model (Liu, 2009) (in the absence of severe departures 
from normality) or robust regression model/nonparametric methods (in the presence of severe 
departures from normality).The LDA model assumes a common mean across treatment groups at 
baseline and a different mean for each treatment group at each of the postbaseline time points. In 
this model, the response vector consists of the baseline and postbaseline values. Time is treated as 
a categorical variable so that no restriction is imposed on the trajectory of the means over time. 
The model will also adjust for the randomization stratification factor hsCRP concentration (≤ upper 
limit of normal/ > upper limit of normal) and its interaction with time.
Summary statistics will be provided over time for the Long-term Extension Period.
9.6.2
Multiplicity
Multiplicity adjustment by the Hochberg procedure will be made in this study for the primary 
efficacy endpoint analysis.
9.6.3
Subgroup Analyses
Subgroup analyses of the primary endpoint by the randomization stratification factor, baseline 
demographic and disease characteristics will be provided to explore the consistency of the 
treatment effect across various subgroups.  Details of the analysis will be provided in the SAP.
9.7
Safety Analysis
Safety will be assessed by clinical review of all relevant parameters including treatment-emergent 
adverse events (TEAEs), laboratory tests, vital signs, weight, and ECGs. No inferential testing for 
statistical significance will be performed.
TEAEs will be classified using the MedDRA classification system.  All TEAEs will be 
summarized by system organ class, preferred term, severity, and relationship to IP. TEAEs leading
to death or to discontinuation from treatment and serious TEAEs 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, vital signs, weight, and ECG data will be summarized descriptively by time point.  In 
addition, shift tables showing the number of subjects with low, normal, and high values compared 
to the normal ranges at baseline versus postbaseline will be provided for laboratory tests.
9.8
Interim Analysis
An interim analysis (IA) will be conducted when approximately 30 subjects in the biologic-naïve 
main study complete 12 weeks of treatment.  A Steering Committee (SC) comprised of 
independent BMS committee members independent of the Study Team and external AS expert(s) 
will review the data from the IA and will convey one of the following decisions to the blinded 
study team:

Continue the study without modification

Terminate the study for futility

Discontinue a treatment group based on preliminary assessment of dose-dependent risk-benefit 
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
Add an additional dose cohort (dose not to exceed 150 mg)
If the SC determines that an additional dose cohort is needed, then the additional dose cohort will 
be initiated in the biologic-naïve main study only as described in Section 3.1.2.
The SC will not play a role in the study conduct.  The study team responsible for managing the 
study will remain blinded. Details and timing of the interim analysis will be described in a Steering 
Committee charter. Additional interim analyses may be conducted.
9.9
Other Topics
9.9.1
Internal Safety Management Team
In addition to ongoing safety monitoring conducted by Investigators and individual study 
personnel, cumulative and interval blinded AEs, SAEs, discontinuations due to AEs, and abnormal 
laboratory findings will be reviewed internally by the Celgene Safety Management Team (SMT).  
The SMT is comprised of lead representatives from multiple Celgene functions engaged in the 
CC-999677 development program.  The scope, conduct, processes, and accountabilities are 
specified by Celgene Standard Operating Procedure (SOP).
9.9.2
Independent External Data Monitoring Committee
Formal unblinded safety and efficacy assessments of the study data will be performed by an 
external, independent DMC. The external DMC will not be involved in any decision making at the 
IA but may make a recommendation to stop the study based on their assessment of the overall 
Benefit/Risk of clinical data.  A DMC will be convened that will include physician experts with 
experience in treating subjects with AS and a statistician, all of whom are not otherwise involved 
in the study conduct and in whom there is no identified conflict of interest.  Operational details for 
the DMC will be detailed in a separate DMC charter.
9.9.3
Pharmacokinetic Analyses
The pharmacokinetic analysis will be performed using the PK population as defined in Section 9.2.
Intense PK collection: Pharmacokinetic parameters of CC-99677 (Cmax, Tmax, AUC[0-T], 
AUC[TAU] and CLT/F) and CC-0782951 (Cmax, Tmax, AUC[0-T], AUC[TAU], MR_Cmax, 
MR_AUC[0-T], and MR_AUC[TAU]) in plasma may be estimated from concentration-time data 
using noncompartmental analysis, as appropriate. 
Sparse PK collection: At Weeks 0, 4, 8, 12, 16, 20, and 24, concentrations of CC-99677 and CC-
0782951 will be reported.
Descriptive statistics will be provided for CC-99677 concentrations and PK parameters, and the 
results will be presented in tabular and graphic form as appropriate. PK parameters for both intense 
and sparse PK will be reported as per the BMS PK Harmonization Document Guidance for 
Contract Research Organizations for Analysis and Reporting of Pharmacokinetic (PK) Data in 
Clinical Studies.
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The relationship between plasma exposure of CC-99677 and selected clinical endpoints (eg, 
toxicities, efficacy and/or biomarkers) may be explored.
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10
ADVERSE EVENTS
10.1
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in 
a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (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 IP should be reported as an AE. Overdose, 
accidental or intentional, whether or not it is associated with an AE should be reported on the 
overdose CRF. (See Section 7.2 for the definition of overdose.) Any sequela of an accidental or 
intentional overdose of an IP which meets the definition of an adverse event, should be reported 
as an AE on the AE CRF. If the sequela of an overdose meets serious criteria, then it must be 
marked as serious on the CRF. The overdose itself should not be reported as an AE.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary.  There is no known specific antidote for CC-99677 overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring of 
any or all of the following parameters:  the subject’s clinical symptoms, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or findings from other tests and/or 
procedures.
All AEs including AEs related to SARS-CoV-2 infection, will be recorded by the Investigator 
from the time the subject signs informed consent until 28 days after the last dose of IP as well as 
those SAEs made known to the Investigator at any time thereafter that are suspected of being 
related to IP. All adverse events (serious/non-serious) will be recorded on the CRF and in the 
subject’s source documents.  In addition, all SARS-CoV-2 infection-related AEs or SAEs will 
trigger additional data collection through specialized clinical safety program (CSP) eCRF pages, 
which will allow the Sponsor to further evaluate these events.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event.
The SAE is recorded within the eCRF and the data is transmitted electronically to Celgene Drug 
Safety within 24 hours of the Investigator's knowledge of the event. In the event electronic 
transmission is not available, a paper SAE Report Form will be completed and sent directly to 
Celgene Drug Safety, ensuring the event is recorded on the CRF as well.
10.2
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
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10.2.1
Seriousness 
An SAE is any AE occurring at any dose that:

Results in death;

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.

a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the CRF. Hospitalization or prolonged hospitalization 
for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition, unrelated to the 
studied indication, that has not worsened from baseline. 

emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above.
For each AE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
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10.2.2
Severity/Intensity
For each AE the Investigator must assess the severity/ intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, 
Version 5.0)
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to the 
following scale:

Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required

Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required

Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible

Grade 4 = Life-threatening – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable

Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is based 
on subject/event outcome or action criteria associated with events that pose a threat to a subject’s 
life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3
Causality
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event.
Causality should be assessed and provided for each AE based on currently available information.  
Causality is to be reassessed and provided as additional information becomes available.
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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.
10.2.4
Duration
For each AE, the Investigator will provide a record of the start and stop dates of the event.  After 
the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs, non-serious AEs of special interest (as defined in
Section 10.5) and SARS-CoV-2 related AEs will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the participant is lost to follow-up.
10.2.5
Action Taken
The Investigator will report the action taken with IP as a result of each AE as applicable 
(eg, discontinuation, interruption, or dose reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event. 
10.2.6
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

results in discontinuation from the study;

requires treatment, modification/ interruption of IP dose, or any other therapeutic intervention; 
or

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 as the AE.  If the abnormality was not a part of a diagnosis or 
syndrome, then the laboratory abnormality should be recorded as the AE. If possible, the laboratory 
abnormality should be recorded as a medical term and not simply as an abnormal laboratory result 
(eg, record thrombocytopenia rather than decreased platelets).
10.4
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.  
In the event of a pregnancy occurring in a female subject of childbearing potential or female partner 
of a male subject, Celgene will follow up with the clinical Investigator each trimester of pregnancy 
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and for 1 year following the birth of the infant (if applicable).  Please reference the pregnancy 
information consent (permission) forms for data collection for additional information.
10.4.1
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on 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 email, phone or 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form.  
The female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation.
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 within 24 hours of the Investigator’s 
knowledge of the event.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as an SAE.  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 as an SAE to Celgene Drug Safety 
within 24 hours of the Investigator’s knowledge of the event.
10.4.2
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP should 
notify the Investigator, and the pregnant female partner should be advised to call their healthcare 
provider immediately.
10.5
Adverse Events of Special Interest
Investigators should identify AEs that meet the following criteria for adverse events of special
interest (AESIs).
10.5.1
Photosensitivity Reactions
A toxicology study in mice suggests that CC-99677 has the potential for photosensitivity. 
Therefore, subjects should take precautions to limit light exposure while receiving CC-99677 
(Section 4.2).  In the event of a suspected photosensitivity rash, the adverse event should be 
discussed with the Medical Monitor.  At the Investigator’s discretion, in consultation with the 
Medical Monitor, a skin biopsy and/or consultation with a dermatologist may be obtained to further 
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characterize the rash. Please refer to Section 11 for discontinuation of IP based on potential 
photosensitivity reactions.
10.5.2
Hepatic Enzyme Elevations
In the 120-mg dose cohort of the MAD part of CC-99677-CP-001, 3 out of 6 subjects experienced 
an increase in serum transaminase levels above the ULN, (Section 1.4). All subjects were 
asymptomatic, no interventions were required, and hepatic enzymes returned to normal. There 
were no treatment interruptions. A plan to closely monitor hepatic enzyme elevations is outlined 
in APPENDIX G, Hepatotoxicity Monitoring Criteria for Interruption and Discontinuation of IP,
based on liver function test abnormalities.
10.5.3
Monitoring, Recording and Reporting of Adverse Events of Special 
Interest
To better characterize and understand any potential AEs for hepatic enzyme elevations and 
photosensitivity the severity/intensity of AEs will be graded based upon the subject’s symptoms 
according to the current active minor version of the Common Terminology Criteria for Adverse 
Events (CTCAE, Version 5.0):
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
10.6
Reporting of Serious Adverse Events
Any AE that meets serious criterion requires reporting as an SAE within 24 hours of the 
Investigator’s knowledge of the event. This instruction pertains to initial SAE reports as well as 
any follow-up reports.
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP) or any 
SAE made known to the Investigator at any time thereafter that are suspected of being related to 
IP.  Serious adverse events occurring prior to treatment (after signing the ICF) are to be recorded 
within the CRF, but do not require reporting to Celgene Drug Safety.
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant initial 
and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
The SAE is recorded within the eCRF, and the data is transmitted electronically to Celgene Drug 
Safety. In the event electronic transmission is not available, a paper SAE Report Form will be 
completed and sent directly to Celgene Drug Safety, ensuring the event is recorded on the CRF as 
well.
10.7
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-99677 based on the IB.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be reported 
in an expedited manner in accordance with 21 Code of Federal Regulations (CFR) 312.32.
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For countries within the European Economic Area (EEA), Celgene or its authorized representative 
will report in an expedited manner to Regulatory Authorities and Ethics Committees concerned, 
suspected unexpected serious adverse reactions (SUSARs) in accordance with Directive 
2001/20/EC and the Detailed Guidance on collection, verification and presentation of adverse 
reaction reports arising from clinical trials on investigational products for human use (ENTR/CT3) 
and also in accordance with country-specific requirements.
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 the IRB/EC. See Section 14.3 for record retention information.
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11
DISCONTINUATIONS
11.1
Individual Stopping Criteria
The subject will be discontinued from the investigational product:

If 1 subject develops a Grade 3 AE or higher (according to CTCAE Version 5.0 grading 
system) considered to be at least possibly drug-related 

If the subject meets discontinuation criteria outlined in APPENDIX G (Hepatotoxicity 
Monitoring Criteria for Interruption and Discontinuation of Investigational Product)
Note: In the case of Grade 3 or 4 safety laboratory AEs that are considered at least possibly 
drug-related, repeat all abnormal safety laboratory assessments within 48 to 72 hours to refute 
or confirm the findings. The decision to temporarily interrupt the IP will be based on the 
Investigator’s clinical judgment.

Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test 
in a female subject of childbearing potential regardless of disease state) occurring while the 
subject is receiving IP (Section 10.4.1)
11.2
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product:

Adverse Event

Withdrawal by subject

Death

Lost to follow-up

Other (to be specified on the CRF)
The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
11.3
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the study:

Screen failure

Adverse event

Withdrawal by subject

Death

Lost to follow-up

Other (to be specified on the CRF)
The reason for study discontinuation should be recorded in the CRF and in the source documents.
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12
EMERGENCY PROCEDURES
12.1
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on the 
Emergency Contact Information page of the protocol (after title page). This global Emergency Call 
Center is available 24 hours a day and 7 days a week. The representatives are responsible for 
obtaining your call-back information and contacting the on-call Celgene/contract research 
organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for emergency 
calls. 
12.2
Emergency Identification of Investigational Products
The blind must not be broken during the course of the study unless in the opinion of the 
Investigator, it is absolutely necessary to safely treat the subject.  If it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued if, in the opinion of 
the Investigator, continuing IP can negatively affect the outcome of the subject’s treatment.
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, the Investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the interest 
of the subject. 
The Investigator should ensure that the code is broken only in accordance with the protocol. The 
Investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the Investigator in the 
subject’s source documentation.
Emergency unblinding should only be performed by the Investigator through the Interactive Web 
Response System (IWRS).
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13
REGULATORY CONSIDERATIONS
13.1
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, and 
Investigator abide by Good Clinical Practice (GCP), as described in International Conference for
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
13.2
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in the 
local regulations.  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, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the information 
provided by Celgene on public registry websites) is considered Celgene confidential information.  
Only information that is previously disclosed by Celgene on a public registry website may be 
freely disclosed by the Investigator or its institution, or as outlined in the Clinical Trial Agreement.  
Celgene protocol, amendment and IB information is not to be made publicly available (for example 
on the Investigator’s or their institution’s website) without express written approval from Celgene.  
Information proposed for posting on the Investigator’s or their institution’s website must be 
submitted to Celgene for review and approval, providing at least 5 business days for review.
At the time results of this study are made available to the public, 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.
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13.3
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study and 
of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be reconsented 
with the revised version of the ICF.  The revised ICF signed and dated by the study subject and by 
the person consenting the study subject must be maintained in the Investigator’s study files and a 
copy given to the study subject.
13.4
Confidentiality
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 ICF, it is the responsibility of the Investigator to obtain such permission in writing 
from the appropriate individual.
13.5
Protocol Amendments
Any amendment to this protocol must be approved by the 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/EC approval but will be submitted to the IRB/EC for 
information purposes.
13.6
Institutional Review Board/Independent Ethics Committee Review and 
Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will be 
submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their dates 
of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is sought. 
If applicable, the documents will also be submitted to the authorities in accordance with local legal 
requirements.
IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
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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.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
13.7
Ongoing Information for Institutional Review Board/ Ethics Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible; 

Periodic reports on the progress of the study;

Deviations from the protocol or anything that may involve added risk to subjects.
13.8
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc).
In addition, the Investigator or 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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14
DATA HANDLING AND RECORDKEEPING 
14.1
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the study 
and the distribution of the IP are complete, accurate, filed and retained.  Examples of source 
documents include: hospital records; clinic and office charts; laboratory notes; memoranda; 
subject’s diaries or evaluation checklists; dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; 
microfiche; X-ray film and reports; and records kept at the pharmacy, and the laboratories, as well 
as copies of CRFs or CD-ROM.
14.2
Data Management
Data will be collected via CRF and entered into the clinical database per 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.
14.3
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:

Signed ICFs for all subjects;

Subject identification code list, screening log (if applicable), and enrollment log;

Record of all communications between the Investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the Investigator, 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.); 

All other documents as listed in Section 13 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. 
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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 or institution should take measures to prevent accidental or premature destruction of 
these documents.
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15
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative for 
compliance with applicable government regulations with respect to current GCP and SOPs.
15.1
Study Monitoring and Source Data Verification
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 Investigators’ 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, IP 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.
15.2
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/ECs, regulatory authorities (eg, FDA, EMA, Health Canada) and company 
authorized representatives.  The Investigator should make every effort to be available for the audits 
and/or inspections.  If the Investigator is contacted by any regulatory authority regarding an 
inspection, he/she should contact Celgene immediately.
15.3
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, purity, or 
performance of any drug product manufactured by or on behalf of Celgene Corporation after it is 
released for distribution.  PQCs may reduce the usability of the product for its intended function 
or affect performance of the product and therefore pose a significant risk to the subject.  Examples 
of PQCs include (but are not limited to): mixed product, mislabeling, lack of effect, seal/packaging 
breach, product missing/short/overage, contamination, suspected falsified, tampered, diverted or 
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stolen material, and general product/packaging damage. If you become aware of a suspected PQC, 
you are obligated to report the issue immediately.  You can do so by emailing 
 or by contacting the Celgene Customer Care Center 
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16
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the exception 
of the information provided by Celgene on public registry websites, is considered Celgene 
confidential information and is not to be used in any publications.  Celgene protocol-related 
information proposed for use in a publication must be submitted to Celgene for review and 
approval and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Period 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on several 
considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study Steering Committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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17
REFERENCES
Anderson JJ, Baron G, van der Heijde D, Felson DT, Dougados M.  Ankylosing spondylitis 
assessment group preliminary definition of short-term improvement in ankylosing spondylitis.  
Arthritis Rheum 2001;44(8):1876-86.
Arends S, Spoorenberg A, Efde M, Bos R, Leijsma MK, Bootsma H, et al. Higher bone turnover 
is related to spinal radiographic damage and low bone mineral density in ankylosing spondylitis 
patients with active disease: A cross-sectional analysis. PLoS One. 2014;9(6):e99685.
Brandt J, Listing L, Sieper J, Rudwaleit M, van der Heijde D, Braun J.  Development and 
preselection of criteria for short term improvement after anti-TNF alpha treatment in ankylosing 
spondylitis. Ann Rheum Dis 2004;63(11):1438-44.
Braun J, Sieper J, Breban M, Collantes-Estevez E, Davis J, Inman R, et al. Anti-tumour necrosis 
factor a therapy for ankylosing spondylitis: international experience. Ann Rheum Dis 
2002;61(Suppl III):iii51–iii60.
Braun J, Baraliakos X, Hermann KG, Landewé R, Machado PM, Maksymowych WP, et al.  Effect 
of certolizumab pegol over 96 weeks of treatment on inflammation of the spine and sacroiliac 
joints, as measured by MRI, and the association between clinical and MRI outcomes in patients 
with axial spondyloarthritis. RMD Open 2017;3(1):e000430.
Brown MA, Pile KD, Kennedy LG, Calin A, Darke C, Bell J, et al. HLA class I associations of 
ankylosing spondylitis in the white population in the United Kingdom. Ann Rheum Dis.
1996;55(4):268-70.
Brown MA, Kenna T, Wordsworth BP.  Genetics of ankylosing spondylitis — insights into 
pathogenesis. Nat Rev Rheumatol. 2016;12(2):81-91.
Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, Mallorie P, et al.  A new approach to 
defining functional ability on ankylosing spondylitis: the development of the Bath Ankylosing 
Spondylitis Functional Index.  J Rheumatol. 1994;21(12):2281-5.
Calin A, Nakache JP, Gueguen A, Zeidler H, Mielants H, Dougados M.  Defining disease activity 
in ankylosing spondylitis: is a combination of variables (Bath Ankylosing Spondylitis Disease 
Activity Index) an appropriate instrument?  Rheumatology (Oxford). 1999;38(9): 878-82.
CC-99677 Investigator’s Brochure.
Costantino F, Breban M, Garchon H-J.  Genetics and Functional Genomics of Spondyloarthritis.  
Front Immunol. 2018:9:2933. 
Davis, JC Jr, van der Heijde D, Braun J, Dougados M, Cush J, Clegg DO, et al.  Recombinant 
human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a 
randomized, controlled trial.  Arthritis Rheum. 2003;48(11):3230-6.
Deodhar A, Poddubnyy D, Pacheco-Tena C, Salvarani C, Lespessailles E, Rahman P, et al.  
Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis:  
Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo–Controlled Trial in 
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Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors. 
Arthritis Rheumatol 2019;71(4):599-611.
de Winter JJ, van Mens LJ, van der Heijde D, Landewé R, Baeten DL. Prevalence of peripheral 
and extra-
articular disease in ankylosing spondylitis versus non-radiographic axial 
spondyloarthritis: a meta-analysis. Arthritis Res Ther 2016;18:196.
Doward LC, Spoorenberg A, Cook SA, Whalley D, Helliwell PS, Kay LJ, et al.  Development of 
the 
ASQoL: 
a 
quality 
of 
life 
instrument 
specific 
to 
ankylosing 
spondylitis.  
Ann Rheum Dis. 2003;62(1):20–6.
European Medicines Agency.  Guideline on the Clinical Investigation of Medicinal Products for 
the Treatment of Axial Spondyloarthritis.  2017; EMA/CPMP/EWP/4891/03 Rev.1, Corr 1*
Feld J, Chandran V, Haroon N, Inman R, Gladman D. Axial disease in psoriatic arthritis and 
ankylosing spondylitis: a critical comparison. Nat Rev Rheumatol 2018;14(6):363-71.
Gracey E, Yao Y, Green B, Qaiyum Z, Baglaenko Y, Lin A, et al. Sexual Dimorphism in the Th17 
Signature of Ankylosing Spondylitis. Arthritis Rheumatol 2016:68(3):679–89.
Guideline on the Clinical investigation of medicinal products for the treatment for the treatment of 
Axial Spondyloarthritis EMA/CPMP/EWP/4891/03 Rev.1, Corr 1*
Hanson A, Brown MA.  Genetics and the Causes of Ankylosing Spondylitis. Rheum Dis Clin 
North Am. 2017;43(3):401–14.
Haroon NN, Sriganthan J, Al Ghanim N, Inman RD, Cheung AM.  Effect of TNF-alpha inhibitor 
treatment on bone mineral density in patients with ankylosing spondylitis: A systematic review 
and meta-analysis. Semin Arthritis Rheum. 2014;44(22):155–61.
Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, Landewé R, van der Tempel H, Mielants 
H, et al.  Assessment of enthesitis in ankylosing spondylitis.  Ann Rheum Dis. 2003;62(2):127-32.
Hitti E, Iakovleva T, Brook T, Deppenmeier S, Gruber AD, Radzioch D, et al. Mitogen-activated 
protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and 
translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine
rich element. Mol Cell Biol. 2006;26(6):2399-407.
Inman RD, Davis JC Jr, van der Heijde D, Diekman L, Sieper J, Kim SI, et al.  Efficacy and safety 
of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, 
placebo-controlled, phase III trial. Arthritis Rheum 2008;58(11):3402-12.
Jenkinson TR, Mallorie PA, Whitelock HC, Kennedy LG, Garrett SL, Calin A.  Defining Spinal 
Mobility 
in 
Ankylosing 
Spondylitis 
(AS): 
The 
Bath 
AS 
Metrology 
Index. 
J Rheumatol 1994;21(9):1694-8.
Kiltz U, van der Heijde D, Boonen A, Braun J.  The ASAS Health Index (ASAS HI) - a new tool 
to assess the health status of patients with spondyloarthritis.  Clin Exp Rheumatol 2014;32(5 Suppl. 
85):S105-S108.
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Klingberg E, Lorentzon M, Mellström D, Geijer M, Göthlin J, Hilme E, et al. Osteoporosis in 
ankylosing spondylitis - prevalence, risk factors and methods of assessment. Arthritis Res Ther 
2012:14(3):R108.
Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF- alpha induces 
osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK 
ligand. J Clin Invest. 2000;106(12):1481-8.
Lambert RG, Salonen D, Rahman P, Inman RD, Wong RL, Einstein SG, et al.  Adalimumab 
significantly reduces spinal and sacroiliac joint inflammation in patients with ankylosing 
spondylitis 
a 
multicenter, 
randomized, 
double-blind, 
placebo-controlled 
study.  
Arthritis Rheum. 2007;56(12):4005-14.
Landewé R, Braun J, Deodhar A, Dougados M, Maksymowych P, Mease P, et al. Efficacy of 
certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing 
spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study.
Ann Rheum Dis. 2014;73(1):39-47.
Li P, Schwarz EM, O’Keefe RJ, Ma L, Looney RJ, Ritchlin CT, et al. Systemic tumor necrosis 
factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis 
factor alpha-transgenic mice. Arthritis Rheum. 2004;50(1):265-76.
Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate or dependent 
variable in analyses of change from baseline in clinical trials? Stat Med. 2009;28(20):2509-30.
Maas F, Arends S, Brouwer E, Essers E, Van der Veer E, Efde M, et al.  Reduction in Spinal 
Radiographic Progression in Ankylosing Spondylitis Patients Receiving Prolonged Treatment 
With Tumor Necrosis Factor Inhibitors.  Arthritis Care Res (Hoboken). 2017;69(7):1011-19.
Machado P, Landewé R, Lie E, Kvien T, Braun J, Baker D, et al. Ankylosing Spondylitis Disease 
Activity Score (ASDAS): defining cut-off values for disease activity states and improvement 
scores. Ann Rheum Dis. 2011;70(1):47-53.
Machado P, Landewé R, van der Heijde D.  Ankylosing Spondylitis Disease Activity Score 
(ASDAS):
2018 update of the nomenclature for disease activity states.  Ann Rheum Dis. 
2018;77(10):1539-40.
Maksymowych P, Inman R, Salonen D, Dhillon SS, Williams M, Stone M, et al. Spondyloarthritis 
Research Consortium of Canada Magnetic Resonance Imaging Index For Assessment of Sacroiliac 
Joint Inflammation in Ankylosing Spondylitis.  Arthritis Rheum. 2005;53(5):703-9.
Maksymowych P, Salonen D, Inman RD, Rahman P, Lambert RG.  Low-dose Infliximab (3 
mg/kg) Significantly Reduces Spinal Inflammation on Magnetic Resonance Imaging in Patients 
with Ankylosing Spondylitis: A Randomized Placebo-controlled Study.  J Rheumatol. 
2010;37(8);1728-34.
Mease, P.  Emerging Immunomodulatory Therapies and New Treatment Paradigms for Axial 
Spondyloarthritis.  Curr RheumatolRep. 2019;21(7):35.
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Mehrotra DV, Li X, Liu J, Lu K. Analysis of Longitudinal Clinical Trials with Missing Data Using 
Multiple Imputation in Conjunction with Robust Regression. Biometrics. 2012;68(4):1250-9.
Molnar C, Scherer A, Baraliakos X, de Hooge M, Micheroli R, Exer P, et al.  TNF blockers inhibit 
spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from 
the Swiss Clinical Quality Management cohort. Ann Rheum Dis. 2018;77(1):63-69.
O'Neill TP. HLA-B27 transgenic rats: animal model of human HLA-B27-associated disorders. 
Toxicol Pathol 1997;25(4):407-8.
Poddubnyy D, Fedorova A, Listin J, Haibel H, Baraliakos X, Braun J et al.  Physical Function and 
Spinal Mobility Remain Stable Despite Radiographic Spinal Progression in Patients with 
Ankylosing Spondylitis Treated with TNF-α Inhibitors for Up to 10 Years. 
J Rheumatol 
2016;43(12); 2142-8.
Pimentel-Santos FM, Ligeiro D, Matos M, Mourão A, Costa J, Santos H, Barcelos A, et al. Whole 
blood transcriptional profiling in ankylosing spondylitis identifies novel candidate genes that 
might contribute to the inflammatory and tissue-destructive disease aspects. 
Arthritis 
Res Ther. 2011;13(2):R57.
Ranganathan V, Ciccia F, Zeng F, Sari I, Guggino G, Muralitharan J, et al.  Macrophage Migration 
Inhibitory Factor Induces Inflammation and Predicts Spinal Progression in Ankylosing 
Spondylitis.  Arthritis Rheumatol 2017; 69(9):1796-1806.
Reveille JD. Major histocompatibility genes and ankylosing spondylitis. Best Pract Res Clin 
Rheumatol. 2006; 20(3):601-9.
Reveille JD, Weisman MH.  The Epidemiology of Back Pain, Axial Spondyloarthritis and 
HLA-B27 in the United States.  Am J Med Sci. 2013;345(6): 431–6.
Romero-Sanchez C, Tsou H, Jan M-S, Wong R-H, Chang I-C, Londoño J, et al. Serum monocyte 
chemotactic protein-1 concentrations distinguish patients with ankylosing spondylitis from 
patients with mechanical low back pain. J Spinal Disord Tech. 2011;24(3):202–7.
Ronkina N, Menon MB, Schwermann J, Tiedje C, Hitti E, Kotlyarov A, et al.  MAPKAP kinases 
MK2 and KM in inflammation: complex regulation of TNF biosynthesis via expression and 
phosphorylation of tristetraprolin.  Biochem Pharmacol.  2010;80(12):1915-20.
Rostami S, Hoff M, Brown MA, Hveem K, Holmen OL, Fritsche LG, et al.
Prediction of 
Ankylosing Spondylitis in the HUNT Study by a Genetic Risk Score Combining 110 
Single-nucleotide Polymorphisms of Genome-wide Significance. J Rheumatol 2019;46:1-7.
Rudwaleit M, Landewé R, van der Heijde D, Listing J, Brandt J, Braun J et al.  The development 
of Assessment of SpondyloArthritis international Society classification criteria for axial 
spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty 
appraisal.  Ann Rheum Dis. 2009a;68(6):770–6.
Rudwaleit M, van der Heijde D, Landewé R, Listing J, Akkoc N, Brandt J, et al.  The development 
of Assessment of SpondyloArthritis international Society classification criteria for axial 
spondyloarthritis (part II): validation and final selection.  Ann Rheum Dis 2009b;68(6):777-83.
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Schwartzman M, Maksymowych WP. Is There a Role for MRI to Establish Treatment Indications 
and Effectively Monitor Response in Patients with Axial Spondyloarthritis?  Rheum Dis Clin 
North Am. 2019;45(3):341-58.
Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Burgos-Vargas R, Dougados M, et al.  The 
Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess 
spondyloarthritis.  Ann Rheum Dis 2009;68(Suppl 2);ii1-ii44.
Sieper J, Deodhar A, Marzo-Ortega H, Aelion JA, Blanco R, Jui-Cheng T, et al.  Secukinumab 
efficacy in anti-TNF-naive and anti-TNF-experienced subjects with active ankylosing spondylitis: 
results from the MEASURE 2 Study.  Ann Rheum Dis. 2017;76:571–75.
Smolen JS, Schöls M, Braun J, Dougados M, FitzGerald O, Gladman D, et al.  Treating axial 
spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 
update of recommendations by an international task force. Ann Rheum Dis. 2018;77(1):3-17.
Stolwijk C, van Tubergen A, Castillo-Ortiz JD, Boonen A.
Prevalence of extra-articular 
manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis. 
Ann Rheum Dis. 2015;74(1):65-73.
Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, et al. Genomic atlas of the 
human plasma proteome. Nature. 2018;558(7708):73-9.
Turner MJ, Sowders DP, DeLay ML, Mohapatra R, Bai S, Smith JA, et al. HLA-B27 misfolding 
in transgenic rats is associated with activation of the unfolded protein response.
J Immunol. 2005;175(4):2438-48.
van der Heijde D, Lie E, Kvien TK, Sieper J, Van den Bosch F, Listing J, et al.  ASDAS, a highly 
discriminatory ASAS-endorsed disease activity score in patients with ankylosing spondylitis.  Ann 
Rheum Dis. 2009; 68(12):1811-18.
van der Heijde D, Ramiro S, Landewé R, Baraliakos X, Van den Bosch F, Sepriano A, et al. 2016 
update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann 
Rheum Dis. 2017a;76(6):978-91.
van der Heijde D, Deodhar A, Wei JC, Drescher E, Fleishaker D, Hendrikx T, et al.  Tofacitinib 
in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo controlled, dose-
ranging study.  Ann Rheum Dis. 2017b;76(8):1340-47.
van der Heijde D, Baraliakos X, Gensler L, Maksymowych W, Tseluyko V, Nadashkevich O, et 
al.  Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active 
ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial.  
Lancet. 2018;392(10162):2378-87.
van der Linden S, Valkenburg HA, Cats A.  Evaluation of Diagnostic Criteria for Ankylosing 
Spondylitis. 
 
A 
Proposal 
for 
Modification 
of 
the 
New 
York 
Criteria.  
Arthritis Rheum. 1984;27(4):361-8.
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Wagner C, Visvanathan S, Braun J, van der Heijde D, Deodhar A, Hsu B, et al. Serum markers 
associated with clinical improvement in patients with ankylosing spondylitis treated with 
golimumab.  Ann Rheum Dis. 2012;71(5):674-80.
Wang R, Ward MM. 
Epidemiology of axial spondyloarthritis: An update.  Curr Opin 
Rheumatol. 2018;30(2): 137-43.
Ware JE Jr, Sherbourne CD.  The MOS 36-item short-form health survey (SF-36).  I.  Conceptual 
framework and item selection Med Care. 1992;30(6):473-83.
West NR, Hegazy AN, Owens BMJ, Bullers SJ, Linggi B, Buonocore S, et al. Oncostatin M drives 
intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in 
patients with inflammatory bowel disease. Nat Med. 2017; 23(5)579-89
Zeboulon N, Dougados M, Gossec L.  Prevalence and characteristics of uveitis in the 
spondyloarthropathies: a systematic literature review. Ann Rheum Dis. 2008;67(7):955-9.
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18
APPENDICES
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APPENDIX A
TABLE OF ABBREVIATIONS
Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ADL
Activity of daily living
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
ALP
Alkaline phosphatase
AS
Ankylosing spondylitis
ASAS
Assessment In Spondyloarthritis International Society
ASAS HI
Assessment of Spondyloarthritis International Society Health Index
ASDAS
Ankylosing Spondylitis Disease Activity
ASDAS-CRP
Ankylosing Spondylitis Disease Activity with C-reactive protein as the acute-
phase reactant
AP
Anterior-Posterior
ASQOL
Ankylosing Spondylitis Quality of Life questionnaire
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the curve
AUC(0-T)
Area under the plasma concentration-time curve from time zero to last 
measurable concentration
AUCLST
Area under the concentration-time curve from time zero to the last measurable 
time point
AUC(TAU)
Area under the concentration-time curve over the dosing interval
axSpA
Axial Spondyloarthritis
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
BASMI-Linear
Bath Ankylosing Spondylitis Metrology Index-Linear
BCRP
Breast cancer resistance protein
β-CTX
β-subunit of C-terminal telopeptide
β-hCG
β-subunit of human chorionic gonadotropin
BMD
Bone mineral density
BMS
Bristol Myers Squibb
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CLT/F
Apparent total body clearance
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Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
Cmax
Maximum plasma concentration of drug
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus disease 2019
COX
Cyclooxygenase
CRF
Case report form
CRP
C-reactive protein
CS
Clinically significant
CSP
Clinical safety program
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DMARDS
Disease modifying anti-rheumatic drugs
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EEA
European Economic Area
EMA
European Medicines Agency
EOT
End of treatment
ET
Early termination
EudraCT
European Union Drug Regulating Authorities Clinical Trials (ie, European 
Clinical Trials Database)
FAS
Full analysis set
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
HbA1c
Hemoglobin A1C
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HDL
High-density lipoprotein
hsCRP
High- sensitivity C-reactive protein
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Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
HIV
Human immunodeficiency virus
HLA-B 27
Human leukocyte antigen - B27
HLAB27Tg
Human leukocyte antigen - B27 transgenic
hr
Hour
ICF
Informed consent form
ICH
International Council for Harmonisation
IB
Investigators Brochure
IgG
Immunoglobulin-G
Ig-M
Immunoglobulin-M
IL-2
Interleukin-2
IL-6
Interleukin-6
IL-17
Interleukin-17
IL-23
Interleukin-23
IMPD
Investigational Medicinal Product Dossier
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
IUD
Intrauterine device
IWRS
Interactive web response system
JAK
Janus kinase
LDA
Longitudinal data analysis
LDL
Low-density lipoprotein
LFT
Liver function test
LPS
Lipopolysaccharide stimulation
mAb
Monoclonal antibody
MAD
Multiple-ascending dose
MAPK
Mitogen activated protein kinase
MASES
Maastricht Ankylosing Spondylitis Enthesitis Score
MCID
Minimum clinically important difference
MCP-1
Monocyte chemoattractant protein-1
MCS
Mental Component Summary
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Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
MedDRA
Medical Dictionary for Drug Regulatory Activities
MK2
Mitogen-activated protein (MAP) kinase-activated protein kinase 2
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MR_AUC(0-T)
Metabolite to parent molar ratio of AUC(0-T)
MR_AUC(TAU)
Metabolite to parent molar ratio of AUC(TAU)
MR_Cmax, OC 
Metabolite to parent molar ratio of Cmax Oral Contraceptive
NCS
Not clinically significant
NOAEL
No observed adverse effect level
NOEL
No observed effect level
NRI
Nonresponder imputation
NRS
Numerical Rating Scales
NSAIDS
Nonsteroidal anti-inflammatory drug
OATP
Organic anion transporting polypeptide
OCP
Osteoclast precursors
OCT
Organic cation transporter
P1NP
Procollagen I intact N-terminal peptide
PBMC
Peripheral blood mononuclear cell
PCS
Physical Component Summary
PD
Pharmacodynamics
PG
Pharmacogenomics
P-gp
P-glycoprotein
PK
Pharmacokinetics
PP
Per-protocol
PQC
Product quality complaint
PRN
As needed
PT
Prothrombin time
QD
Once daily
RBC
Red blood cell count
RNA
Ribonucleic acid
SAE
Serious adverse event
SAD
Single Ascending Dose
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Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SF-36
Short Form-36
SI
Sacroiliac 
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SMT
Safety Management Team
SNP
Single nucleotide polymorphism
SOP
Standard operating procedure
SpA
Spondyloarthritis
SPARCC
Spondyloarthritis Research Consortium of Canada
SUSAR
Suspected unexpected serious adverse reaction
t½
Terminal elimination half-life
TB
Tuberculosis
TBL
Total bilirubin
TE
Target engagement
TEAEs
Treatment-emergent adverse events
Tmax
Time to Cmax
TNF
Tumor necrosis factor
TNF-α
Tumor necrosis factor-alpha
ULN
Upper limit of normal
UV
Ultraviolet
WBC
White blood cell count
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APPENDIX B
MODIFIED NEW YORK CRITERIA FOR ANKYLOSING 
SPONDYLITIS (1984)
Clinical Criteria

Low back pain and stiffness for more than 3 months that improves with exercise, but is not 
relieved by rest

Limitation of motion of the lumbar spine in the sagittal and frontal planes

Limitation of chest expansion relative to normal values correlated for age and sex
Radiological Criterion

Sacroiliitis grade ≥ 2 bilaterally or grade 3 to 4 unilaterally
A designation of “definite AS” requires the radiological criterion to be met in association with at 
least one clinical criterion
Source:  van der Linden, 1984.
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APPENDIX C
EXAMPLES OF DRUGS THAT ARE EXCLUDED BASED ON 
POTENTIAL DRUG-DRUG INTERACTIONS
Table 7:
Examples of Moderate or Strong Inhibitors and Moderate or 
Strong Inducers of CYP3A4/5 That are Excluded
Category 
Inhibitors
Inducers
Antibiotic
ciprofloxacin, clarithromycin, 
elithromycin, erythromycin 
rifampin, rifabutin, rifapentin, 
nafcillin
Anticonvulsant
phenytoin, carbamazepine, 
phenobarbital, cenobamate
Antiviral
lopinavir, efavirenz, 
asunaprevir/beclabuvir/daclatasvir, 
tipranavir/ritonavir
Antidepressant
fluvoxamine, nefazodone
thioridazine 
Antifungal
fluconazole, itraconazole, 
ketoconazole, posaconazole, 
voriconazole
Cardiovascular 
drug
diltiazem, dronedarone, verapamil 
Other
aprepitant, conivaptan, 
cyclosporine, grapefruit juice, 
tofisopam
Source: 
 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers.
Note:  This list of CYP3A4/5 inhibitors is not exhaustive, for questions please consult the Medical Monitor.  The 
Indiana University (2016) “Cytochrome P450 Drug Interaction Table” should be utilized to determine inhibitors of 
CYP3A4/5. (http://medicine.iupui.edu/clinpharm/ddis/table.aspx).
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Table 8:
Examples of Moderate or Strong Inhibitors of P-gp, Moderate or 
Strong Inducers of P-gp, and Strong Inhibitors of BCRP That are 
Excluded
Transporter
Category
Inhibitors
Inducers
P-gp
Antibiotic
clarithromycin
rifampin, rifabutin
Antifungal
itraconazole
Anticonvulsant
Carbamazepine, phenytoin
Antiviral
efavirenz, ritonavir 
Cardiovascular 
drug
amiodarone, carvedilol, 
dronedarone, propafenone, 
quinidine, ranolazine, 
verapamil
BCRP
Chemotherapy
eltrombopag
Herbal supplement
curcumin
Immunosuppressive 
drug
cyclosporine A 
Abbreviations:  P-gp = P-glycoprotein; BCRP = Breast cancer resistance protein.
Source: 
 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers.
Note:  This list is not exhaustive, for questions please consult the Medical Monitor.
Table 9:
Examples of Substrates of One or More Potentially Affected 
Transporters with a Narrow Therapeutic Index and Should be 
Excluded
Category
Substrate
Blood thinner
dabigatran etexilate
Cardiovascular drug
digoxin, procainamide
Immunosuppressive drug
cyclosporine, leflunomide, mycophenolic 
acid, methotrexate, sirolimus
Note:  This list is not comprehensive. The investigator should consult the product insert for any concomitant 
medication and use best clinical judgement or contact the study Medical Monitor if there are questions.
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APPENDIX D
EXAMPLES OF DRUGS THAT ARE SUBSTRATES FOR 
SELECTED TRANSPORTERS AND SHOULD BE USED WITH 
CAUTION
Table 10:
Examples of Drugs That Are Substrates for BCRP, P-gp, 
OATP1B1/3, and OCT1 With a Narrow Therapeutic Index and 
Should be Used With Caution
Transporter
Category
Substrate
BCRP
Cardiovascular drug
prazosin
P-gp
Antidiabetes
saxagliptin, sitagliptin
Blood thinner
rivaroxaban, ticagrelor
Cardiovascular drug
aliskiren, ambrisentan, talinolol
Other
colchicine, fexofenadine, tolvaptan
OATP1B1/3
Anti-diabetes
repaglinide, glyburide
Cardiovascular drug
ambrisentan, telmisartan, valsartan, olmesartan
Lipid lowering agent
atorvastatin, ezetimibe, fluvastatin, simvastatin 
acid, pitavastatin
OCT1
Analgesic
tramadol
Neurologic drug
gabapentin, pramipexole
Other
varenicline
Abbreviations: BCRP = breast cancer resistance protein; OATP = organic anion transporting polypeptide; OCT = 
organic cation transporter; P-gp = p-glycoprotein.
Note:  This list is not comprehensive. The investigator should consult the product insert for any concomitant 
medication and use best clinical judgement or contact the study Medical Monitor if there are questions.  Substrates 
of these transporters that have a narrow therapeutic index are excluded.
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APPENDIX E
TUBERCULOSIS HIGH BURDEN COUNTRY LIST
1) Angola
2) Bangladesh
3) Brazil
4) Cambodia
5) Central African Republic
6) China
7) Congo
8) Democratic People’s Republic of Korea
9) Democratic Republic of Congo
10) Ethiopia
11) India
12) Indonesia
13) Kenya
14) Lesotho
15) Liberia
16) Mozambique
17) Myanmar
18) Namibia
19) Nigeria
20) Pakistan
21) Papua New Guinea
22) Philippines
23) Russian Federation
24) Sierra Leone
25) South Africa
26) Tanzania
27) Thailand
28) United Republic of Viet Nam
29) Zambia
30) Zimbabwe
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APPENDIX F
MULTI-DRUG RESISTANT TUBERCULOSIS HIGH BURDEN 
COUNTRY LIST 
1) Angola
2) Azerbaijan
3) Bangladesh
4) Belarus
5) China
6) Democratic People’s Republic of Korea
7) Democratic Republic of Congo
8) Ethiopia
9) India
10) Kazakhstan
11) Kenya
12) Kyrgyzstan
13) Indonesia
14) Moldova
15) Mozambique
16) Myanmar
17) Nigeria
18) Pakistan
19) Papua New Guinea
20) Peru
21) Philippines
22) Russian Federation
23) South Africa
24) Thailand
25) Ukraine
26) United Republic of Viet Nam
27) Uzbekistan
28) Republic of Somalia
29) Tajikistan
30) Zimbabwe
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APPENDIX G
HEPATOTOXICITY MONITORING CRITERIA FOR 
INTERRUPTION AND DISCONTINUATION OF 
INVESTIGATIONAL PRODUCT*
Table 11:
Hepatotoxicity Monitoring Criteria**
Laboratory Test
Action
ALT or AST > 3 x ULN but ≤8 x 
ULN
And
TBL ≤2 x ULN and INR ≤1.5
Continue with IP treatment
Repeat all LFTs within 48-72 hours to refute or confirm the 
findings*
If abnormal findings are confirmed, close observation is required 
(repeat LFTs 2-3 times per week) for at least 2 weeks
Subject is to be followed until the laboratory value(s) return to 
baseline.
Any of the following:
ALT or AST > 3 x ULN and 
(TBL > 2 x ULN or INR > 1.5)
ALT or AST > 8 x ULN 
ALT or AST > 5 x ULN for 
more than 2 weeks 
ALT or AST > 3 x ULN with 
the appearance of fatigue, 
nausea, vomiting, right upper 
quadrant pain or tenderness, 
fever, rash, and/or eosinophilia 
(>5%)
Interrupt IP treatment 
Repeat all LFTs within 48-72 hours to confirm or refute the 
abnormal findings* 
If abnormal findings are confirmed and cannot be attributed to 
causes other than IP treatment, study drug should be permanently 
discontinued and close observation is required (repeat LFTs 2-3 
times per week) for at least 2 weeks; subject is to be followed until 
the laboratory value(s) return to baseline
If abnormal findings are not confirmed and/or findings can be 
attributed to causes other than IP treatment, close observation is
required (repeat LFTs to be based on results on repeat testing) and 
discussion with MM should take place to determine whether IP can 
be re-started
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BLM = baseline measurement(s); INR = international normalized ratio; IP = investigational product; LFT = liver 
function test; MM = Medical Monitor; TBL = total bilirubin; ULN = upper limit of normal.
* All LFTs refer to the following tests: ALT, AST, total bilirubin, alkaline phosphatase, prothrombin time (to 
determine INR). Other causes of LFT elevation should be ruled out:  a history of alcohol use and biliary colic as 
potential causes of abnormal liver function tests should be elicited.  Tests for other causes of increased AST or ALT 
include those for infections (hepatitis A, hepatitis B, hepatitis C, hepatitis E), acetaminophen toxicity, toxicology 
screen, and autoimmune diseases (antinuclear antibodies, anti-smooth muscle antibodies, anti-liver/kidney 
microsomal antibodies type 1, immunoglobulin G [IgG]).  Additional tests and evaluations may be requested by the  
and include  right upper quadrant ultrasonogram.
** Based on Guidance for Industry Drug-induced Liver Injury: Premarketing Clinical Evaluation;
(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm [FDA, 2009])
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CC-99677-AS-001 Amendment 2.0: 16 Jun 2021
1.
JUSTIFICATION FOR AMENDMENT
The primary purpose of this amendment is:
!
In response to Health Authority feedback, include mitigation measures in the protocol for 
potential Drug-Drug Interactions (DDIs) where CC-99677 could be a victim
!
In response to Health Authority feedback, specify revised washout periods for prohibited 
medications 
!
In response to Health Authority feedback, for Females of child-bearing potential (FCBP):
∀
List pregnancy and breastfeeding as specific exclusion criteria
∀
Add monthly home urine pregnancy tests, considered acceptable on days in which the 
subject will not be attending study visits on-site 
!
In response to Health Authority feedback, provide rationale for the planned interim 
analysis and provide examples of criteria that may be used to trigger an additional dose
group
!
In response to Health Authority feedback, include individual and study stopping criteria 
appropriate for the study population
Significant changes included in this amendment are summarized below:
!
Section 1.4 Clinical Experience
∀
Data cut-off for administration of CC-99677 was updated to September 23, 2020 to 
align with Investigator’s Brochure (Edition 7.0)
∀
Added additional wording to introduce an ongoing Phase 1 CC-99677 DDI study to 
evaluate effects of cytochrome P450 inhibition and induction of the pharmacokinetics 
(PK) of CC-99677 and effects of CC-99677 on the pharmacokinetics of digoxin, 
metformin, methotrexate, midazolam, rosuvastatin, and sulfasalazine (CC-99677-CP-
002)  
∀
Added additional wording to introduce Study CC-99677-CP-003, an ongoing clinical 
pharmacology study in female healthy volunteers to assess the effects of CC-99677 
on the PK of an oral contraceptives (OC)
∀
Added additional wording to introduce Study CC-99677-CP-004, an additional 
ongoing clinical pharmacology study to evaluate the safety, tolerability, PK, 
pharmacodynamics (PD) and pharmacogenomics of CC-99677 in healthy adult 
Japanese volunteers  
!
Section 1.4.2 Pharmacokinetics 
∀
Added section to provide results from CP-002 DDI study:  
o
The effect of CC-99677 on methotrexate and sulfasalazine was minimal, 
suggesting a limited clinically relevant DDI with breast cancer resistance protein
(BCRP)
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CC-99677-AS-001 Amendment 2.0: 16 Jun 2021
o
For narrow therapeutic index drugs, BCRP substrates should be used with caution 
o
Concomitant dosing of methotrexate and sulfasalazine did not impact the 
pharmacokinetic (PK) parameters of CC-99677 and CC0782951 based on 
comparison of historical data of PK data from CP-001 and consistent with a 
minimal extent of biliary secretion of CC-99677, suggesting that coadministration 
of methotrexate or sulfasalazine would have limited impact on exposures of CC-
99677 and CC0782951 
!
Section 1.5.1 Rationale for the Study Design
∀
Added a paragraph to describe planned Interim Analysis (IA) and the decision 
process and an example of criteria for the introduction of an additional dose cohort
!
Section 1.5.1.1 COVID-19 Pandemic-related Risk Assessment 
-
Added additional wording “Based on the mechanism of action, pharmacological 
modulation of the MK2 pathway by CC-99677 may alter the host response to 
infection and potentially predispose to infections, including COVID-19”
!
Section 2.1 Study Endpoints
∀
Added additional secondary endpoint for high-sensitivity C-reactive protein 
(hsCRP) to support secondary endpoint Ankylosing Spondylitis Disease Activity 
with C-reactive protein as the acute-phase reactant
∀
Revised timepoints for exploratory endpoint, “Change from baseline in ASDAS-
CRP,” to Week 4 through Week 8 and Week 16 through Week 64
!
Section 3.1.7.1 Study Stopping Criteria
∀
Added study stopping criteria (criteria for Urgent Review of Clinical Data by the 
Data Monitoring Committee [DMC]) specifying the number and type of adverse 
events (AEs) (utilizing the standardized Common Terminology Criteria for Adverse 
Events [CTCAE] grading system for severity)
!
Section 4.2 Inclusion Criteria
∀
Combined criteria for FCBP as follows:  FCBP must either commit to true abstinence 
from heterosexual contact (which must be reviewed on a monthly basis and source 
documented) or agree to use one highly effective method of contraception.
∀
Revised criterion for FCBP to specify that they must not be pregnant and must have 
two negative pregnancy tests
∀
Added criterion to allow concomitant use of sulfasalazine based on results from DDI 
study summarized in Section 1.4.2.
!
Section 4.3 Exclusion Criteria, Prior and/or Current Medications/Therapies
∀
Added exclusion criterion for moderate or strong cytochrome P450 (CYP)3A4/5 
inhibitors: “Use of any medications known to be a moderate or strong CYP3A4/5 
inhibitor until study completion.”
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Summary of Changes CC-99677-AS-001
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CC-99677-AS-001 Amendment 2.0: 16 Jun 2021
∀
Added exclusion criterion for moderate or strong p-glycoprotein (P-gp) and strong 
BCRP inhibitors: “Use of any medications that are known to be either moderate or 
strong P-gp or strong BCRP inhibitors until study completion”.
∀
Based on data from study CC-99677-CP-002, there is unlikely to be a clinically 
significant interaction with BCRP substrates that have a wide therapeutic index.  
Therefore, revised criterion for medications that are substrates of one or more 
transporters P-gp, organic cation transporter (OCT)1, organic anion transporting 
polypeptide (OATP)1B1, and OATP1B3 and have a narrow therapeutic index: “Use 
of any medications that are substrates of one or more of the transporters P-gp, OCT1, 
OATP1B1, and OATP1B3 and have a narrow therapeutic index (eg, methotrexate, 
digoxin, cyclosporine, and mycophenolic acid and leflunomide).  Note:  BCRP 
substrates with a narrow therapeutic index (e.g., prazosin) should be used with 
caution.  Sulfasalazine is not excluded based on results from CC-99677-CP-002 (see 
Section 1.4.2).”
o
Additional data related to other transporters and CYP3A4/5 are forthcoming.
∀
Revised criterion for investigational SARS-CoV-2 vaccination, “If a study participant 
has received a COVID-19 vaccine prior to screening, enrollment must be delayed 
until the biologic impact of the vaccine is stabilized, as determined by discussion 
between the investigator and the BMS clinical trial physician, (See Section 8.4)”
∀
Added criterion related to botanical preparations: “Any botanical preparations (eg, 
herbal supplements or traditional Chinese medicines derived from plants, minerals, 
or animals) intended to treat AS or other immunological diseases within 4 weeks 
prior to Study Day 1.”
!
Section 4.3 Exclusion Criteria, General Health
∀
Added exclusion criterion, “Females of childbearing potential (FCBP) must not be
lactating or breastfeeding during the study period.”
∀
Added exclusion criterion, “Females of childbearing potential (FCBP) must not 
donate eggs during the study or within 28 days of the last dose of study drug.”
∀
Added exclusion criterion, “Males must not donate sperm or semen during the study 
or within 28 days of the last dose of study drug” to be consistent with contraceptive 
requirements for CC-99677
!
Section 4.4 Inclusion Criteria for Biologic-Failure Substudy
∀
Revised minimum washout periods prior to Baseline for biologics or their 
corresponding biosimilars:
o
etanercept: 4 weeks
o
infliximab: 8 weeks
o
adalimumab, certolizumab pegol, golimumab, ixekizumab: 12 weeks
o
secukinumab: 24 weeks
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EDMS Doc. Number: 25662166 - 25212666
CC-99677
Summary of Changes CC-99677-AS-001
Celgene Corporation
Confidential and Proprietary
6
CC-99677-AS-001 Amendment 2.0: 16 Jun 2021
!
Section 5 Table 3 and Table 4
∀
Table 3, added lipid panel at Early Termination Visit
∀
Table 4, added lipid panel at Early Termination Visit and Observational Follow-up 
Visit
∀
Updated footnote to include negative serum pregnancy test at every visit.  In Table 4, 
updated footnote to specify that monthly pregnancy testing is required, and that at 
home pregnancy test kits will be provided to maintain monthly pregnancy testing 
between Weeks 24 and 64  
!
Section 6 Procedures
∀
Updated entire section to include reference to Table 4, “Table of Events, Long-term 
Extension Period (52- Weeks)”
!
Section 6.1 Screening Period
∀
Added wording for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2);
serology collection after a documented or suspected SARS-CoV-2 infection
!
Section 6.2 Treatment Period
∀
Updated pregnancy test requirements to include serum pregnancy test prior to dosing
∀
Updated biomarkers and pharmacodynamic assessments for SARS-CoV-2 serology to 
specify sample is for biobanking
∀
Added SARS-CoV-2 serology sample taken for documented or suspected infection
!
Section 6.3 Early Termination
∀
Updated pregnancy test requirements to include serum pregnancy test
∀
Added Lipid panel
∀
Updated biomarkers and pharmacodynamic assessments for SARS-CoV-2 serology to 
specify sample is for biobanking
∀
Added SARS-CoV-2 serology sample taken for documented or suspected infection
!
Section 6.4 Post-treatment Observational Follow-up Period
∀
Updated pregnancy test requirements to include serum pregnancy test prior to dosing
∀
Added wording for SARS-CoV-2 serology collection after a documented or suspected 
SARS-CoV-2 infection
!
Section 6.5.3, Clinical Laboratory Assessments
∀
Revised testing for hepatitis B and hepatitis C to include B surface antigen (HBsAg) 
and antibody, hepatitis B core antibodies only
∀
Chemistry panel revised to remove duplicate wording for lipid panel and to include 
serum creatinine and troponin-T
Approved
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EDMS Doc. Number: 25662166 - 25212666
CC-99677
Summary of Changes CC-99677-AS-001
Celgene Corporation
Confidential and Proprietary
7
CC-99677-AS-001 Amendment 2.0: 16 Jun 2021
!
Section 6.6 Efficacy Assessment
∀
Added wording, “Every effort must be made to ensure the same assessor completes 
the clinical efficacy assessments for each participant at all visits at approximately the 
same time throughout the study, according to the Table of Events (Table 3 and Table 
4).”
!
Section 6.6.3 Bath Ankylosing Spondylitis Disease Activity Index 
∀
Added wording for the recall period, “during the last week”
!
Section 6.6.4 Bath Ankylosing Spondylitis Functional Index 
∀
Added wording for the recall period, “during the last week”
!
Section 6.8 Biomarkers, Pharmacodynamics, Pharmacogenetics
∀
Added wording, “For those biomarkers that require approval from national health 
authorities, biomarker samples cannot be collected in those countries until approval 
is received (See Section 0 and Section 0).  Note:  Assays for some biomarkers may not 
be available in all countries.”
!
Section 6.8.1 Biomarkers/Pharmacodynamics
∀
Added wording for SARS-CoV-2 serology collection after a documented or suspected 
SARS-CoV-2 infection
!
Section 6.9, Patient Reported Outcomes
∀
Updated Section 6.9 header from subject to patient reported outcomes. 
!
Section 8.1 Permitted Concomitant Medications and Procedures:
∀
Updated list of medications to include concomitant use of sulfasalazine
!
Section 8.2 Permitted Medications That Require Careful Monitoring
∀
Added cross-reference to revised appendix that list permitted medications that should 
be used with caution
!
Section 8.3 Prohibited Concomitant Medications
∀
Removed use of sulfasalazine from the list
∀
Added moderate or strong CYP3A4/5 inhibitors
∀
Added moderate or strong P-gp and strong BCRP inhibitors
∀
Added any botanical preparations
!
Section 8.4 Vaccination Guidelines
∀
Updated to provide additional guidance on SARS-CoV-2 vaccination
!
Section 10.1, Monitoring, Recording and Reporting of Adverse Events
∀
Added wording for data collection of adverse events (AEs) related to SARS-CoV-2 
infection
Approved
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Approved
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EDMS Doc. Number: 25662166 - 25212666
CC-99677
Summary of Changes CC-99677-AS-001
Celgene Corporation
Confidential and Proprietary
8
CC-99677-AS-001 Amendment 2.0: 16 Jun 2021
!
Section 11 Discontinuations
∀
Added Section 11.1 Individual Stopping Criteria
∀
Revised Section 11.2 Treatment Discontinuation
!
Section 18 Appendices
∀
Revised Appendix C to include the following tables with excluded medications:
o
Table 7:  Examples of drugs that are moderate or strong CYP3A4/5 inhibitors that 
are excluded
o
Table 8:  Examples of drugs that are moderate or strong inhibitors of P-gp and 
strong inhibitors of BCRP that are excluded
o
Table 9:  Examples of substrates of one or more potentially affected transporters 
with a narrow therapeutic index and should be excluded 
∀
Revised Appendix D to include the following tables with examples of drugs that are 
substrates for selected transporters and should be used with caution:
o
Table 10:  Examples of drugs that are substrates of BCRP with a narrow 
therapeutic index and should be used with caution
o
Table 11:  Examples of drugs that are substrates for P-gp, OATP1B1/3 and OCTs
with a narrow therapeutic index and should be used with caution
o
Table 12:  Examples of drugs that are substrates for CYP3A4/5 and should be 
used with caution
Approved
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EDMS Doc. Number: 25212673 - 25212666
CC-99677
Summary of Changes CC-99677-AS-001
Celgene Corporation
Confidential and Proprietary
3
CC-99677-AS-001 Amendment 1.0: 06 November 2020
1.
JUSTIFICATION FOR AMENDMENT
The primary purpose of this amendment is to include a planned Interim Analysis (IA), the 
addition of a Steering Committee (SC) who will assist in decision making from the IA results, 
provide the option of adding an additional dose cohort at the (IA), and the addition of a 1-year 
Long-term Extension (LTE) Period.
Significant changes included in this amendment are summarized below:
!
Protocol Summary and Section 2, Study Objectives and Endpoints
Primary objective updated to reflect dose dependent evaluation of CC-99677.  Secondary 
and exploratory objectives updated to include timepoints for placebo-controlled and long-
term extension period.  
!
Protocol Summary, Section 3.1.4 and Section 9.8, Interim Analysis (IA)
A planned IA will be conducted when approximately 30 subjects in the biologic-naïve 
main study complete 12 weeks of treatment and will offer the option of adding an 
additional dose cohort (not to exceed 150 mg).  Results from the IA will support one of 
the following decisions:
∀
Continue the study without modification
∀
Terminate the study for futility
∀
Discontinue a treatment group based on preliminary assessment of dose-
dependent risk-benefit 
∀
Add an additional dose cohort (dose not to exceed 150 mg)
!
Protocol Summary, Section 3.1.8 and Section 9.9.2, Steering Committee (SC)
The SC will convey a decision to the blinded Study Team to terminate study for futility 
or add an additional dose. The SC will be composed of both unblinded BMS committee 
members independent of the Study Team and external AS expert(s) to provide objectivity 
on decision making.  
Note:  The External DMC will not be involved in any decision making at the IA but can 
make a recommendation to stop the study at any time based on their assessment of the 
overall Benefit/Risk.
!
Protocol Summary, Section 3.1.2, and Section 7.2, Additional Dose Cohort
If the SC conveys a decision to include an additional dose cohort, then the additional dose 
cohort will offer an opportunity to explore dose ranging within this study after proof of 
concept has been established, and also eliminates the need for a separate dose ranging 
study.  If a decision is made to add an additional dose this dose will not exceed 150 mg.
!
Protocol Summary, Section 1.1.5, Section 3.1 and Section 3.2, Study Duration for 
Subjects (52-week Long-term Extension Period) and Table 4, Table of Events, Long-term 
Extension Period (52-Weeks)
The 52-week long-term extension period following Week 12 is added to provide 
additional exploratory long-term safety and efficacy information and enable those 
Approved
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EDMS Doc. Number: 25212673 - 25212666
CC-99677
Summary of Changes CC-99677-AS-001
Celgene Corporation
Confidential and Proprietary
4
CC-99677-AS-001 Amendment 1.0: 06 November 2020
subjects randomized to placebo in the placebo-controlled period the opportunity to 
receive CC-99677 during the extension period. 
!
Protocol Summary, Section 1.1.5, and Section 3.1.3, Biologic-failure Substudy, Study 
Duration for Subjects (52-week Long-term Extension Period) and Table 4, Table of 
Events, Long-term Extension Period (52-Weeks)
The 52-week long-term extension period following Week 12 is added to provide 
additional exploratory long-term safety and efficacy information and enable those 
subjects randomized to placebo in the placebo-controlled period the opportunity to 
receive CC-99677 during the extension period. 
!
Section 3.1.1, Biologic-Naïve Main Study and Section 3.1.3, Biologic-failure Substudy 
(Week 16 eligibility criteria to continue in LTE period)
The primary purpose of the Week 16 efficacy assessment (ASAS 20) is to help determine 
who may obtain benefit from long-term treatment.  The 16-week timepoint provides the 
shortest duration to reasonably assess efficacy of CC-99677 in those subjects receiving 
placebo through Week 12.  In other trials of AS, attainment of ASAS 20 was observed in 
a high proportion of subjects as early as 4 weeks following onset of treatment.  Therefore, 
it is anticipated that clinical benefits of CC-99677 should already be apparent following 4 
weeks of treatment.  Discontinuing treatment in nonresponders ensures that subjects who 
are unlikely to derive benefits from CC-99677 do not remain in the study beyond 16 
weeks.
This amendment also includes other administrative, corrective and/or minor changes, including 
but not limited to those summarized below:
!
Section 1.3 Nonclinical Experience was updated to include major metabolite 
(CC0782951) data that is not expected to alter the clinical Drug-drug-interaction 
profile of CC-99677.
!
Section 1.3.1 Nonclinical toxicology was updated to include long term chronic 
toxicity data.
!
Section 1.5.11 COVID-19 Pandemic-related Risk Assessment was added to describe 
benefit-risk for participation in this AS study with CC-99677 
!
Section 1.5.4 Rationale for Pharmacodynamics and Potential Predictive Biomarkers
was updated to include rationale for biobanking of SARS COV-2 serology samples
!
Section 3.1.5 Primary Analysis description added
!
Section 3.1.6 and Section 9.9.1, Internal Safety Management Team description of 
Council for International Organizations of Medical Sciences, Working Group VI 
(CIOMS VI) was removed as the scope, conduct, processes, and accountabilities of 
the Safety Management Team (SMT) are specified by Celgene Standard Operating 
Procedure (SOP).
!
Section 3.1.7 description of the External Data Monitoring Committee (DMC) was 
updated to reflect roles and responsibilities of DMC in respect to review of safety and 
efficacy study related data.
Approved
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EDMS Doc. Number: 25212673 - 25212666
CC-99677
Summary of Changes CC-99677-AS-001
Celgene Corporation
Confidential and Proprietary
5
CC-99677-AS-001 Amendment 1.0: 06 November 2020
!
Section 4.1, Number of subjects revised to a sample size of approximately 147 
subjects.
!
Sections 4.1, 9.3, 9.6, and 9.6.2, Sample Size and Power Considerations, sample size 
calculation adjusted to 147 based on nonresponder imputation.  Power considerations 
updated to include Hochberg procedure to test two active treatment groups versus 
placebo in order to be more statistically rigorous.  This methodology will protect the 
overall type 1 error as the alpha value.  The primary efficacy endpoint still maintains 
81% power (which is defined as declaring at least one dose with statistical 
significance).
!
Section 4.2 Inclusion Criterion #4 updated to more accurately reflect highly effective 
method of contraception
!
Section 4.2 Inclusion Criterion #6 updated to include additional photoprotection 
guidelines to avoid ultraviolet exposure with use of tanning beds or sunbathing
!
Section 4.3 Exclusion Criterion # 12 and Section 8.3 updated to exclude use of 
diclofenac or sulindac due to potential for transporter-related drug-drug interaction
with CC-99677 and potential increased risk of liver toxicity
!
Section 4.3 Exclusion Criterion # 15 updated to include investigational drugs for 
COVID-19
!
Section 4.3 Exclusion Criterion # 16 added to include investigational vaccine for 
SARS-CoV-2 
!
Section 4.3 Exclusion Criterion # 25 updated to include note for prior SARS-CoV-2 
infection 
!
Section 4.3 Exclusion Criterion # 29 updated to include platelet count < 100,000/mm3
or > 500,000/mm3
!
Section 4.5 Exclusion Criteria for Biologic-Failure Substudy Criterion #1 updated to 
correctly reflect that subjects participating in biologic failure substudy must not meet 
any of the exclusion criteria listed for subjects in the biologic-naïve main study.
!
Section 5 Table of Events, Section 6.2, Section 6.3, Section 6.4 and Section 6.5.3 
added PT/INR testing to more closely align with Food and Drug Administration 
(FDA) Drug-Induced Liver Injury (DILI) Guidance.
!
Section 5 Table of Events, Sections 6.1, 6.2, 6.3, 6.4 and 6.5.3 added COVID 19 
serology per new BMS guidance for banking of serum sample at Baseline and at 
study exit, added assessments for long-term extension period
!
Section 6.7.1, Sparse Pharmacokinetics Blood Draw added visits 8, 9 and 10.
!
Section 6.8.1, Biomarkers/Pharmacodynamics added SARS-CoV-2 serology sample 
for biobanking.
!
Section 8.2, Permitted Medications that Require Careful Monitoring, added 
information on CC-99677-CP-002 and CC-99677-CP-003 drug-drug interaction 
studies.
Approved
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EDMS Doc. Number: 25212673 - 25212666
CC-99677
Summary of Changes CC-99677-AS-001
Celgene Corporation
Confidential and Proprietary
6
CC-99677-AS-001 Amendment 1.0: 06 November 2020
!
Section 10.1 and Section 10.2.4 Adverse Events (AEs), updated to include AEs 
related to SARS-CoV-2 infection.
!
Section 11.3, Criteria for Urgent Review of Clinical Data by the Data Monitoring 
Committee (DMC), removed as DMC-related text will be outlined in a separate DMC 
Charter.
!
Appendix F, Hepatotoxicity Monitoring Criteria, table simplified to provide clear 
guidance to investigators for liver enzyme monitoring.
Approved
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