Clinical trial NCT02638948
Conditions: Rheumatoid Arthritis
Sponsor: Bristol-Myers Squibb
Start date: 2016-02-16; Completion date: 2018-05-03
Enrollment: 508 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether the study drug, BMS-986142, is safe and effective in treating moderate to severe rheumatoid arthritis in subjects with an inadequate response to methotrexate or methotrexate and up to 2 tumour necrosis factor (TNF) Inhibitors. Patients who qualify will be randomized to either one of 3 doses of BMS-986142 or placebo in 1:1:1 randomization for 12 weeks. Disease activity and safety will be assessed over the course of the study.

Detailed description:

Arms: arm 1: Placebo + Methotrexate dose as specified arm 2: BMS-986142 at dose level 1+ Methotrexate as specified arm 3: BMS-986142 at dose level 2 + Methotrexate as specified
Interventions: intervention 1: BMS-986142 intervention 2: Placebo intervention 3: Methotrexate
Intervention descriptions: intervention 1: BMS986142 specific dose on specific days intervention 2: Placebo of BMS-986142 specific dose on specific days intervention 3: Methotrexate specific dose on specific days

Protocol documents:
Prot_000.pdf: 
Page:
1
Protocol Number:
IM006016
IND Number:
122,786
EUDRACT Number
2015-002887-17
Date:
14-Sep-2015
Revised Date:
29-Oct-2017
Clinical Protocol IM006016
Phase 2, Randomized, Multi-Center, Double-Blind, Dose-Ranging, Placebo Controlled, Adaptive 
Design Study to Evaluate the Efficacy and Safety/Pharmacokinetics of BMS-986142 in Subjects 
with Moderate to Severe Rheumatoid Arthritis with an Inadequate Response to Methotrexate 
with or without TNF Inhibitors
Revised Protocol: 03
Study Director and Medical Monitor
Miroslawa Nowak, MD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
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that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Revised Protocol No.: 03
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 03
29-Oct-2017
This protocol was updated mainly to incorporate preliminary results of 
drug-drug interactions studies IM006-031 and IM006-032 as described in 
Dear Investigator Letter dated 17-Oct-2016.
Revisions were also made to provide further clarifications on study 
timelines, leflunomide washout, inclusion and exclusion criteria, PI 
expectations on x-ray and MRI results, Physicians Global Assessment of 
Disease Activity (PGA) and Joint Count Assessments, as well as to 
include administrative changes.
Revised Protocol 02
04-Aug-2016
Incorporates Amendment 07
Amendment 07
04-Aug-2016
 
Administrative 
Letter 03
21-Jun-2016
Editorial revision to Table 5.1-1 Flow Chart for Protocol IM006016 -
Screening Period, to align with Section 3.3.1 Inclusion Criteria 2e
Revised Protocol 01
03-May-2016
Incorporates Amendment 05
Amendment 05
03-May-2016
Incorporate changes in response to health authorities’ comments and 
update information collected during course of study.
Administrative 
Letter 02
16-Dec-2016
Correct the typographical error in the packaging/appearance of the study 
drugs (BMS-986142, 50 mg and placebo) in Section 4 of the protocol. 
Administrative 
Letter 01
13-Nov-2015
Clarify information on Additional Research Amendment that describes in 
details Optional Sampling.
Original Protocol
14-Sep-2015
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SYNOPSIS
Clinical Protocol IM006016
Protocol Title: Phase 2, Randomized, Multi-Center, Double-Blind, Dose-Ranging, Placebo Controlled, Adaptive 
Design Study to Evaluate the Efficacy and Safety/Pharmacokinetics of BMS-986142 in Subjects with Moderate to 
Severe Rheumatoid Arthritis with an Inadequate Response to Methotrexate with or without TNF Inhibitors
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): 
BMS-986142 is a reversible Bruton’s tyrosine kinase (BTK) inhibitor that will be orally administered in a double-
blind fashion to rheumatoid arthritis (RA) subjects currently on a background of methotrexate (MTX) treatment. 
Four treatments will be administered: placebo, 100, 200, and 350 mg of BMS-986142 daily for 12 weeks.
Additionally, new dose levels of BMS-986142 may be added based on the results of Week 4 interim analysis.
Study Phase:  2
Research Hypothesis: At least one of the dose levels of BMS-986142 administered daily is more effective than 
placebo on a background of methotrexate (MTX) in achieving ACR20 and ACR70 response after 12 weeks of 
treatment in subjects with moderately-to severely active RA with an inadequate response to MTX with or without
TNF inhibitors.
Primary Objective: 
To compare the efficacy of BMS-986142 versus placebo (PBO) on a background of MTX as assessed by ACR20 
and ACR70 response rates at Week 12.
Secondary Objectives: 
1)
Assess additional efficacy outcomes of BMS-986142 at Week 12 and over 12 weeks of treatment as measured 
by ACR20, ACR50 and ACR70 response rates, DAS28-CRP change from baseline, DAS28-ESR change from 
baseline, Clinical Disease Activity Index ( CDAI), Simplified Disease Index (SDAI), and Boolean remission.
2)
Assess the safety and tolerability of BMS-986142. 
3)
Evaluate pre-dose concentration (Ctrough) of BMS-986142.
4)
Assess the efficacy of BMS-986142+MTX to -MTX in reducing synovitis, osteitis, bone erosions, and cartilage 
loss in hands/wrists by MRI at Weeks 4, and 12 from baseline.
 
 
 
 
 
 
 
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Study Design:  
This is a 12 week randomized, double-blind (DB), placebo-controlled, dose-ranging study with adaptive design 
features based on an interim analysis. The study will initially have a Screening Period (with 2 screening visits for 
subjects that require DMARD washout) that will be followed by up to 12 weeks of DB treatment and then a follow-
up period of 30 days. At the end of the DB study period, alternate treatments for RA should be discussed with 
subjects. 
Ongoing assessment of safety will be performed by an independent Data Monitoring Committee (DMC).
Screening Period:
The standard duration of the Screening Period is up to 28 days, with two Screening Visits allowed for subjects who 
require washout. Should more time be needed, the duration of the Screening Period may be extended up to another 
week (total of five weeks) depending on current DMARDs washout, drug stabilization, MRI technical issues, and 
subject scheduling. 
The start of the trial is defined as first visit for first subject screened. End of trial is defined as the last visit or 
scheduled procedure shown in the Time & Events schedule for the last subject. Study completion is defined as the 
final date on which data for the primary endpoint was or is expected to be collected, if this is not the same.
Study Summary:  Subjects with moderate to severely active RA who have had an inadequate response to MTX 
with or without prior inadequate response to up to 2 TNF inhibitors will receive BMS-986142 or placebo daily for 
up to 12 weeks.
Upon meeting the Inclusion/Exclusion criteria, approximately 328 subjects will be randomized to 1 of the 
4 treatment arms as shown in Figure 1 below. 
Interim analyses (IA) of clinical and PK data up to 12 weeks will be performed after approximately 20 subjects per 
treatment arm reach Week 4 (complete 4 weeks of treatment or discontinue) and complete the specified assessments 
for efficacy (ie, DAS28-CRP), safety, and PK. The purpose of this interim analysis is to adapt study design 
including dose, and sample size.
Subjects who were enrolled before the IA is completed will continue the originally assigned dose level if they have
received at least 1 treatment and the dose is considered safe. 
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Figure 1:
Study Design Schematic
Duration of Study:
Approximately 4 weeks for screening,  12 weeks of treatment, and 4 weeks of safety follow-up. Total duration for
the study is approximately 20 weeks for the study and safety follow-up. 
Number of Subjects:
About 328 subjects will need to be randomized for the 4 arms of this study.  The study will utilize an equal 
randomization scheme that will result in approximately 82 subjects in each arm. Should the IA analysis for futility 
and dose adaptation suggest that an additional one or 2 dose levels be added, then up to 82 additional subjects per 
arm may be randomized for up to 408 total potential subjects and randomization ratio will be adjusted accordingly.
At this time, BMS (the Sponsor) has elected to stop recruitment to the study on November 30th 2017. The company 
regularly reviews its ongoing studies within development programs to determine acceptability of continuation due to 
changing business needs, benefit-risk and/or the desire to accelerate decisions to advance a program. The Sponsor 
want(s) to emphasize that the stopping of enrollment in this study, prior to recruiting the planned number of subjects 
is not related to any adverse events (AEs) associated with the use of BMS-986142.
Study Population:
Men or women (not nursing or pregnant) 18 years of age with a diagnosis of RA by standard criteria at least 
16 weeks prior to screening and who are inadequate responders to MTX with or without inadequate response to up 
to 2 TNF inhibitors.
Key Inclusion Criteria:
Note:  Please see main protocol for complete listing of Inclusion/Exclusion criteria
1.
Documented diagnosis of adult-onset RA as defined by standard criteria (ACR/EULAR [2010]) at least 16 
weeks prior to screening. 
2.
ACR global functional status class of 1 to 3.
3.
Subjects must be MTX inadequate responders based on investigator’s judgment.  Subjects must have been 
taking MTX for at least 3 months at a minimal weekly dose of 15 mg, and at a stable dose for 4 weeks prior to 
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randomization (Day 1). A lower dose of MTX is permitted, if there is verifiable documentation in the medical 
record that the subject could not receive or reach a weekly dose of 15 mg due to toxicity or intolerance and the 
dose is at least 10 mg MTX at the time of screening. In Japan, Korea, Taiwan, Canada, and any other country 
that requires the same rule, a minimum dose of 7.5 mg per week is permitted. 
NOTE:  Subjects using parenteral MTX for administration of their weekly dose may be included.
To minimize potential of MTX toxicity, all subjects should receive folic acid, folinic acid, or leucovorin 
according to manufacturer recommendations and local medical standard of care guidelines. 
4.
Subject failed or was intolerant to ≤ 2 TNF inhibitor(s), (failed, defined as the inability to achieve desired 
efficacy at an approved labeled dose for at least 12 weeks as determined by the investigator). Target population 
includes at least 70% of patients that had inadequate response to MTX and up to 30% of patients in addition to 
inadequate response to MTX need to have failure or intolerance to up to 2 TNF inhibitors.
5.
Minimum of 6 swollen and 6 tender joints on a 66/68 joint count on Screening Visit #1 for those not requiring 
washout and on Screening Visit #2 for those requiring DMARD washout.
6.
Evidence of swelling in at least 1 joint of hand or wrist by clinical examination on Screening Visit #1 for those 
not requiring washout and on Screening Visit #2 for those requiring washout.
7.
Subjects must have a hsCRP of ≥ 0.8 mg/dL (8mg/L) [by central laboratory values] or an ESR ≥28 mm/hr on 
Screening Visit #1 for those not requiring washout of DMARDs and on Screening Visit #2 for those requiring 
washout.  
8.
This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, 
subject has not been randomized / has not been treated). If re-enrolled, the subject must be re-consented and a 
new subject number obtained.
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for BMS-986142
Medication 
Potency 
IP/Non-IP 
BMS-986142-01 Film Coated Tablet
50 mg
IP
Matching Film-Coated placebo for 50 mg 
BMS-986142-01 tablets
placebo
IP
BMS-986142-01 Film Coated Tablet
150 mg
IP
Matching Film Coated Placebo for 150 
mg BMS-986142-01 tablets
placebo
IP
Methotrexate - background therapy
subject taking on entry
See protocol Section 
3.3.1, Inclusion Criteria 
2c for possible doses
Non-IP
Study Assessments: 
Efficacy will be assessed using various RA endpoints including ACR 20/50/70 scores, CDAI, SDAI and Boolean 
remission rates, DAS28-CRP, DAS28-ESR and MRI. Physical function will be assessed via HAQ-DI. Safety 
(through reporting of adverse events, clinical laboratory results, physical examination, which includes vital signs and 
ECGs), population pharmacokinetics, and exposure-response relationships will also be assessed.
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Statistical Considerations:
Sample Size:
The sample size calculation is driven by the power to compare the proportion of subjects who achieve ACR70 
response at Week 12 between each BMS-986142 dose arm and placebo arm. The target population consists of mixed 
subjects who are MTX-IR (≥ 70%) and TNF-IR (≤ 30%). For co-primary endpoint of ACR70 at Week 12, 82 
subjects per arm will provide ~ 90% power to detect a treatment difference of 17% at the type I error rate of α = 0.05
(two-sided), assuming the placebo response rate of 2.5%. The assumed treatment difference of 17% is about double 
of median difference observed from historical data on approved drugs across different mechanism of actions 
(MOAs).
For the other co-primary endpoint of ACR20 at Week 12, 82 subjects per arm will provide >99% power to detect a 
difference of 34% over placebo at the type I error rate of α = 0.05 (two-sided), assuming placebo response rate of 
33%. The assumed treatment difference of 34% and placebo response rate of 33% were based on the observed data 
from approved drugs across different MOAs.
An interim analysis (IA) will be conducted when about 20 subjects per treatment arm reach week 4 (complete 4 
weeks of treatment or discontinue). Based on the totality of efficacy, safety, and PK data at Week 4 IA, the 
following adaptation(s) may be recommended:

Stop inefficacious or unsafe dose(s)

Introduce new dose(s) arms if needed and enroll up to about 82 subjects per new arm

Complete full enrolment for all efficacious arms (up to about 82 subjects per arm)

Stop the study enrollment if all dose arms are stopped for safety or futility.
The total sample size (range from 328 to 408 subjects) varies depending on actual enrollment rate, number of 
dropped dose arm(s) and number of newly added dose arm(s). The details of interim analysis and the criteria to 
adapt dose arm(s) and stop for futility are specified in the section 8.5.
Endpoints:
Co-Primary
–
ACR20 response rate at Week 12 
–
ACR70 response rate at Week 12
Secondary
–
Signs and Symptoms: ACR20/ACR50/70 over time 
–
Remission and change from baseline:  DAS28-CRP, DAS-ESR, SDAI, CDAI, Boolean over time
–
PK: Ctrough of BMS-986142 
–
Change in RAMRIS Scores of synovitis, osteitis, bone erosion and cartilage loss from baseline to Week 4 
and Week 12 
Statistical Analyses:  
Efficacy analysis: 
The co-primary endpoint ACR 20 and ACR70 response rate at Week 12 will be summarized for each treatment 
group using point estimate and 90% confidence intervals (CIs). Treatment difference of ACR 20/ACR70 response 
rate at Week 12 between each BMS-986142 arm versus placebo will be provided with point estimate and two-sided 
95% CIs. The chi-square tests will be used to compare the ACR response rates at Week 12 between each of the 
active treatment arms and the placebo arm at type I error rate of 0.05. Within each treatment group, the statistical 
testing will be performed for ACR20 at level of 0.05 first. If it is statistically significant, then the statistical testing 
will be performed for ACR70. Otherwise, stop testing for this treatment group. All treatment groups will follow the 
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same testing procedure. All subjects who discontinue prematurely during the treatment period or receive rescue 
therapy will be counted as non-responder at subsequent visits.
Safety analysis: 
All safety presentations will be based on the As-Treated population. Frequency distribution and individual listings of 
all adverse events, laboratory abnormalities and vital signs will be generated. Changes in clinical laboratory test 
results from baseline will be provided. No formal statistical tests on the treatment difference will be performed for 
any safety analyses.
Pharmacokinetic analysis:
Ctrough values will be descriptively summarized by treatment and study days.
Preliminary population PK and dose/exposure-response (ie, DAS28-CRP and selected safety endpoints) analysis 
will be conducted at the time when Week 4 interim analysis is conducted to assist new dose selection as described in 
interim analysis section (See section 8.5). 
Once the study is completed, the concentration vs. time data from this study combined with PK data from additional 
studies will be used to further develop a population PK model. This model will be used to evaluate the effects of 
various covariates on the PK of BMS-986142. 
 
 
Week 4 Interim analysis (IA):
After about 20 subjects per treatment arm have completed at least 4 weeks of the treatment period or discontinued 
the treatment, an interim analysis will be conducted to assess the efficacy of the BMS-986142 dose arms and the 
overall safety. The interim analysis will use pre-specified efficacy, safety and PK endpoints. The results of the 
interim analysis will be reviewed by an unblinded sponsor team who is not involved in the study conduct and who 
will provide recommendations with regard to the adaptive design decisions to the blinded study team. The details of 
interim analysis and the criteria to adapt dose arm(s) and stop for futility are specified in the Section 8.5.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03 ......................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 
 
 
 
 
 
 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
 
 
 
 
 
 
 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.3.4 MRI Contraindications ............................................................................ 
 
 
 
 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.2.1 Immunizations ................................................................................. 
3.4.2.2 Infectious Complications ................................................................ 
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3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.3.1 Administration Window ........................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Double Blind Period ................................................................................ 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
4.10 Retained Samples for Bioavailability / Bioequivalence ................................. 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Adverse Event and Vital Sign Assessments .............................................. 
5.3.2 Tuberculosis Screening ............................................................................ 
5.3.3 Electrocardiogram ................................................................................... 
5.3.4 Physical Examination .............................................................................. 
5.3.5 Laboratory Test Assessments ................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.2 Secondary Efficacy Assessments .............................................................. 
 
5.4.4 Imaging Assessments ............................................................................... 
5.4.4.1 MRI Assessment .............................................................................. 
5.4.5 Clinical Assessor Requirements ............................................................... 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetics: Collection and Processing ........................................ 
5.5.2 Pharmacokinetic Sample Analyses .......................................................... 
5.5.3 Labeling and Shipping of Biological Samples ......................................... 
 
 
 
5.8 Outcomes Research Assessments ..................................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
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6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.2.1 Efficacy Endpoints .......................................................................... 
8.3.2.2 Safety Endpoints.............................................................................. 
8.3.2.3 Pharmacokinetic Endpoints ............................................................ 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
 
 
 
 
 
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1.2
Research Hypothesis 
At least one of the dose levels of BMS-986142 administered daily is more effective than placebo 
on a background of MTX in achieving ACR20 and ACR70 response after 12 weeks of treatment 
in subjects with moderately-to severely active RA with an inadequate response to MTX with or 
without TNF inhibitors.
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1.3
Objectives
1.3.1
Primary Objectives
To compare the efficacy of BMS-986142 versus placebo (PBO) on a background of MTX as 
assessed by ACR20 and ACR70 response rates at Week 12.
1.3.2
Secondary Objectives

Assess additional efficacy outcomes of BMS-986142 at Week 12 and over 12 weeks of 
treatment as measured by ACR20, ACR50 and ACR70 response rates, DAS28-CRP 
change from baseline, DAS28-ESR change from baseline, Clinical Disease Activity 
Index (CDAI), Simplified Disease Index (SDAI), and Boolean remission.

Assess the safety and tolerability of BMS-986142. 

Evaluate Ctrough of BMS-986142.

Compare the efficacy of BMS-986142 + MTX to MTX alone in reducing synovitis, 
osteitis, bone erosion and cartilage loss in hands/wrists by MRI at Weeks 4, and 12, from 
baseline.
 
 
 
 
 
 
 
 
 
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1.5
Overall Risk/Benefit Assessment
As described above, BMS-986142, a highly selective reversible BTK inhibitor, is an 
immunosuppressive compound currently developed for the treatment of autoimmune 
inflammatory diseases such as RA. The possible clinical spectrum of use is wide, potentially 
spanning many autoimmune diseases. The risk/benefit ratio will dictate whether BMS-986142 is 
a viable new therapy for autoimmune inflammatory disease. BMS-986142 has been administered 
to healthy normal volunteers for the first time in Study IM006001, and based on an interim 
analysis of preliminary data from both SAD and MAD parts of the study; it has been well 
tolerated with a favorable safety profile.  The only safety signal that has been identified is a 
potential for mild, reversible, asymptomatic increases in hepatic transaminases (as described in 
section 1.4.4). In order to mitigate risks related to immunosuppression BMS will implement:

Extended exclusion criteria for serious infections. Complete blood count (CBC) 
differential counts and measurement of serum Ig-levels (IgG, IgA and IgM) and pro 
inflammatory cytokines will be monitored throughout the study

Prescreening for latent Tuberculosis as well as viral infections like hepatitis B and C

Any vaccination with live vaccines will be prohibited during the study as well as within 
30 days prior to the first dose of study medication.
In the case of BMS-986142, the preclinical safety studies have highlighted a few idiosyncratic
adverse events, which were reversible and manifested at exposures higher than the ones that we 
have explored in the FIH study. The pancreatic manifestation in rats appeared to be species 
specific but to assure safety of subjects in the FIH study, monitoring of pancreatic enzymes, such 
as amylase and lipase, as well as fasting glucose was implemented. There was no safety signal 
detected with regard to the pancreas, and no dose related pattern in any abnormalities on interim 
analysis of data in any of these tests. Therefore, amylase and lipase will not be routinely 
monitored in this study. Fasting glucose level will be monitored as part of standard safety 
laboratory panel.
 
 
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
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BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 

Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.

Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.

If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.

Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
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The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a 12 week randomized, double-blind, placebo-controlled, dose-ranging study with 
adaptive design features based on an interim analysis.  Subjects with moderate to severely active
RA who have had an inadequate response to MTX or up to 2 TNF inhibitors will receive 
BMS-986142 or placebo daily for up to 12 weeks, followed by a 30-day follow-up period.
Four treatments will be administered: placebo, 100, 200, and 350 mg of BMS-986142 daily for 
12 weeks. Based on the interim analysis, the doses may be adaptive.
Screening Period:
Upon obtaining the informed consent, a subject’s eligibility will be determined. To be eligible,
subjects must be considered an inadequate responder to MTX therapy or have experienced an
inadequate response to MTX and inadequate response to at least one, but not more than two, 
TNF inhibitors by a treating physician or investigator, see inclusion criteria (see section 3.3.1.
Subjects receiving non-biologic DMARDs must discontinue all DMARDs except MTX prior to
the beginning of BMS-986142 treatment as follows:

DMARDs including but not limited to sulfasalazine, chloroquine, hydroxychloroquine
azathioprine, minocycline, oral or parenteral gold, quinacrine, d-penicillamine, 
cyclosporine and sirolimus, and must be washed out for 4 weeks prior to screening visit 
#2.

Leflunomide: subjects should not be on leflunomide at the time of screening.

For subjects who were recently  treated with leflunomide prior to screening: Subjects will be
allowed to enroll only if they are willing to undergo the following drug elimination
procedure (recommended to achieve non-detectable plasma levels [less than 0.02 mg/L or 0.02 
mcg/mL] 

Administer cholestyramine 8 grams 3 times daily for 11 days. (The 11 days
do not need to be consecutive unless there is a need to lower the plasma level
rapidly); then
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
Verify plasma levels less than 0.02 mg/L (0.02 mcg/mL) by two separate tests at least
14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine 
treatment should be considered.
For subjects who are no longer treated with leflunomide prior to screening for at least 10 
weeks: Leflunomide plasma levels will be obtained at Screening; if the levels are non-
detectable [less than 0.02 mg/L or 0.02 mcg/mL], the subject is eligible to enroll immediately if 
they have not been treated with leflunomide within 10 weeks prior to Screening. If there are still
detectable leflunomide plasma levels, the subject may enroll only if they follow the above drug 
elimination procedure.
The standard duration of the Screening Period is up to 28 days, with two Screening Visits 
allowed for subjects who require washout.
Should more time be needed, the duration of the Screening Period may be extended up to another 
week (total of five weeks) depending on current DMARDs washout, drug stabilization, MRI 
technical issues, and subject scheduling. 
Double-Blind Period:
Upon meeting
the Inclusion/Exclusion criteria and completing the screening period, 
approximately 328 subjects will be randomized to 1 of the 4 treatment arms in an equal ratio as 
shown in the study schematic Figure 3.1-1 below.
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Figure 3.1-1:
Study Design Schematic
During this period, the dose of methotrexate, NSAIDs, and oral prednisone (or its equivalent) 
should remain stable.  Intra-articular corticosteroid injections and intramuscular injections are 
not permitted.  Analgesics are permitted with certain restrictions (see Section 3.3).
At the end of the DB period, alternate therapies for RA should be discussed with subjects.
The start of the trial is defined as first visit for first subject screened. End of trial is defined as the 
last visit or scheduled procedure shown in the Time & Events schedule for the last subject. Study 
completion is defined as the final date on which data for the primary endpoint was or is expected 
to be collected, if this is not the same.
Interim Analyses:
Interim Analyses (IA) of clinical and PK data will be performed after approximately 20 subjects 
per treatment arm reach Week 4 (complete 4 weeks of treatment or discontinue) and complete 
the specified assessments for efficacy (ie, DAS28-CRP), safety, and PK. Details of interim 
analyses are described in Section 8.5 (Interim analysis).
3.2
Post Study Access to Therapy
At the end of the study, BMS will not continue to provide BMS supplied study drug to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the subject receives appropriate standard of care to treat the condition under study.
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3.3
Study Population
Men or women (not nursing or pregnant) 18 years of age with a diagnosis of RA by standard 
criteria at least 16 weeks prior to screening and who are inadequate responders to MTX or up to 
2 TNF inhibitors.
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a)
Subject is willing to participate in the study and has signed the informed consent form.
2. Target Population
a) Documented diagnosis of adult-onset RA as defined by standard criteria (ACR/EULAR 
[2010]) at least 16 weeks prior to screening. See Appendix 2.
b) ACR global functional status class of 1 to 3.
c) Subjects must be MTX inadequate responders based on investigator’s judgment. 
Subjects must have been taking MTX for at least 3 months at a minimal weekly dose of 
15 mg, and at a stable dose for 4 weeks prior to randomization (Day 1). A lower dose of 
MTX is permitted, if there is verifiable documentation in the medical record that the 
subject could not receive or reach a weekly dose of 15 mg due to toxicity or intolerance 
and the dose is at least 10 mg MTX at the time of screening. In Japan, Korea, Taiwan, 
Canada, and any other country that requires the same rule, a minimum dose of 7.5 mg per 
week is permitted. 
NOTE:  Subjects using parenteral MTX for administration of their weekly dose may be 
included.
To minimize potential of MTX toxicity, all subjects should receive folic acid, folinic 
acid, or leucovorin according to manufacturer recommendations and local medical 
standard of care guidelines. 
d) Subject failed or was intolerant to 2 TNF inhibitor(s), (failed, defined as the inability to 
achieve desired efficacy at an approved labeled dose for at least 12 weeks as determined 
by the investigator). Target population includes least 70% of patients that had inadequate 
response to MTX and up to 30% of patients in addition to inadequate response to MTX 
need to have failure or intolerance to up to 2 TNF inhibitors.
Note: If subject is an MTX-IR only, then subject only needs to fulfill inclusion 2c. If 
subject is both MTX-IR and has failed up to 2 TNF inhibitors, then both inclusion 2c and 
2d need to be fulfilled.
e) Minimum of 6 swollen and 6 tender joints on a 66/68 joint count on Screening Visit #1 
for those not requiring washout and on Screening Visit #2 for those requiring DMARD 
washout.
f)
Evidence of swelling in at least 1 joint of hand or wrist by clinical examination on 
Screening Visit #1 for those not requiring washout and on Screening Visit #2 for those 
requiring washout.
g) Subjects must have an hsCRP of 0.8 mg/dL (8mg/L) [by central laboratory values or by 
local laboratory values in special circumstances as approved by MM] or an ESR 
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28 mm/hr on Screening Visit #1 for those not requiring washout of DMARDs and on 
Screening Visit #2 for those requiring washout.  
h) This study permits the re-enrollment of a subject that has discontinued the study as a
pre-treatment failure (ie, subject has not been randomized / has not been treated). If 
re-enrolled, the subject must be re-consented and a new subject number obtained.
3. Age and Reproductive Status
a) Males and Females, ages 18 years old, inclusive.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with BMS-986142 plus 90 days post-treatment completion or longer if 
required based on country specific guidelines for MTX use (please refer to MTX product 
label for details on your country specific guidelines).
e) Male subjects must be willing to refrain from sperm donation during the entire study and 
for 5 half-lives of study drug plus 90 days (duration of sperm turnover) for a total of 93
days after dosing has been completed or longer if required based on country specific 
guidelines for MTX use (please refer to MTX product label for details on your country 
specific guidelines). Males who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment with BMS-
986142 plus 5 half-lives of BMS-986142 (~3 days) plus 90 days (duration of sperm 
turnover) for a total of 93 days post-treatment completion or longer if required based on 
country specific guidelines for MTX use (please refer to MTX product label for details on 
your country specific guidelines).
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
g) Women/men who are not using hormonal contraceptives (oral, parenteral or implantable). 
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly.
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly. WOCBP and female partners of male subjects are expected to use one of the 
highly effective methods of contraception listed below. Per country guidelines, a less effective 
method of contraception may be required to be added to the one highly effective method based 
on background use of MTX that is a known teratogen. Male subjects must inform their female 
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partners who are WOCBP of the contraceptive requirements of the protocol and are expected to 
adhere to using contraception with their partner.

Nonhormonal IUDs

Bilateral tubal occlusion

Vasectomised partner with documented azoospermia 90 days after procedure

Vasectomised partner is a highly effective birth control method provided that
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomised partner has received medical assessment of the surgical success.

Complete abstinence

Complete abstinence is defined as the complete avoidance of heterosexual 
intercourse.

Complete abstinence is an acceptable form of contraception for all study drugs and 
must be used throughout the duration of study and for the duration of time as 
specified above under Duration of Mandatory Contraception.

It is not necessary to use any other method of contraception when complete 
abstinence is elected.

Subjects who choose complete abstinence must continue to have pregnancy tests, 
as specified in Section 5.3.

Acceptable alternate methods of highly effective contraception must be discussed 
in the event that the subject chooses to forego complete abstinence.

The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the subject.
LESS EFFECTIVE METHODS OF CONTRACEPTION

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge with spermicide

Male or female condom with or without spermicide*
HORMONE BASED METHODS OF CONTRACEPTION

Female partners of male subjects participating in the study may use hormone based
contraceptives as one of the acceptable methods of contraception since they will not be
receiving study drug.
* A male and a female condom must not be used together.
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BIRTH CONTROL METHODS WHICH ARE CONSIDERED UNACCEPTABLE IN
CLINICAL TRIALS
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus
interruptus), spermicide only, and lactation amenorrhea method (LAM) are not acceptable
methods of contraception.
CONTRACEPTIVE RECOMMENDATIONS FOR MALE SUBJECTS AND THEIR
WOCBP PARTNERS
Male subjects should always inform their female partners who are WOCBP of the contraceptive
requirements of the protocol and are expected to adhere to using contraception with their partner.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Subjects with:
i)
documented juvenile rheumatoid arthritis
ii) Felty’s syndrome
b) Biologic treatments other than TNF inhibitors.
c) Subjects who are currently receiving immunomodulators other than methotrexate.
d) Subjects who have been treated with Intramuscular (IM)
or Intra-articular
glucocorticosteroids within 4 weeks of randomization (Day 1).
Oral steroid use is permitted, but only if 10 mg/day of prednisone (or prednisone
equivalents)
2. Medical History and Concurrent Diseases
a) Subjects at risk for tuberculosis (TB).  Specifically, subjects with: 
i)
Current clinical, radiographic or laboratory evidence of active TB.
ii) A history of active TB within the last 3 years even if it was treated.
iii) A history of active TB greater than 3 years ago unless there is documentation 
that the prior anti-TB treatment was appropriate in duration and type.
iv) Therapy for Latent TB which has not been completed as per local country 
guidelines.
v) This exclusion criteria was a duplicate of Exclusion 2b and was removed in 
Amendment 5, bullet is being left to maintain numbering.
b) Subjects with any bacterial infection within the last 60 days prior to screening 
(enrollment), unless treated and resolved with antibiotics, or any chronic or history of 
recurrent bacterial infection (such as chronic pyelonephritis, osteomyelitis, and 
bronchiectasis).
c) Subjects who have a history of systemic fungal infections (such as histoplasmosis,
blastoplasmosis, or coccidioides).
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d) Subjects with herpes zoster symptoms that resolved less than 60 days prior to screening 
visit (enrollment).
e) Subjects with evidence (as assessed by the investigator) of active or latent bacterial or 
viral infection at the time of potential enrollment, including subjects with history or 
evidence of Hepatitis B or Hepatitis C, history or evidence of Human Immunodeficiency 
Virus (HIV) infection.
f)
Subjects with autoimmune disease other than RA (eg, Systemic lupus erythematosus 
[SLE], multiple sclerosis [MS], vasculitis).
g) Significant concurrent medical condition at the time of screening or baseline visit,
including, but not limited to, the following:

Any major illness/condition or evidence of an unstable clinical condition (eg, renal, 
hepatic, hematologic, gastrointestinal, endocrine, pulmonary or local active 
infection/infectious illness) that, in the Investigator’s judgment will substantially 
increase the risk to the subject if he or she participates in the study.

Cancer or history of cancer or lymphoproliferative disease within the previous 5 years 
(other than resected cutaneous basal cell or squamous cell carcinoma that has been 
treated with no evidence of recurrence).

Class III or IV congestive heart failure as defined by the New York Heart Association

Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris)
and/or any history of significant cerebrovascular disease within 24 weeks before 
screening

Any other concomitant medical conditions that, in the opinion of the investigator, 
might place the subject at unacceptable risk for participation in this study.
h) Subjects with surgery on more than 5 joints.
i)
Subjects with a history of (within 12 months of signing the consent), or known current 
problems with drug or alcohol abuse or known cirrhosis including alcoholic cirrhosis.
j)
Subjects with a history or suspicion of unreliability, poor cooperation, or non-compliance 
with medical treatment.
k) Subjects who have received treatment with an investigational drug within 28 days or less 
than 5 terminal half-lives of elimination (whichever is longer) of randomization (Day 1).
l)
Subjects who have been administered live vaccines within 30 days prior to dosing. 
m) Subjects with the inability to have a MRI performed; reasons include the following: 
magnetizable metallic parts/devices (including cardiac pacemaker) on and in the body, 
severe claustrophobia, body size
incompatible with the scanner, severe renal 
insufficiency (ie, GFR 
30
mL/min/1.73m2). See Section 3.3.4
for MRI 
contraindications.
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3. Physical and Laboratory Test Findings
a) Subjects with positive tests for current or previous Hepatitis B infection as indicated by 
screening using Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody 
(anti-HBs) and Hepatitis B core antibody (anti-HBc). Subjects with positive HBsAg or 
anti-HBc antibody are excluded from the study (See Appendix 1). Subjects with negative 
Hepatitis B surface antigen but with high risks for latent HBV infections including 
subjects with known family history of HBV infection, HBV carrier, personal medical 
history of hepatitis or blood transfusion history must also be tested for quantitative HBV 
DNA. Subjects with positive findings are excluded from the study.
b) Hepatitis C antibody-positive subjects who are also HCV positive by confirmatory testing 
such as PCR.
c) Have any clinically significant laboratory abnormalities including but not limited to:
i)
Hepatic
(1) ALT 1.5 x ULN (upper limit of normal)
(2) AST 1.5 x ULN
(3) Total bilirubin 1.5 x ULN 
ii) Hematology
(1) Hemoglobin < 9 g/dL
(2) Absolute neutrophil count < 1,000/mm3 (1.0 x 109/L)
(3) Platelets < 100,000/mm3 (100 x 109/L)
d) Any other significant laboratory abnormalities or ECG findings that, in the opinion of the 
Investigator, might place the subject at unacceptable risk for participation in this study 
(please discuss with Medical Monitor if there are any questions in regards to
inclusions/exclusion criteria)
4. Allergies and Adverse Drug Reaction
a) Subjects who have a known allergy to gadolinium or contrast agents.
 
 
 
 
 
 
 
  
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7. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Subjects who are illiterate.  This study requires the use of an ePRO device which requires 
the subject to complete responses to the questions.  Due to potential bias the questions 
cannot be read to the subjects. 
3.3.3
Women of Childbearing Potential
A Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels.

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal 
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3.3.4
MRI Contraindications 
The radiologist at the site’s MRI facility is responsible for determining if a subject is 
contraindicated from having this procedure. If the subject is contraindicated, the subject must be 
dropped from the study. The following is a list of some common conditions that may preclude 
the subject from having MRI of the hands or wrists. However, this should not be used as a 
substitute for local clinical standards of care. The ultimate decision to perform MRI in an 
individual subject in this study rests with the site radiologist, the investigator, and the standard 
set by the local Ethics Committee:
1. Subjects who have a history of claustrophobia.
2. Subjects who have a physical limitation related to fitting in the bore of the magnet (ie, 
body weight in excess of 250 pounds or 113.4 kilograms).
3. Subjects with tattooed eye-liner or tattoos directly on the hand or wrist (area to be 
imaged).
4. Subjects who have a history of allergic reaction to contrast agents.
5. Subjects who had exposure to a radiological contrast agent within the 72 hours prior to 
the MRI examination.
6. Subjects who have a fused joint in the wrist or joint replacements in the hand or wrist that 
are being evaluated by the MRI examination.
7. Subjects with a pacemaker, epicardial pacemaker wires, MRI-incompatible cardiac valve 
prostheses, 
MRI-incompatible 
vascular 
clips 
less 
than 
two-months 
old, 
or 
MRI-incompatible aneurysm clips of any age.
8. Subjects with MRI-incompatible cochlear implants.
9. Subjects with spinal nerve stimulators.
10. Subjects with an infusion pump.
11. Subjects with metallic fragments in the eyes/orbits or in the vicinity of the brain or major 
neurovascular structures of the body, subjects with an employment history which 
involves exposure to welding, or subjects who have shrapnel any place in their body.
12. Subjects with severe renal insufficiency (ie, glomerular filtration rate or GFR
< 30mL/min/1.73m2), are excluded from the study as they are at increased risk of 
Nephrogenic Systemic Fibrosis following administration of gadolinium-based MRI 
contrast agents. Subjects with GFR 30 - 60mL/min/1.73m2 should be followed carefully 
following the administration of gadolinium-based MRI contrast agents.
  
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3.4.2
Other Restrictions and Precautions
The prescribing label of all concomitant medications used as subject’s background therapy 
should be evaluated by the investigator for continued administration during the subject’s 
participation in this study (eg, known toxicities, drug-drug interactions).
Lists of concomitant medication requiring precautions and restrictions due to the potential 
drug-drug interactions are presented in Section 3.3.
3.4.2.1
Immunizations
Live vaccines should not be administered to subjects during the study (including the screening 
period). Inactivated vaccines (eg, influenza) are allowed however the efficacy may be attenuated. 
No data are available on the therapeutic effect of vaccinations in subjects receiving a BTK
inhibitor. A subject who discontinues from the study should not receive a live vaccine injection
until 30 days after discontinuing study medication.
3.4.2.2
Infectious Complications
Subjects who develop significant infectious complications during the study should be treated 
appropriately and have study medication withheld, and restarted only when clinically resolved 
and the investigator considers it appropriate.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Use of prohibited medication

Pregnancy
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
Male subjects must discontinue treatment if their female partners become pregnant during 
the trial. After discontinuation, male subjects are required to continue using a method of 
contraception that prevents the exposure of the fetus to the male’s semen (ie, male 
condom, female condom, complete abstinence, etc.) for the entire length of the pregnancy 
or 93 days, whichever is less

Subject’s request to stop study treatment or withdrawal of informed consent

Investigator judgement

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness

Unblinding a subject for any reason (emergency or non-emergency)
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5 The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
In this study, ACR20 and ACR70 and other efficacy measures are key endpoints of the study. 
Post study follow-up is of critical importance and is essential to preserving subject safety and the 
integrity of the study. Subjects who discontinue study drug must continue to be followed for 
collection of outcome and/or survival follow-up data as required and in line with Section 5 until 
death or the conclusion of the study.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
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authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drugs include both Non-investigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. 

Study required premedication, and 

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications

Diagnostic agents (such as glucose for glucose challenge) given as part of the protocol 
requirements and must also be included in the dosing data collection.
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Table 4-1:
Study Drugs for BMS-986142 Blinded Treatment
Product Description / 
Class and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging/ Appearance
Storage Conditions
(per label)
BMS-986142-01
Film Coated Tablet
50 mg
IP
Blinded Label
Plain, yellow,  round, film 
coated tablet
HDPE Bottle
Store 2 to 8°C ;
Store in a tightly closed 
container
Placebo for 
BMS-986142-01 Film 
Coated Tablet, 
50 mg
Placebo
IP
Blinded Label
Plain, yellow,  round, film 
coated tablet 
HDPE Bottle
Store 2 to 8°C ;
Store in a tightly closed 
container
BMS-986142-01 Film 
Coated Tablet
150 mg
IP
Blinded Label
Plain, yellow, oval film 
coated tablet
HDPE Bottle
Store 2 to 8°C ;
Store in a tightly closed 
container
Placebo for 
BMS-986142-01 Film 
Coated Tablet, 
150mg
Placebo
IP
Blinded Label
Plain, yellow, oval film 
coated tablet
HDPE Bottle
Store 2 to 8°C ;
Store in a tightly closed 
container
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, Investigational Product(s) (also described in Table 4-1) are:

BMS-986142, 50 mg (round), 35 tablets/bottle

BMS-986142, 150 mg (oval), 35 tablets/bottle

Matching Placebo (round) for 50 mg BMS-986142, 35 tablets/bottle

Matching Placebo (oval) for 150 mg BMS-986142, 35 tablets/bottle
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be
considered as non-investigational products. 
In this protocol, non-investigational product(s) include, but are not limited to: 

Methotrexate (subject must be on this DMARD before study screening to be eligible 
for study)

Prednisone or other Glucocorticoids

NSAIDs and analgesics.
The Sponsor will not be providing these medications since they are part of subject’s standard of 
care.  
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
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Please refer to the current version of the Investigator Brochure and/or pharmacy reference sheets 
for complete storage, handling, dispensing information for BMS-986142.
4.3.1
Administration Window
If abnormal laboratory test results or clinical adverse events indicate toxicity that, in the 
judgment of the investigator, could place the subjects at risk, study medication administration 
should be skipped and the investigator should notify the BMS Study Medical Monitor. Subjects 
may receive further study medication only if resolution of the adverse event or abnormal 
laboratory finding is documented or, at a minimum, the subject’s status returns to what it was at 
baseline.
4.4
Method of Assigning Subject Identification
At the time of the screening visit, immediately after written informed consent is obtained and 
before performing any study-related procedures, the investigator or coordinator will call into the 
Interactive Voice Response System (IVRS or IWRS) designated by BMS for assignment of a 
5-digit subject number that will be unique across all sites. Enrolled subjects, including those not 
dosed, will be assigned unique sequential subject numbers by the IVRS system starting with 
00001, 00002, 00003, etc. for identification throughout the study. This subject number must not
be reused for any other participant in the study.
After completion of all screening evaluations, on Day 1, all eligible subjects will be randomly 
assigned to 1 of 4 treatment arms (BMS-986142, 100 mg; BMS-986142, 200 mg; BMS-986142,
350 mg; and Placebo) in an equal ratio. To randomize a subject, a phone call will be placed into 
the randomization option of the IVRS in order to obtain a subject’s randomized treatment 
assignment. Randomization will be assigned in the order in which subjects qualify for treatment, 
not in the order of study enrollment. The IVRS will be available 24-hours a day, 7 days a week, 
via a toll-free number. Randomization will be stratified by prior treatment status (MTX-IR vs 
TNF-IR) and geographic region.
If a subject meets re-screening criteria highlighted in see Section 3.3.1, they must be 
re-consented, the investigator or coordinator will call into the Interactive Voice Response System 
(IVRS or IWRS) designated by BMS for assignment of a 5-digit subject number that will be 
unique across all sites.
Specific instructions (including an enrollment/randomization worksheet) for the central 
enrollment and randomization procedure using an IVRS will be provided to the site. 
Randomized schedules will be generated and kept by the Randomization Group within Drug 
Supply Management of Bristol-Myers Squibb. The randomization ratio may be adjusted if any 
dose arm will be discontinued and/or new dose arm will be added based on Week 4 interim 
analysis.
At all study visits when study drug is dispensed, each subject will be assigned specific container 
numbers by the IVRS. Container numbers will be assigned non-sequentially and will correspond 
to the numbers printed on the containers and bottles containing study drug, and will be recorded 
on the appropriate eCRF. 
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4.5
Selection and Timing of Dose for Each Subject
Selection and timing of doses are described for each period below.
4.5.1
Double Blind Period
All drug dosing should occur after all study-related assessments, including blood draws, are 
completed. 
After randomization, study drug will be dispensed according to the assignment by the IVRS 
system. Doses of BMS-986142 at 100 mg, 200 mg, 350 mg or matching placebo are to be 
administered orally q24h (one time/day) with water and may be taken with or without food.  
Four tablets, one from each bottle, will be taken, all at the same time, once/day every day. On 
Day 1, and at Week 2, 4, 8, and 12 study drug will be administered in the morning at the 
study site and after blood samples have been collected. However, at other visits, drug should 
be taken at approximately the same time each day.
Study drug is blinded and is supplied in bottles.  Each subject will be dispensed a set of four (4) 
bottles at each study visit. Each bottle contains 35 tablets of blinded study drug.  The 5 additional
tablets in each bottle allow for the ± 5 day window between each visit in the double-blind phase 
of the study.  Study drug bottles that were dispensed to the subject must be brought back to the 
study site by the subject at Weeks 2, 4, 8, and 12 during the double-blind period.
4.6
Blinding/Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject’s management, the blind for that subject may be 
broken by the investigator. The subject’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine
that the unblinded information is necessary, ie, that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made.
For this study, the method of unblinding for emergency purposes is IVRS.
For information on how to unblind in case of an emergency, consult the IVRS manual
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor.
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The Bioanalytical Sciences department or its designate will be unblinded to the randomized 
treatment assignments in order to minimize unnecessary analysis of samples from control group 
subjects.
To implement the adaptive design that is planned in advance, an interim analysis will be 
conducted prior to the formal locking of the study database. In order to allow for a high quality 
and/or validated data analysis and a timely analysis of data, the unblinded team may consist of 
up to two people from each relevant function role within BMS. 

Global Biometric Sciences - Up to 2 statisticians and 2 programmers 

Clinical Pharmacology and Pharmacometrics - Up to 2 pharmacometric and 
pharmacokinetic scientists and 2 pharmacometric programmers

 

Bioinformatics -Up to 2 bioinformaticians
This configuration ensures that the unblinded team has the resources to independently conduct its 
own analyses. The study team does not have access to any unblinded data and is not involved in 
the review or discussion of unblinded data. 
4.7
Treatment Compliance
Treatment compliance in this study will be determined by counts of returned tablets of study 
drug and information provided by questioning the subject.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures 
must be filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the 
containers. The method of disposal, ie, incinerator, licensed sanitary landfill, or 
licensed waste disposal vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the 
Monitor to review throughout the clinical trial period.
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If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
4.10
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Flow Chart for Protocol IM006016 - Screening Perioda
Procedure
Screening 
Visit #1
Screening 
Visit #2b
Notes 
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
Enroll subjects (contact Central 
Randomization System)
X
Contact IVRS for subject number after signing 
consent. If subject does not meet eligibility 
criteria, contact IVRS to screen fail subject.
Safety Assessments
Physical Examination
X
X
ECG
X
Chest X-ray (CXR)
X
Required only if not performed within 6 months 
of signing informed consent or if documentation 
of previous CXR is not on file.
Height and Weight
X
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Table 5.1-1:
Flow Chart for Protocol IM006016 - Screening Perioda
Procedure
Screening 
Visit #1
Screening 
Visit #2b
Notes 
Vital Signs
X
X
TB screening test(s)
X
See Section 5.3.2 for important details
Adverse Events Assessment
X
X
HBsAg, HBcAb, HbsAb
X
May also include HBV DNA testing where 
required locally 
Hepatitis C antibody
X
If positive, reflex to HCV confirmation such as 
PCR
HIV testing
X
Performed locally; at discretion of investigator
Laboratory Assessments
Hematology (CBC with 
differential)
X
X
Chemistry panel
X
X
Must include liver function testing; see Section 
5.3.5 for details. For screening, PI discretion if 
fasting glucose is needed. Must include 
leflunomide level if appropriate. 
Estimated Glomerular Filtration 
Rate (eGFR)
X
X
As performed by Modification of Diet in Renal 
Disease (MDRD) Study equation
Urinalysis
X
Urine pregnancy test 
X
X
WOCBP only; See Section 3.3.3
ESR (performed locally)
X
X
Unblinded result that may be communicated to 
study staff to determine eligibility
hsCRP
X
X
Assessments
Tender (68)/swollen (66) Joint 
Count 
X
X
6 Swollen/Tender joints required at this visit for 
eligibility
ACR Functional Status 
assessment
X
Efficacy Assessment
MRI of clinically dominant 
hand/wrist
X
Perform approximately 14 days prior to 
randomization to allow review by central 
imaging lab and perform repeat if required 
See Section 5.4.4.1
a Screening is within 28 days if possible, to a maximum of 5 weeks if necessary which includes both SV1 and SV2; 
see Section 3.1 for information
b Screening Visit #2 is for subjects that are required to undergo washout for hydroxychloroquine/chloroquine 
and/or sulfasalazine
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Table 5.1-2:
Flow Chart for Protocol IM006016 - Double-Blinded Treatment Perioda
Subjects who discontinue at any time during the Treatment Period must complete the Early Termination (ET) Visit assessments
Procedure
Day 1
Wk 2
(approx. 
D 15)
Wk 4
(approx. 
D 28)
Wk 8
(approx. 
D 56)
Wk 12 
or
ET
(approx. 
D 84)
30 day 
FU Visit
(approx. 
Day 114 )
Notes
Safety Assessments
Physical Exam
X
X
X
Height and Weight
X
X
X
ECG
X
X
X
X
Not required if early termination (ET) 
visit
Vital Signs
X
X
X
X
X
X
See Section 5.3.1 for details
Adverse Events Assessment
X
X
X
X
X
X
Laboratory Assessments
Hematology (CBC with 
differential)
X
X
X
X
X
X
Chemistry panel
X
X
X
X
X
X
Must include liver function testing; see 
Section 5.3.5 for details. For double-
blinded period, fasting glucose is 
required.
Estimated Glomerular Filtration 
Rate (eGFR) - AUDIT
X
X
X
X
X
X
As performed by Modification of Diet in 
Renal Disease (MDRD) Study equation
Fasting lipid panel
X
X
X
X
At least 10 hour fasting prior to 
collection of sample
IgM, IgA, and IgG
X
X
X
X
Urinalysis
X
X
X
Rheumatoid Factor
X
X
X
Anti-CCP2
X
X
X
X
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Table 5.1-2:
Flow Chart for Protocol IM006016 - Double-Blinded Treatment Perioda
Subjects who discontinue at any time during the Treatment Period must complete the Early Termination (ET) Visit assessments
Procedure
Day 1
Wk 2
(approx. 
D 15)
Wk 4
(approx. 
D 28)
Wk 8
(approx. 
D 56)
Wk 12 
or
ET
(approx. 
D 84)
30 day 
FU Visit
(approx. 
Day 114 )
Notes
ANA
X
X
X
Anti- Ro (SS-A) and Anti-La 
(SS-B)
X
X
X
Urine pregnancy test
X
X
X
X
X
WOCBP only; results confirmed prior to 
administration of study drug. See 
Section 3.3.3
ESR (performed locally)
X
X
X
X
X
X
Performed locally. Every effort should 
be made to ensure the person analyzing 
the ESR results is not involved in the
efficacy assessments (see Section 5.4)
hsCRP
X
X
X
X
X
X
Pharmacokinetics
X
X
X
X
X
See Section 5.5.1 for details
Efficacy Assessments
Tender (68)/ Swollen (66) Joint 
Count 
X
X
X
X
X
X
Must have at least 6 swollen/tender 
joints prior to randomization
Subject Assessment of Pain
X
X
X
X
X
X
QoL assessments; see Section 5.8
Subject’s Global Assessment of 
Disease Activity
X
X
X
X
X
X
Physician’s Global Assessment of 
Disease Activity
X
X
X
X
X
X
Physical Function (HAQ-DI)
X
X
X
X
X
X
Fatigue (VAS)
X
X
X
SF-36
X
X
X
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Table 5.1-2:
Flow Chart for Protocol IM006016 - Double-Blinded Treatment Perioda
Subjects who discontinue at any time during the Treatment Period must complete the Early Termination (ET) Visit assessments
Procedure
Day 1
Wk 2
(approx. 
D 15)
Wk 4
(approx. 
D 28)
Wk 8
(approx. 
D 56)
Wk 12 
or
ET
(approx. 
D 84)
30 day 
FU Visit
(approx. 
Day 114 )
Notes
Stiffness
X
X
X
Bristol Rheumatoid Arthritis 
Multidimensional Questionnaire 
(BRAF-MDQ)
X
X
X
MRI (same hand/wrist imaged at 
screening)
X
X
Subjects who terminate the study 
early require an MRI at the early 
termination (ET) visit only if ET < 4 
weeks or > 8 weeks from date of 
randomization and should have their 
early termination (ET) MRI NO 
MORE than 7 days from their Early 
Termination (ET) Visit
See Section 5.4.4.1
Study Drug Administration
Randomize through IVRS system
X
Dosing of Study Medication
Daily
On Day 1, subjects will be observed for 
2 hours after dosing administration
Dispense Study Medication 
X
X
X
Reconciliation of Study Medication 
X
X
X
X
X
a For the Double-Blind part of the study, visits have windows of ±5 days around the calculated visit date
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value).
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects.  Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
5.2
Study Materials
All investigator sites within this study will use an Electronic Data Capture (EDC) tool to submit 
study data to BMS. Electronic Case Reports Forms and drug logs will be provided by BMS. An 
electronic device (ePRO) will be provided to complete questionnaires and investigator/subject 
assessments. Urine pregnancy test kits, laboratory specimen collection kits and instructions for 
collection will be provided by the central laboratory vendor. IVRS worksheets and instruction 
manuals will be provided by the IVRS vendor. Sites will be provided with the Common 
Terminology Criteria for Adverse Event grading (CTCAE). Link is below:
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
Subjects will also be provided with cooler bags and gel packs for transporting study drug as it 
needs to be kept refrigerated.
The site will provide all required materials for the tests performed locally (ie, relevant clinical 
laboratory tests and urine drug screens). The site will have available a well-calibrated scale for 
recording body weight, a 12-lead ECG machine, and a calibrated sphygmomanometer and 
thermometer for vital signs assessments. A current and fully-stocked basic cardiac life support 
(BCLS)] cart will be immediately available on the premises. The site will have urine collection 
containers, a refrigerated centrifuge, a monitored and alarmed refrigerator, and freezer (-20°C or 
below), as well as containers and dry ice for shipment and storage of blood and urine samples. 
The site will provide all materials required for accurate source documentation of study activities 
and for housing the subjects during the study. The site will source marketed product from a 
single commercial lot.
BMS will provide a BMS-approved protocol and any amendments or administrative letters (if 
required), and investigator brochure. Case report forms (electronic or hard copy) will be 
provided by BMS. 
 
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5.3
Safety Assessments
On Day 1, the results of all assessments must be reviewed to assure that eligibility requirements 
are met before contacting the Central Randomization System for the subject’s randomization 
assignment.
Subjects who discontinue will complete the Week 12/Early Termination (ET) Visit assessments 
for the corresponding period. Subjects who complete the study will complete the 30-day follow-
up visit assessments. The Early Termination Visit should be as soon as possible after the last 
dose of study medication (investigational product) and prior to the subject receiving a prohibited 
concomitant medication. 
All assessments should be performed or administered prior to study drug administration 
unless otherwise indicated.
Every effort must be made to ensure the same evaluator will complete the assessments for 
each subject at all visits.
Only data for the procedures and assessments specified in this protocol should be submitted to 
BMS on a case report form. Additional procedures and assessments may be performed as part of 
your institutional or medical practice standard of care; however, data for these assessments 
should remain in the subject’s medical record and should not be provided to BMS, unless 
specifically requested from the sponsor. Safety assessments include the following:

Adverse Events

Safety laboratory values

Physical examination

Vital signs

ECG
5.3.1
Adverse Event and Vital Sign Assessments
At Day 1 of the double-blind (DB) period, vital signs collection (blood pressure, heart rate, 
respiration rate, temperature) will occur prior to first dose of study medication is given from the 
assigned kit. At subsequent visits, vital sign collection will be completed prior to the 
administration of the dose of assigned study drug.
Subjects will be observed at the site for a minimum of 2 hours after receiving their first dose of 
study medication (tablets) on Day 1 of the DB Period The observation period should be extended 
if clinically indicated.
Any adverse events that occur will be reported on the appropriate eCRF (see Section 6.1.1.)
All subjects who receive a dose of investigational product will be evaluated for safety testing. 
Safety outcomes include adverse events (AEs), clinically significant changes in vital signs, 
laboratory test abnormalities, and clinical tolerability of the investigational product. The 
Investigator will determine the severity of each adverse event as mild, moderate, severe, or very 
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severe. Laboratory findings which the investigator feels are clinically relevant should be 
recorded as adverse events. In addition, the investigator will determine the relationship of the AE
to the administration of the investigational product.
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
5.3.2
Tuberculosis Screening
Detailed medical and social history should be obtained to assess subject’s risk for tuberculosis. 
Chest x-ray, physical examination, and medical history should be used to assess for active 
tuberculosis (TB). 
Acceptable methods of testing for active or latent tuberculosis include tuberculin skin testing or 
Interferon release assays such as ELISpot or QuantiFERON® testing for tuberculosis. A 
tuberculin skin test will be performed and interpreted according to local country health 
authorities and/or medical society guidelines (ie, that provide recommendations for tuberculin 
skin testing for subjects who are to receive biologics, who are immunosuppressed, who have a 
prior history of BCG vaccination, or have a prior positive test).17,18,19,20,21
Tuberculin skin 
testing and interferon release assays are not contraindicated for persons who have been 
vaccinated with BCG. 
After tuberculin skin testing is performed at screening, the 48 to 72 hour reading must be 
completed prior to administration of study drug. Negative test results for Interferon release 
assays should also be confirmed prior to administration of study drug.
If Interferon release assay results are indeterminate, one of two options for tuberculosis testing 
should be performed as follows: 1) The Interferon release assay test should be repeated. The 
second Interferon release assay result will replace the first test result. 2) Tuberculin skin testing 
should be performed as an alternative method of screening. If the second Interferon release assay 
test result is also indeterminate, tuberculin skin testing should be performed and the subject 
should not be enrolled into the study until a negative tuberculin skin test is documented.
5.3.3
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be recorded at the times noted in the Time and Events 
Table 5.1-1 and Table 5.1-2)
5.3.4
Physical Examination
A complete medical history will be obtained at the screening visit.
Complete and/or interim physical examinations may be performed by a Doctor of Medicine 
(MD), Doctor of Osteopathy (DO), Physician’s Assistant (PA), or Nurse Practitioner (NP). 
While the interim physical examination may not be as comprehensive as the initial full 
examination, key aspects of the interim examination should evaluate important body systems as 
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clinically indicated. These body systems include at a minimum, the heart, lungs, abdomen, and 
skin. Evaluation of lymph nodes, liver, spleen, breast and other body systems is at the discretion 
of the examiner. An interim physical examination may note any changes in the subject’s 
condition (body systems) since the last assessment and does not preclude examination of any of 
the body systems as clinically indicated.
Every effort should be made to ensure the same evaluator will complete the physical examination 
for each subject at specified visits throughout the study. Documentation of who performed the 
examination is to be recorded in source notes.
5.3.5
Laboratory Test Assessments
A central/local laboratory will perform the analyses and will provide reference ranges for these 
tests.
Detailed instructions on the collection, processing, and shipping of all blood and urine samples 
will be provided to the investigator in a separate manual at or before the time of study initiation.
The following clinical laboratory tests will be performed:
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN)
Uric acid
Fasting glucose (for screening, PI discretion if 
fasting is needed. For double-blinded period, 
fasting is required)
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatine kinase
Liver function testing
Lipid Panel (includes fasting lipids)
ESR (local lab)
hsCRP
Urinalysis
Protein
Glucose
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Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive 
on the dipstick
Serology
Serum for hepatitis C antibody, hepatitis B surface antigen, hepatitis B core antibody, 
hepatitis B surface antibody
Auto-immune serology: ANA, Anti-Ro, Anti-La, Anti CCP2, Rheumatoid Factor
Immunoglobulin levels: IgM, IgA and IgG.
HIV testing (investigator discretion; local lab)
Other Analyses
Pregnancy test (WOCBP only: screening, predose, discharge).
Follicle stimulating hormone (FSH) (screening only for women only) 
Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
on the laboratory pages of the CRF or by another mechanism as agreed upon between the 
investigator and BMS (eg, provided electronically). If the units of a test result differ from those 
printed on the CRF, the recorded laboratory values must specify the correct units. Any abnormal 
laboratory test result considered clinically significant by the investigator must be recorded on the 
appropriate AE page of the CRF (see Section 6.1.1).
5.4
Efficacy Assessments
Efficacy assessments are described in the following sections. See Appendix 3 for detailed 
definitions.
5.4.1
Primary Efficacy Assessment

ACR20 response rate at Week 12 

ACR70 response rate at Week 12
5.4.2
Secondary Efficacy Assessments

Signs and Symptoms: ACR20/ACR50/70 over time 

Remission and change from baseline:  DAS28-CRP, DAS-ESR, SDAI, CDAI, 
Boolean over time

PK:  predose concentration (Ctrough) of BMS-986142 at time-points specified in 
Table 5.5.1-1

MRI assessment of change from baseline in synovitis, osteitis (bone marrow edema), 
bone erosion and cartilage loss (joint space narrowing) in hands/wrists at timepoints 
specified in Table 5.1-2
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5.4.4
Imaging Assessments
Any incidental findings of potential clinical relevance on chest x-ray or any additional imaging 
performed that are not directly associated with the objectives of the protocol should be evaluated 
and handled by the Study Investigator as per standard medical/clinical judgment. Images will be 
submitted to imaging core lab for central analysis. Assessment of hand and wrist MRI by 
Investigator is not expected.
5.4.4.1
MRI Assessment
MRI scanners used in the study must be deemed qualified by BMS/assigned Imaging Core Lab 
prior to subject scans. The hand/wrist that is clinically most swollen at Screening Visit will be 
imaged using a whole body MRI system. Of note, the Screening Visit MRI is considered the 
baseline MRI assessment for this study. The SAME hand/wrist that was imaged at Screening will 
be imaged at Week 4, and Week 12 on the SAME MRI scanner as was used at screening. The 
Screening Visit MRI is to be performed approximately 14 days prior to randomization. Week 4 
and Week 12 MRIs are to be performed ± 7 days of the scheduled Week 4 visit and Week 12 
visit, respectively. Subjects who terminate the study early require an MRI at the early 
termination (ET) visit only if ET < 4 weeks or > 8 weeks from date of randomization and 
should have their early termination (ET) MRI NO MORE than 7 days from their Early 
Termination (ET) Visit.  
Sites should schedule two MRI appointments with radiology department 7 days apart in the event 
that a MRI exam needs to be repeated due to technical difficulties. Technical issues with MRI 
identified at the investigator site or Imaging Core Lab should be re-imaged within 7 days of 
notification.
Subjects with severe renal insufficiency (ie, estimated glomerular filtration rate (eGFR) or GFR 
< 30 mL/min/1.73m2), will be excluded from the study, as they are at increased risk of 
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Nephrogenic Systemic Fibrosis, a rare, but serious, condition associated with the use of 
gadolinium-based MRI contrast agents.
Synovitis, osteitis (bone marrow edema), bone erosion and cartilage loss (joint-space narrowing) 
will be scored according to the OMERACT RAMRIS22. Change at follow-up from baseline in 
each RAMRIS score will be calculated. Scoring will be performed centrally by 2 independent, 
experienced readers who will be blinded to clinical details, radiographic findings, treatment arm 
and MRI sequence (Screening, Week 4, Week 12, and/or ET, if applicable).
Additional information is provided in a separate MRI imaging manual.
5.4.5
Clinical Assessor Requirements
The Physicians Global Assessment of Disease Activity (PGA) can be performed by the 
investigator or sub-investigator. The sub-investigator may be a Doctor of Medicine (MD) or 
Doctor of Osteopathy (DO), Physicians Assistant (PA) or Nurse Practitioner (NP).
If possible, the Joint Count Assessor should not perform the PGA for the same subject and will 
be blinded to all other assessments for that subject (eg, safety evaluation, laboratory test 
assessments etc). If possible, the PGA assessor should not perform the Joint Count Assessments 
for the same subject. For both assessments: 1) Every effort should be made to ensure the same 
assessor is used for a given subject throughout the study and 2) The clinical assessor cannot be 
unblinded to study medication assignment for the subject. - AUDIT
Visits should be scheduled with the availability of the assessor taken into account. If the assessor 
is unable to complete the evaluation, then another qualified individual can take the place of the 
initial evaluator, as long as the restrictions, described above, are still met and all efforts are made 
to assure consistency between subject evaluations. 
Training and instruction on joint count assessments will be discussed at the Investigator’s 
Meeting or at workshops.
5.5
Pharmacokinetic Assessments
Pharmacokinetics of BMS-986142 will be derived from plasma concentration versus time data. 
The pharmacokinetic parameters to be assessed include:

Ctrough Predose (Trough): observed plasma concentration at time-points specified in 
Table 5.5.1-1
Individual subject pharmacokinetic parameter values will be derived. 
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5.5.1
Pharmacokinetics:  Collection and Processing
Table 5.5.1-1 lists the sampling schedule to be followed for the assessment of pharmacokinetics. 
Further details of blood collection and processing will be provided to the site in the procedure 
manual.
Table 5.5.1-1:
Pharmacokinetic Sampling Schedule for BMS-986142a
Study Week (Day)
Event
Timeb
(Relative To BMS-
986142 Dose
Hour: Min
BMS-986142
Blood Sample for Plasma
Week 1 (Day 1)
02:00
X
04:00
X
06:00
X
Week 2 (Day 15)
predose
00:00
X
01:00
X
03:00
X
06:00
X
Week 4
predose
00:00
X
Week 8
predose
00:00
X
Week 12
predose
00:00
X
AEa
AE
X
a For subjects who discontinue due to an adverse event, the listed sample can be taken at the discretion of the 
Investigator.
b Targeted time listed, actual time needs to be recorded in CRF
5.5.2
Pharmacokinetic Sample Analyses
The plasma samples will be analyzed for BMS-986142 by a validated LC-MS/MS assay. 
Pharmacokinetic samples collected from a subject who received placebo will not be analyzed.
In addition, plasma samples will be archived for potential metabolite analysis, if the need arises 
and to the extent possible.
5.5.3
Labeling and Shipping of Biological Samples
Detailed instructions for the pharmacokinetic blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the procedure manual.
 
 
 
 
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5.8
Outcomes Research Assessments 
Questionnaires and investigator/subject assessments will be completed, prior to study drug 
administration, on an electronic tablet (ePRO) and information gathered on this device will serve 
as the source document where possible. 
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The following assessments will be performed: 
a) ACR Physician’s Global Assessment of Disease Activity VAS:  See Appendix 4
b) ACR Subject Assessment of Physical Function Scale (HAQ): The Health Assessment 
Questionnaire (HAQ), published in 1980, is one of the most widely used, 
comprehensive, validated, patient-oriented outcome assessment instruments available. 
HAQ disability index takes into account the subject’s use of aids, devices, or 
assistance in the scoring algorithm for a disability category. See Appendix 5.
c) ACR Subject Assessment of Disease Activity VAS: Global disease assessment of 
disease activity by patients measured on 10 cm VAS. See Appendix 6
d) ACR Subject Assessment of Pain VAS:  Pain reported by subjects, measured on 10 
cm VAS. See Appendix 7.
e) Joint Count Assessment Components for DAS28-CRP (Right and Left side). Disease 
Activity Score. See Appendix 8. 
f)
Fatigue VAS is a brief, valid measure for monitoring fatigue an important symptom 
in RA and its effects on patients with RA. See Appendix 9
g) Stiffness related questions are a valid measure for monitoring stiffness, an important 
symptom in RA, and its effects on patients with RA. Questions about stiffness will be
asked of each subject and recorded in the CRF.
h) SF-36:  Short Form-36. Questionnaire on health assessment. See Appendix 10.
i)
Bristol Rheumatoid Arthritis Multidimensional Questionnaire (BRAF-MDQ):  
Fatigue assessment.  See Appendix 11.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
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Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
Sponsor or designate will be reporting adverse events to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations 21 CFR Parts 312 and 320.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are not 
limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.)
Potential drug induced liver injury (DILI) is also considered an important medical 
event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.4
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure
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
routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to sponsor
or designate within 24 hours of awareness of the event. SAEs must be recorded on the SAE 
Report Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The 
preferred method for SAE data reporting collection is through the eCRF.  The paper 
SAE/pregnancy surveillance forms are only intended as a back-up option when the eCRF system 
is not functioning.  In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting.  In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately.  When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
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If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to sponsor or 
designate using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
BMS will be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious Adverse 
Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an 
SAE 

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific 
corrective therapy.
All significant drug-related laboratory abnormalities must be followed to resolution or 
stabilization. 
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
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6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5
half lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
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6.7
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
A Data Monitoring Committee (DMC) will monitor overall efficacy and safety data regularly to 
ensure that the benefits and risks of study participation remain acceptable. Based on the regular 
reviews of emerging data, the DMC may recommend to the Sponsor alteration and/or 
termination of the trial or a treatment group, or cessation of further enrollment into a treatment 
group.
Data summaries and listings will be provided to the DMC to facilitate their safety assessment at 
the regularly scheduled times as well as on an ad hoc basis if needed. The DMC will review 
safety data including serious adverse events and events of special interest, focusing on early 
signal detection. Further details on the frequency, content and methods of data reports to the 
DMC will be outlined in the Charter of that Committee along with the processes and procedures 
the committee will follow.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The sample size calculation is driven by the power to compare the proportion of subjects who 
achieve ACR70 response at Week 12 between each BMS-986142 dose arm and placebo arm. 
The target population consists of mixed subjects who are MTX-IR (70%) and TNF-IR
(30%). For co-primary endpoint of ACR70 at Week 12, 82 subjects per arm will provide ~
90% power to detect a treatment difference of 17% at the type I error rate of α = 0.05 (two-
sided), assuming the placebo response rate of 2.5%. The assumed treatment difference of 17% is 
about double of median difference observed from historical data on approved drugs across 
different mechanism of actions (MOAs).
If the placebo response rate in ACR70 at Week 12 is higher than planned 2.5% (eg, 5%), 
82 subjects per arm can still provide 84% power to detect a difference of 17%. 
For the population of MTX-IR (70%), 57 subjects per arm will provide 78% power to detect a 
treatment difference of 18% in ACR70 at the Type 1 error rate of α = 0.05 (two-sided), assuming 
the placebo response rate is 2.5%.
For the other co-primary endpoint of ACR20 at Week 12, 82 subjects per arm will provide 
>99% power to detect a difference of 34% over placebo at the type I error rate of α = 0.05 (two-
sided), assuming placebo response rate of 33%. The assumed treatment difference of 34% and 
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placebo response rate of 33% were based on the observed data from approved drugs across 
different MOAs.
For the population of MTX-IR (70%), 57 subjects per arm will provide 95% power to detect a 
treatment difference of 35% in ACR20 at the Type 1 error rate of α = 0.05 (two-sided), assuming 
the placebo response rate is 40%.
An interim analysis (IA) will be conducted when about 20 subjects reach week 4 (complete 4 
weeks of treatment or discontinue). Based on the totality of efficacy, safety, and PK at Week 4 
IA, the following adaptation(s) may be recommended:

Stop inefficacious or unsafe dose(s)

Introduce new dose(s) arms if needed and enroll (up to about 82 subjects per arm)

Complete full enrolment for all efficacious arms (up to about 82 subjects per arm)

Stop the study enrollment if all dose arms are stopped for safety or futility;
The total sample size varies depending on the interim analysis results (range from 328 to 408 
subjects). The details of interim analysis and the criteria to adapt dose arm(s) and stop for futility 
are specified in the Section 8.5.
8.2
Populations for Analyses

All Enrolled Subjects, defined as all subjects who sign an informed consent;

All Randomized Subjects, defined as all subjects who are randomized to a treatment; 

All Randomized and Treated Subjects, defined as modified intent-to-treat (mITT) 
subjects who are randomized and receive at least one dose of study medication;

All Treated Subjects, defined as all subjects who receive at least one dose of study 
treatment;

 
 

Pharmacokinetic Population, defined as all subjects who receive any study medication 
and have any available concentration-time data. 
All subjects who receive at least one dose of study treatment (all treated subjects) will be 
included in the safety analysis population and mITT subjects will be included in the efficacy 
analysis population. More details will be provided in the statistical analysis plan. 
8.3
Endpoints
8.3.1
Primary Endpoint(s) 
Co-Primary endpoints:

Proportion of subjects who achieve ACR70 response rate at Week 12  
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
Proportion of subjects who achieve ACR20 response rate at Week 12
8.3.2
Secondary Endpoint(s) 
8.3.2.1
Efficacy Endpoints 

Proportion of subjects who achieve ACR20 over time from baseline to Week 12

Proportion of subjects who achieve ACR50 over time from baseline to Week 12

Proportion of subjects who achieve ACR70 over time from baseline to Week 12

Proportion of subjects who achieve DAS28-CRP < 2.6 over time from baseline to 
Week 12

Proportion of subjects who achieve DAS28-ESR < 2.6 over time from baseline to 
Week 12

Proportion of subjects who achieve CDAI 2.8 over time from baseline to Week 12

Proportion of subjects who achieve SDAI 3.3 over time from baseline to Week 12

Proportion of subjects who achieve Boolean Remission over time from baseline to 
Week 12

Change from baseline in DAS28-CRP score over time up to Week 12

Change from baseline in DAS28-ESR score over time up to Week 12

Change from baseline in CDAI score over time up to Week 12

Change from baseline in SDAI score over time up to Week 12

Change from baseline in RAMRIS scores of synovitis, osteitis (bone marrow edema), 
bone erosion and cartilage loss (joint-space narrowing) (MRI) to Week 4, and 
Week 12
8.3.2.2
Safety Endpoints 

Incidence and severity of all Adverse Events (AEs), Serious AEs, and pre-established 
Events of Special Interest

Incidence and severity of clinically significant changes in vital signs

Incidence and severity of clinically significant electrocardiogram (ECG) abnormalities

Incidence and severity of clinically significant abnormalities in general laboratory tests
8.3.2.3
Pharmacokinetic Endpoints
Ctrough: Predose (Trough) level plasma concentration of BMS-986142 at time points specified 
in Section 5.5.1.
 
 
 
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized descriptively by means and 
standard deviation for continuous variables, and frequency distribution for categorical variables. 
Summary will be performed on mITT analysis population.
8.4.2
Efficacy Analyses
Primary efficacy analysis:
The Chi-square tests will be used to compare the ACR70 response rates at Week 12 between 
each of the active treatment arms and the placebo arm. The p-value will be provided for each 
comparison between the active treatment and the placebo arm. In addition, the difference of the 
response rates between each active treatment and the placebo will be estimated and their 
corresponding 95% confidence interval will be calculated.
All subjects discontinuing prematurely during the double-blind period, regardless of reason, will 
be counted as non-responders at subsequent visits. Summaries will be performed using mITT 
analysis population. The same analysis will be performed for ACR20 response at Week 12.
Secondary efficacy analysis: 

Proportion of subjects who achieve ACR20 over time from baseline to Week 12

Proportion of subjects who achieve ACR50 over time from baseline to Week 12

Proportion of subjects who achieve ACR70 over time from baseline to Week 12

Proportion of subjects who achieve DAS28-CRP < 2.6 over time from baseline to 
Week 12

Proportion of subjects who achieve DAS28-ESR < 2.6 over time from baseline to 
Week 12

Proportion of subjects who achieve CDAI 2.8 over time from baseline to Week 12

Proportion of subjects who achieve SDAI 3.3 over time from baseline to Week 12

Proportion of subjects who achieve Boolean Remission over time from baseline to 
Week 12
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For each of the above endpoints, the estimate and its corresponding 95% confidence interval will 
be calculated for the difference of the proportions between each active treatment arm and the 
placebo arm at the specified visit, similar to the primary analysis.
For each of the following endpoints, the mixed effect model will be fit with treatment and visit as 
the fixed effects and measurements within each subject as the repeated measurements. The 
baseline value will be added into the model as a covariate if necessary. Based on the mixed effect 
model, the estimate and 95% confidence interval will be calculated for the difference between 
each active treatment and the placebo at each specified visit:

Change from baseline in DAS28-CRP score over time up to Week 12

Change from baseline in DAS28-ESR score over time up to Week 12

Change from baseline in CDAI score over time up to Week 12

Change from baseline in SDAI score over time up to Week 12

Change from baseline in RAMRIS Scores of  synovitis, osteitis, bone erosion and 
cartilage loss to Week 4 and Week 12 
The details of the analyses, endpoints and grouping schemes (treatment groups) will be provided 
in the statistical analysis plan (SAP).
8.4.3
Safety Analyses
All recorded adverse events will be listed and tabulated by system organ class, preferred term 
and treatment. Vital signs and clinical laboratory test results will be listed and summarized by 
treatment. Any significant physical examination findings, and clinical laboratory results will be 
listed. ECG readings will be evaluated by the investigator and abnormalities, if present, will be 
listed. The pre-established Events of Special Interest will be listed and summarized. The safety 
summaries will be performed using all treated subjects.
8.4.4
Pharmacokinetic Analyses
Ctrough values will be descriptively summarized by treatment and study days.
Preliminary population PK and dose/exposure-response (ie, DAS28-CRP and selected safety 
endpoints) analysis will be conducted at the time when Week 4 interim analysis is conducted. 
Once study is completed, the concentration vs. time data combined with PK data from additional 
studies will be used to further develop a population PK model. This model will be used to 
evaluate the effects of various covariates on the PK of BMS-986142. 
 
 
 
 
 
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8.4.6
Outcomes Research Analyses
The descriptive summary of baseline and change from baseline over time will be performed for 
BRAF-MDQ, Fatigue VAS and Stiffness VAS scores will be performed by treatment and visit. 
8.4.7
Other Analyses 
Not applicable
8.5
Interim Analyses
After about 20 subjects per treatment arm have completed at least 4 weeks of the treatment 
period or discontinued the treatment, an interim analysis will be conducted to assess the efficacy 
of the BMS-986142 dose arms and the overall safety. The interim analysis will use pre-specified 
efficacy, safety and PK endpoints. The results of the interim analysis will be reviewed by an 
unblinded sponsor team who is not involved in the study conduct and who will provide 
recommendations with regard to the adaptive design decisions to the blinded study team. 
Efficacy analysis (DAS28) using Bayesian modeling and dose/exposure response analysis:
The interim analysis will be performed on all available data of DAS28 change from baseline up 
to Week 12 using a Bayesian predictive approach.23 This analysis assumes that the DAS28 at 
Week 4 and at Week 12 in the subjects who have not yet been observed will be similar to what 
was observed for the subjects included at Week 4 and Week 12, respectively. As such the 
unobserved data will be simulated from the predictive distribution conditional on the interim data 
and the prior distribution of the treatment difference (using a non-informative prior). Under the 
Bayesian framework, the posterior distribution of the treatment difference (BMS-986142 active 
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dose – Placebo) will be constructed to determine the predictive probability of ΔΔDAS28 
improvement greater than a cutoff value at the planned end of the trial for each dose arm. 
Note: ΔΔDAS28 improvement: The difference of change from baseline in DAS28-CRP between 
active dose arm and placebo arm. The lower is DAS28 score, the better is the disease status.
The Bayesian predicative analysis and the dose/exposure response analysis will be used to 
facilitate decision-making if new BMS-986142 dose(s) will be needed to fully characterize dose-
efficacy relationship. Pre-specified efficacy endpoint (DAS28) will be assessed with exposure 
endpoints to guide the selection of new dose levels in different scenarios as described below.
Considering the safety margin estimated from non-clinical studies, new dose levels based on the 
interim analysis will not be greater than 350 mg/day.
If the predictive probability of ΔΔDAS28 improvement being greater than 1.0 is high (eg, 
> 80%) in all active arm(s), the BMS team may recommend to maintain the study design and 
treatment arms. In this scenario, all enrolled subjects will continue the treatments without 
modifications and also be included in the final analysis for the existing dose arm. The BMS team 
may also recommend adding an additional dose arm at lower dose level than current active doses 
to explore the suboptimal dose.  In this case, approximately 40 subjects will be randomized into 
the suboptimal dose arm along with existing efficacious dose arms. The new suboptimal dose 
level may be selected based on dose/exposure response analysis.
If the predictive probability of ΔΔDAS28 improvement being greater than 1.0 is high (eg, >80%) 
in 2 BMS-986142 arms (mid and high dose arms), then the BMS team may recommend to 
maintain the study design and these 2 treatment arms. The enrolled subjects will be carried over 
in the existing dose arm and also be included in the final analysis for the existing dose arm. The 
subjects enrolled in the low dose arm will continue the treatment if they have received at least 1 
treatment and treatment is considered safe before the interim analysis is completed. The decision 
to continue enrolling subjects into this treatment arm will depend on the collective assessment of 
the efficacy endpoints (beyond DAS28) and safety data. Even if the relationship between 
dose/exposure and response is adequately characterized from the interim analysis, a lower, sub-
optimal dose (approximately 40 subjects) may be added if further subgroup analysis and 
collective data suggest a distinct trend in each subgroup.
If the predictive probability of ΔΔDAS28 improvement being greater than 1.0 is high (eg, 
> 80%) in 1 BMS-986142 arm (high dose arm), then the BMS team may recommend to maintain 
the study design and this treatment arm. The enrolled subjects will be carried over in the existing 
dose arm and also be included in the final analysis for the existing dose arm. The subjects 
enrolled in the low and mid dose arms will continue the treatment if they have received at least 1 
treatment and treatment is safe before the interim analysis is completed. The decision to continue 
enrolling subjects into these two treatment arms will depend on the collective assessment of the 
efficacy endpoints (beyond DAS28) and safety data. Even if the relationship between 
dose/exposure and response is adequately characterized from the interim analysis, a lower, sub-
optimal dose (approximately 40 subjects) may be added if further subgroup analysis and 
collective data suggest a distinct trend in each subgroup.
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If the predictive probability of ΔΔDAS28 improvement being greater than 0.6 is low (eg, 
< 20%), that dose arm is deemed futile in terms of DAS28CRP change from baseline. However, 
the final futility will also incorporate the results from other efficacy endpoints as defined below.
The proposed stopping rules at the interim analysis, based on the futility assessment and the 
overall safety assessment, are as follows:

Rule 1: If safety issues are identified in all dose arms or all dose arms are futile, stop the 
study

Rule 2: Drop the dose arm(s) with safety issues identified

Rule 3: Drop the futile dose arm(s) and the dose arm cannot be dropped until the lower 
dose arm has been dropped.
If the predictive probability of ΔΔDAS28 improvement being greater than 0.6 is lower than 20% 
in all active treatment arms, BMS team may recommend stopping enrollment and continuing the 
study up to 12 weeks.
Descriptive efficacy analysis (other efficacy endpoints):
In addition to Bayesian predictive analysis above, the following clinical data will be summarized 
at the time of Week 4 interim analysis to facilitate decision-making. 

ACR20/50/70 response over time

DAS28-CRP < 2.6, DAS28-ESR < 2.6, CDAI 2.8, SDAI 3.3 and Boolean remission 
over time

Change from baseline in DAS28-CRP, DAS28-ESR, CDAI, SDAI over time.

Subgroup analysis of above endpoints by region where applicable (e.g., if any region 
consists of more than 50% of total subjects and region is classified by North America, 
Latin America, Europe and Rest of World. One or more regions may be combined for 
analysis if only limited data in individual region is available).
Descriptive safety analysis:
For the following pre-specified safety endpoints:

AE/SAE (including but not limited to hypertension, diarrhea, neutropenia)

Change from baseline in vitals including systolic blood pressure (SBP) and diastolic 
blood pressure (DBP).
The study will be stopped if intolerable safety events are identified in all treatment arms. If 
intolerable safety events are identified in 1 or 2 treatment arms, these arms will be dropped and 
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the study will be continued with caution. New dose levels may be added based on the exposure 
response analysis (not greater than 350 mg daily).If intolerable safety events show a clear 
relationship with higher exposure of BMS-986142, a lower dose will be selected where the 
predicted exposure in ~ 90% of subjects does not exceed the exposure ranges associated with 
safety findings.
Based on the totality of safety and efficacy considerations, ineffective doses will be stopped at 
Week 12 and unsafe dose will be stopped immediately.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations.
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
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that the facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the 
source documents:  This includes the joint count, the subject’s assessment of Pain, the subject’s 
Global Assessment of Disease Activity, the Physician Global Assessment of Disease Activity, 
the Subject’s Assessment of Physical function (HAQ-DI), the Fatigue Scale (VAS), Stiffness 
information, the SF-36, and the Bristol Rheumatoid Arthritis Multidimensional Questionnaire 
(BRAF-MDQ). See Appendices 4-11.
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
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If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product
(those supplied by BMS). Records or logs must comply with applicable regulations and 
guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable 

dates 
and 
initials 
of 
person 
responsible 
for 
Investigational 
Product 
dispensing/accountability, as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
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The investigator will maintain a signature sheet to document signatures and initials of all persons
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:

National Coordinating Investigator 

Subject recruitment (eg, among the top quartile of enrollers)

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study must adhere to the publication requirements set forth in the 
clinical trial agreement (CTA) governing [Study site or Investigator] participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to BMS at 
the earliest practicable time prior to submission or presentation and otherwise within the time 
period set forth in the CTA.
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GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete 
Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have 
pregnancy tests.  Acceptable alternate methods of highly 
effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete 
abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle 
of the patient. This does not mean periodic abstinence (eg, 
calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of 
contraception. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence
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LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
AST
aspartate aminotransferase
AT
aminotransaminases
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
CBC
complete blood count
CFR
Code of Federal Regulations 
CLcr
creatinine clearance
CLNR
nonrenal clearance
CLR
renal clearance
CLS
cardiac life support
cm
Centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
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Term
Definition
D/C
discontinue
dL
deciliter
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
ESR
Expedited Safety Report
F
Bioavailability
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
kg
kilogram
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Term
Definition
z
terminal disposition rate constant
L
liter
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for 
molecular weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for 
molecular weight
MR_AUC(TAU)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for 
molecular weight
MRI
magnetic resonance imaging 
MS
mass spectrometry
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
PD
pharmacodynamics
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PT
prothrombin time
PTT
partial thromboplastin time
QC
quality control
QD, qd
quaque die, once daily
RAMRIS
rheumatoid arthritis magnetic resonance imaging scoring
system
RBC
red blood cell
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Term
Definition
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF
Half life
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
TR_Cmax
Cmax treatment ratio
W
washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity
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SAP_001.pdf: 
Official Title of Study: 
PHASE 2, RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, DOSE-RANGING, 
PLACEBO-CONTROLLED, ADAPTIVE DESIGN STUDY TO EVALUATE THE 
EFFICACY AND SAFETY/PHARMACOKINETICS OF BMS-986142 IN SUBJECTS 
WITH MODERATE TO SEVERE RHEUMATOID ARTHRITIS WITH AN INADEQUATE 
RESPONSE TO METHOTREXATE WITH OR WITHOUT TNF INHIBITORS 
 
NCT Number: NCT02638948 
Document Date (Date in which document was last revised): December 4, 2015 


STATISTICAL ANALYSIS PLAN
FOR DOUBLE-BLIND PERIOD ANALYSES
PHASE 2, RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, DOSE-RANGING, 
PLACEBO-CONTROLLED, ADAPTIVE DESIGN STUDY TO EVALUATE THE 
EFFICACY AND SAFETY/PHARMACOKINETICS OF BMS-986142 IN SUBJECTS 
WITH MODERATE TO SEVERE RHEUMATOID ARTHRITIS WITH AN INADEQUATE 
RESPONSE TO METHOTREXATE WITH OR WITHOUT TNF INHIBITORS
PROTOCOL IM006016
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TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................2
LIST OF TABLES...........................................................................................................................4
LIST OF FIGURES .........................................................................................................................4
2
STUDY DESCRIPTION..............................................................................................6
2.1
Study Design.................................................................................................................6
2.2
Treatment Assignment..................................................................................................7
2.3
Blinding and Unblinding ..............................................................................................8
2.4
Protocol Amendments ..................................................................................................9
3
OBJECTIVES...............................................................................................................9
3.1
Primary Objective.........................................................................................................9
3.2
Secondary Objectives ...................................................................................................9
4
ENDPOINTS ..............................................................................................................10
4.1
Primary Efficacy Endpoint(s).....................................................................................10
4.2
Secondary  Efficacy Endpoint(s)................................................................................10
4.3
Safety Endpoints.........................................................................................................10
4.4
Pharmacokinetic Endpoints ........................................................................................10
5
SAMPLE SIZE AND POWER ..................................................................................11
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES.......................................................................................................12
6.1
Study Periods..............................................................................................................12
6.2
Treatment Regimens...................................................................................................12
6.3
Populations for Analyses ............................................................................................12
7
STATISTICAL ANALYSES.....................................................................................13
7.1
General Methods.........................................................................................................13
7.2
Study Conduct ............................................................................................................14
7.3
Study Population.........................................................................................................14
7.3.1
Subject Disposition.....................................................................................................14
7.3.2
Demography and Baseline Characteristics................................................................14
7.3.3
Medical History and Prior Medication ......................................................................15
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7.4
Extent of Exposure .....................................................................................................16
7.4.1
Study Therapy.............................................................................................................16
7.4.2
Discontinuations from Study Therapy ........................................................................16
7.4.3
Treatment Compliance................................................................................................16
7.4.4
Anti-rheumatic Medication.........................................................................................16
7.5
Efficacy.......................................................................................................................17
7.5.1
Primary Efficacy Endpoints in Double-blind Period .................................................17
7.5.2
Secondary Efficacy Endpoints in Double-blind Period..............................................17
7.5.2.1
Magnetic Resonance Imaging (MRI)..........................................................................18
7.5.3
Subgroup Analyses......................................................................................................19
7.5.4
Sensitivity Analyses.....................................................................................................20
7.5.5
Per-Protocol Analyses................................................................................................20
7.6
Safety..........................................................................................................................20
7.6.1
Adverse Events............................................................................................................21
7.6.2
Adverse Events of Interest ..........................................................................................22
7.6.3
Deaths.........................................................................................................................23
7.6.4
Other Serious Adverse Events ....................................................................................23
7.6.5
Adverse Events Leading to Discontinuation of Study Therapy ..................................23
7.6.6
Multiple Occurrences of Adverse Events....................................................................23
7.6.7
Summaries of Laboratory Data ..................................................................................23
7.6.8
Other Safety Considerations.......................................................................................24
7.6.8.1
ECG ............................................................................................................................24
7.6.8.2
Vital Sign ....................................................................................................................24
7.6.8.3
Physical Examination Findings..................................................................................25
7.7
Pharmacokinetic Analysis ..........................................................................................25
7.9
Interim Analyses.........................................................................................................25
8
CONVENTIONS........................................................................................................28
8.1
Calculations of Key Measures....................................................................................28
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8.1.1
Evaluation of ACR......................................................................................................28
8.1.2
Evaluation of DAS28-CRP and DAS28-ESR..............................................................29
8.1.3
Evaluation of CDAI ....................................................................................................29
8.1.4
Evaluation of SDAI and Boolean-based Remission....................................................30
8.1.5
Evaluation of HAQ Disability Index...........................................................................30
8.1.6
Evaluation of FACIT-Fatigue.....................................................................................30
8.1.7
Evaluation of BRAF-MDQ .........................................................................................31
8.1.8
Evaluation of SF-36 Summary Functions and Components.......................................32
8.2
Handling of Procedures, Conditions and Intra-articular Injections of Joints .............32
8.3
Determination of Responder Data ..............................................................................32
8.4
Baseline Measures ......................................................................................................33
8.5
Missing Measurements...............................................................................................33
8.5.1
Imputation of Missing Data for Binary Variables......................................................33
8.5.2
Imputation of Missing Data for Continuous Variables ..............................................33
8.6
Missing, Unknown or Partial Dates............................................................................33
8.7
Day Ranges for Analysis of Time Points ...................................................................33
9
CONTENT OF REPORTS.........................................................................................34
LIST OF TABLES
Table 1:
Planned Efficacy Analyses ........................................................................13
Table 2:
Subgroup Analyses Factors and Categories...............................................19
Table 3:
Vital sign parameter cut-off values............................................................24
Table 4:
Days Ranges for Assessments at Every Scheduled Visits During 
the Double-blind Period.............................................................................34
LIST OF FIGURES
Figure 1:
Study Design Schematic ..............................................................................7
Figure 2:
BRAF-MDQ Score table............................................................................31
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Research Hypothesis:  
At least one of the dose levels of BMS-986142 administered daily is more effective than placebo 
on a background of MTX in achieving ACR20 and ACR70 response after 12 weeks of treatment 
in subjects with moderately-to severely active RA with an inadequate response to MTX with or 
without TNF inhibitors.
Schedule of Analyses:
The following analyses will be performed:

An interim analysis will be performed for futility and dose adaptation after about 20 patients 
per treatment arm have completed at least 4 weeks of treatment period or discontinued the 
treatment;

The final analysis will be performed after the last treated subject in the study reaches Week 
12 in the double-blind (DB) period. 
2
STUDY DESCRIPTION
2.1
Study Design
This is a 12 week randomized, double-blind, placebo-controlled, dose-ranging study with 
adaptive design features based on an interim analysis.  The study will initially have a Screening 
Period (with 2 screening visits for subjects that require DMARD washout) and be followed by up 
to 12 weeks of DB treatment and a 30 day follow-up period.
Four treatments will be administered:  placebo, 100, 200, and 350 mg of BMS-986142 daily for 
12 weeks. Based on the Week 4 interim analysis, one or more BMS-986142 doses and/or sample 
size may be subsequently modified.
Screening Period:
The standard duration of the Screening Period is up to 30 days, with two Screening Visits 
allowed for subjects who require washout of hydroxychloroquine/chloroquine and/or 
sulfasalazine. Subjects who are on hydroxychloroquine/chloroquine and/or sulfasalazine in 
combination with MTX will have hydroxychloroquine/chloroquine and/or sulfasalazine 
discontinued at the beginning of the Screening Period as they need to be off  those medications 
for at least 30 days and need to be rescreened prior to randomization (Day 1). Should more time 
be needed, the duration of the Screening Period may be extended up to another week (total of 
five weeks) depending on current DMARDs washout, drug stabilization, MRI technical issues, 
and subject scheduling.
Subjects with moderate to severely active RA who have had an inadequate response to MTX or 
up to 2 TNF inhibitors will receive BMS-986142 or placebo daily for up to 12 weeks, followed 
by a 30 day follow-up period. 
Double-Blind Period:
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Upon meeting the inclusion criteria and none of the exclusion criteria and completing the 
screening period, approximately 328 subjects will be randomized to 1 of the 4 treatment arms in 
an equal ratio as shown in the study schematic below.
Figure 1:
Study Design Schematic
During this period, the dose of methotrexate, NSAIDs, and oral prednisone (or its equivalent) 
should remain stable.  Intra-articular corticosteroid injections and intra-muscular injections are 
not permitted.  Analgesics are permitted with certain restrictions (see Section 3.2).
At the end of the DB period, alternate therapies for RA should be discussed with subjects.
Interim Analyses:
Interim Analyses (IA) of clinical and PK data will be performed after approximately 20 subjects 
per treatment arm reach Week 4 (complete 4 weeks of treatment or discontinue) and complete 
the specified assessments for efficacy (e.g., DAS28-CRP), safety, and PK. Details of interim 
analyses are described in Section 7.9 (Interim analysis). 
2.2
Treatment Assignment
After completion of all screening evaluations, on Day 1, all eligible subjects will be randomly 
assigned to 1 of 4 treatment arms (BMS-986142, 100 mg; BMS-986142, 200 mg; BMS-986142, 
350 mg; and Placebo) in an equal ratio. To randomize a subject, a phone call will be placed into 
the randomization option of the interactive voice response system (IVRS) in order to obtain a 
subject’s randomized treatment assignment. Randomization will be assigned in the order in 
which subjects qualify for treatment, not in the order of study enrollment. The IVRS will be 
available 24-hours a day, 7 days a week, via a toll-free number. Randomization will be stratified 
by prior treatment status (MTX-IR vs TNF-IR) and geographic region. 
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Specific instructions (including an enrollment/randomization worksheet) for the central 
enrollment and randomization procedure using an IVRS will be provided to the site. 
Randomized schedules will be generated and kept by the Randomization Group within Drug 
Supply Management of Bristol-Myers Squibb. The randomization ratio may be adjusted if any 
dose arm will be discontinued and/or new dose arm will be added based on Week 4 interim 
analysis.
2.3
Blinding and Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject’s management, the blind for that subject may be 
broken by the investigator. The subject’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made.
For this study, the method of unblinding for emergency purposes is through the IVRS.
For information on how to unblind in case of an emergency, consult the IVRS manual
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor.
The Bioanalytical Sciences department or its designate will be unblinded to the randomized 
treatment assignments in order to minimize unnecessary analysis of samples from control group 
subjects.
To implement the adaptive design that is planned in advance, an interim analysis will be 
conducted prior to the formal locking of the study database. In order to allow for a high quality 
and/or validated data analysis and a timely analysis of data, the unblinded team may consist of 
up to two people from each relevant function role within BMS. 

Global Biometric Sciences - Up to 2 statisticians and 2 programmers 

Clinical Pharmacology and Pharmacometrics -
Up to 2 pharmacometric and 
pharmacokinetic scientists and 2 pharmacometric programmers 

Clinical Biomarkers - Up to 2 clinical biomarker scientists 
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
Bioinformatics -Up to 2 bioinformaticians
This configuration ensures that the unblinded team has the resources to independently conduct its 
own analyses. The study team does not have access to any unblinded data and is not involved in 
the review or discussion of unblinded data. 
2.4
Protocol Amendments
Not applicable.
3
OBJECTIVES
3.1
Primary Objective
To compare the efficacy of BMS-986142 versus placebo (PBO) on a background of MTX as 
assessed by ACR20 and ACR70 response rates at Week 12.
3.2
Secondary Objectives

Assess additional efficacy outcomes of BMS-986142 at Week 12 and over 12 weeks of 
treatment as measured by ACR20, ACR50 and ACR70 response rates, DAS28-CRP change 
from baseline, DAS28-ESR change from baseline, Clinical Disease Activity Index (CDAI), 
Simplified Disease Index (SDAI), and Boolean remission.

Assess the safety and tolerability of BMS-986142. 

Evaluate Ctrough of BMS-986142.

Assess the efficacy of BMS-986142 + MTX to MTX alone in reducing synovitis, osteitis, 
bone erosion and cartilage loss in hands/wrists by MRI at Weeks 4, and 12, from baseline.
 
 
 
 
 
 
 
 
 
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4
ENDPOINTS
4.1
Primary Efficacy Endpoint(s)
Co-Primary endpoints:

Proportion of subjects who achieve ACR20 response rate at Week 12  

Proportion of subjects who achieve ACR70 response rate at Week 12
4.2
Secondary  Efficacy Endpoint(s)

Proportion of subjects who achieve ACR20 over time from baseline to Week 12

Proportion of subjects who achieve ACR50 over time from baseline to Week 12

Proportion of subjects who achieve ACR70 over time from baseline to Week 12

Proportion of subjects who achieve DAS28-CRP < 2.6 over time from baseline to Week 12

Proportion of subjects who achieve DAS28-ESR < 2.6 over time from baseline to Week 12

Proportion of subjects who achieve CDAI ≤ 2.8 over time from baseline to Week 12

Proportion of subjects who achieve SDAI ≤ 3.3 over time from baseline to Week 12

Proportion of subjects who achieve Boolean Remission over time from baseline to Week 12

Change from baseline in DAS28-CRP score over time up to Week 12

Change from baseline in DAS28-ESR score over time up to Week 12

Change from baseline in CDAI score over time up to Week 12

Change from baseline in SDAI score over time up to Week 12

Change from baseline in RAMRIS scores of synovitis, osteitis (bone marrow edema), bone 
erosion and cartilage loss (joint-space narrowing) (MRI) to Week 4, and Week 12
4.3
Safety Endpoints

Incidence and severity of all Adverse Events (AEs), Serious AEs (SAE), and Events of 
Special Interest (EOSI)

Incidence and severity of clinically significant changes in vital signs

Incidence and severity of clinically significant electrocardiogram (ECG) abnormalities

Incidence and severity of clinically significant abnormalities in general laboratory tests
4.4
Pharmacokinetic Endpoints
Ctrough: Trough level plasma concentration of BMS-986142 at time points specified in Section
5.5 of the protocol.
 
 
 
 
 
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5
SAMPLE SIZE AND POWER
The sample size calculation is driven by the power to compare the proportion of subjects who 
achieve ACR70 response at Week 12 between each BMS-986142 dose arm and placebo arm 
without multiplicity adjustment. The target population consists of mixed subjects who are TNF-
IR (≥ 80%) and MTX-IR (≤ 20%). For co-primary endpoint of ACR70 at Week 12, 82 subjects 
per arm will provide ~80% power to detect a treatment difference of 14% at the type I error rate 
of α = 0.05 (two-sided), assuming the placebo response rate of 2.5%. The assumed treatment 
difference of 14% is double of 7% that was median difference observed from historical data on 
approved drugs across different mechanism of actions (MOAs).
If the placebo response rate in ACR70 at Week 12 is higher than planned 2.5% (eg, 5%), 82 
subjects per arm can still provide > 70% power to detect a difference of 14%. 
For the population of TNF-IR ( ≥ 80%), 65 subjects per arm will provide 68% power to detect a 
treatment difference of 14% in ACR70 at the Type 1 error rate of α = 0.05 (two-sided), assuming 
the placebo response rate is 2.5%.
For the other co-primary endpoint of ACR20 at Week 12, 82 subjects per arm will provide 98% 
power to detect a difference of 31% over placebo at the type I error rate of α = 0.05 (two-sided), 
assuming placebo response rate of 22%. The assumed treatment difference of 31% and placebo 
response rate of 22% were based on the observed data from approved drugs across different 
MOAs.
For the population of TNF-IR (≥ 80%), 65 subjects per arm will provide 94% power to detect a 
treatment difference of 30% in ACR20 at the Type 1 error rate of α = 0.05 (two-sided), assuming 
the placebo response rate is 18%.
An interim analysis (IA) will be conducted when about 20 subjects reach week 4 (complete 4 
weeks of treatment or discontinue). Based on the totality of efficacy, safety, and PK at Week 4 
IA, the following adaptation(s) may be recommended:

Stop inefficacious or unsafe dose(s)

Introduce new dose(s) arms if needed and enroll (up to about 82 subjects per arm)

Complete full enrolment for all efficacious arms (up to about 82 subjects per arm)
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
Stop the study enrollment if all dose arms are stopped for safety or futility;
The total sample size varies depending on the interim analysis results (range from 328 to 408 
subjects). The details of interim analysis and the criteria to adapt dose arm(s) and stop for futility 
are specified in the section 7.9.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
The following periods are defined in this SAP for the purpose of analyses and reporting.
Pre-treatment period: It covers the time period which starts from the day of enrollment and 
lasts until the initiation of randomized double-blind treatment 
Double-blind (DB) period: It starts at the time of the first dose of blinded treatment (BMS-
986142 or placebo) and lasts until the date of the last dose of double-blinded treatment + 30 days
or the start of first dose in long-term extension period.
6.2
Treatment Regimens
The eligible subjects will be randomized to receive BMS-986142 (100mg, 200mg and 350mg) or 
Placebo daily (double-dummy) at equal ratio. There may be an instance of new treatment 
group(s) added and one or more treatment arms (other than Placebo) may be dropped based on 
interim analysis. For more details, see study design in the Protocol.
6.3
Populations for Analyses

All Enrolled Subjects: All subjects who sign an informed consent.

All Randomized Subjects: All subjects who are randomized to a treatment.

Modified Intent-to-Treat (MITT) Analysis Population: All randomized subject who have 
received at least one dose of the study medication. Subjects will be grouped according to the 
treatment to which they were randomized by IVRS at the start of the study. The MITT 
analysis population will also be referred to as “All Randomized and Treated Subjects”.

As-Treated Analysis Population: All Subjects who have received at least one dose of study 
medication. Subjects will be grouped according to the treatment that they actually received as 
opposed to the treatment to which they were randomized. Subjects will be grouped on an as 
randomized basis unless the subject received the incorrect medication for the entire period of 
treatment. In that case, the subject will be analyzed in the treatment group associated with the 
incorrect medication he/she received.

Efficacy Analysis Population: This is a subset of the MITT Analysis Population where the 
subjects who are randomized to a treatment arm and discontinued based on the interim
analysis are excluded. All efficacy results involve statistical comparison or modeling will be 
based on this analysis population unless otherwise specified.

 
 

Pharmacokinetic Population: All subjects who have received BMS-986142 and have any 
available concentration-time data. 
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7
STATISTICAL ANALYSES
7.1
General Methods
The table below provides an overview of the efficacy analyses to be performed.  
Table 1:
Planned Efficacy Analyses
Measure of Interest (Primary 
and Secondary Efficacy 
Endpoints):
Analysis Method
Co-primary endpoints: ACR20 and 
70 response rate at Day 85
Binary endpoints :  ACR20, 
ACR50 and ACR70 response rate 
over time from baseline to Day 85;
DAS28-CRP<2.6, DAS28-
ESR<2.6, CDAI<=2.8, SDAI<=3.3 
and Boolean remission over time 
from baseline to Day 85
Chi-Square test, two sided p-value will be provided. Point estimates and 
95% CI of treatment difference.
Point estimate and 95% CI of response rate, point estimates and 95% CI 
of treatment difference.
Continuous endpoints: DAS28-
CRP, DAS28-ESR, CDAI, SDAI, 
MRI scores (synovitis, 
osteitis,bone erosion and cartilage 
loss)
Mixed model analysis, point estimates and 95% CI for mean change from 
baseline within treatment groups, point estimates and 95% CI for mean 
change from baseline between treatment groups.
The Chi-square tests will be used to compare the ACR20 and ACR70 response rates at Day 85
between each of the active treatment arms and the placebo arm. The Chi-square p-value will be 
provided for each comparison between the active treatment and the placebo arm. Within each 
treatment group, the statistical testing will be performed for ACR20 at level of 0.05 first. If it is 
statistically significant, then the statistical testing will be performed for ACR70. Otherwise, 
testing will be stopped for this treatment group. All treatment groups will follow the same testing 
procedure. In addition, the difference of the response rates between each active treatment and the 
placebo will be estimated and their corresponding 95% confidence interval will be calculated. 
All subjects who discontinue prematurely during the treatment period or receive prohibited 
medications (refer to Section 8.3) will be counted as non-responder at subsequent visits.
For each of the binary endpoints, the estimate and its corresponding 95% confidence interval will 
be calculated for the difference of the proportions between each active treatment arm and the 
placebo arm at the specified visit, similar to the primary analysis except no p-values will be 
provided.
The construction of confidence intervals for binary variables will be based on normal 
approximation, if the number of the events in each individual treatment arm is at least 5. 
Otherwise, confidence interval using an exact method will be provided. The exact confidence 
intervals for binary variable within treatment group and between treatment groups will be 
constructed.
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For each of the continuous endpoints, the mixed effect model will be fit with treatment and visit 
as the fixed effects and measurements within each subject as the repeated measurements. The 
baseline value will be added into the model as a covariate if necessary. Based on the mixed effect 
model, the estimate and 95% confidence interval will be calculated for the difference between 
each active treatment and the placebo at each specified visit.
The results will be presented by treatment groups unless otherwise specified. 
7.2
Study Conduct
Relevant protocol deviations, which could have an impact on the primary/key efficacy endpoint, 
will be identified for all subjects who are randomized and receive study medication during the 
double-blind period. Details of relevant protocol deviations are provided in Appendix 1.
All subjects with relevant protocol deviations that could affect the primary efficacy will be 
identified prior to database lock and unblinding of treatment assignment. All relevant protocol 
deviations will be listed and summarized by treatment group. The subjects identified as relevant 
protocol deviation will not be excluded from any analysis population described in Section 6.3.
7.3
Study Population
Frequency distributions or summary statistics of data pertaining to subject disposition, 
demographic characteristics, baseline disease characteristics, and medical history will be 
tabulated and displayed by treatment group.  No statistical test will be carried out for comparison 
of any baseline measures among treatment groups.
These presentations will be provided by randomized treatment group for the MITT analysis 
population unless specified otherwise. 
7.3.1
Subject Disposition
The number of subjects enrolled into the study at screening, the number of subjects randomized, 
the number of subjects entering the double-blind period (DB) and the number of subjects who 
complete the double-blind period will be summarized by treatment group. The number of 
subjects discontinuing from the DB period (subject disposition) will also be summarized, 
together with the reasons for discontinuation, taken from the CRF status pages. The subject 
disposition for the DB period will be based on the MITT analysis population.
7.3.2
Demography and Baseline Characteristics
Demographic and baseline disease characteristics will be summarized by randomized treatment 
group and overall based on the MITT analysis populations. For continuous variables, they will be 
summarized using means, standard deviations and ranges. The distribution of categorical 
variables such as gender, race etc. will be summarized by treatment group using frequency and 
percentage. 
Demographic characteristics include the following: 

Age in years

Weight in kgs

Gender: Male, Female
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
Race

Ethnicity (Hispanic and Non-Hispanic)

Region grouping scheme A (Latin America+East Europe and ROW) [details in Appendix 2]

Region grouping scheme B (North America, Latin America, Europe and ROW) [details in 
Appendix 2]

Stratification (MTX-IR vs. TNF-IR)
Baseline clinical characteristics include the following: 

Duration of disease in years

Duration of disease  (<=2 years, > 2 to 5 years, > 5 years to 10 years, > 10 years)

ACR functional status classification 

RA classification (2010 ACR/EULAR criteria) 

Individual scores of each ACR components 

DAS28-CRP

DAS28-ESR

RF Status: Negative versus Positive

ACPA Status: Negative versus Positive

hsCRP (mg/L)

ESR (mm/hr)

MTX weekly dose

Oral daily steroid dose (prednisone equivalents) in mg at Day 1

Prior non-biologics DMARD therapy: Categorized number of non-biologic DMARDs use 
prior to randomization (0, 1, 2, >=3)

Number of subjects with inadequate and/or intolerance to TNFi (overall Yes/No, then 
categorized by intolerant, no response, insufficient response, and loss of response. Note: 
subject can be included in more than one category)

Number of subjects with a primary failure (i.e., insufficient response to the first course of 
Therapy) (Yes, No)

Number of subjects with TNFi failures: 0, 1, 2, or >2
7.3.3
Medical History and Prior Medication
Medical history and prior medication information before the first study medication will be 
summarized by treatment group using relative frequencies. Listings of medical history and prior 
medication will be presented. The results will be based on the MITT analysis population.
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7.4
Extent of Exposure
7.4.1
Study Therapy
In general, extent of exposure will be summarized for the As-treated analysis population in two 
ways: 

by the number of study drug doses. Frequency distribution of number of doses will be 
summarized

by the number of days the subject is known to be on study drug, ignoring any dosing 
interruptions
In general, exposure to study drug during the double-blind (DB) period in days is calculated as: 
For subjects who discontinue study medication,

Exposure = (date of last DB dose - date of first DB dose + 1) + 30.
The offset of 30 days represents 30 days of follow-up after last dose and is a lot longer than 5 
times of half-life of the study medication. The frequency will be presented according to the 
duration ranges (in days) : <28, 29-56, 57-84 and so on.
7.4.2
Discontinuations from Study Therapy
Discontinuation from study therapy is defined as subject’s termination of the study medication 
without resumption prior to study completion. Discontinuation from study therapy during the 
treatment and DB period will be summarized by reason for the premature termination, taken 
from the study status case report form (CRF) pages. These summaries will be provided based on 
the MITT analysis population by randomized treatment group and overall.
7.4.3
Treatment Compliance
The CRF for this study will capture information on doses of the study medication. All subjects 
who skip any study drug dose will be listed. The number of subjects with missed doses
(excluding missed doses due to premature discontinuation from the study) by number of missed 
doses will be summarized based on the As-treated analysis population for the DB period by
treatment groups.
7.4.4
Anti-rheumatic Medication
For the purpose of this analysis plan, the term DMARDs will refer to non-biologic DMARDs. 
Anti-rheumatic medication summaries will be provided to present the medication use of 
corticosteroids, NSAIDs, and DMARDs. Number and percent of subjects receiving 
corticosteroids, NSAIDs, and DMARDs will be summarized by treatment group for MITT 
analysis population during the DB period. 
In addition, the mean weekly MTX dose at scheduled visit and mean daily dose of 
corticosteroids during the DB period will be summarized.
A comprehensive listing of all concomitant medications will be also provided for the MITT
analysis population.
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7.5
Efficacy
The efficacy analyses will be performed using the efficacy analysis population. The results will 
be grouped by “as randomized” treatment groups, unless otherwise specified. No formal 
statistical testing was pre-specified for other efficacy endpoints except the primary endpoint of 
ACR20 and ACR70 response at Day 85. The analyses of binary endpoints and continuous 
endpoints will be provided over time including the milestone visits (e.g. Day 85). 
Note: If the enrollment is terminated for all treatment arms based on Week 4 interim analysis, the 
sensitivity analyses, per-protocol analyses, sub-group analyses and additional analyses as defined 
in the following sections may not be performed based on smaller sample size.
7.5.1
Primary Efficacy Endpoints in Double-blind Period
The co-primary efficacy endpoints are ACR20 and ACR70 response rate at Day 85.
The Chi-square tests will be used to compare the ACR20/70 response rates at Day 85 between 
each of the active treatment arms and the placebo arm. The Chi-square p-value will be provided 
for each comparison between the active treatment and the placebo arm. Within each treatment 
group, the statistical testing will be performed for ACR20 at level of 0.05 first. If it is statistically
significant, then the statistical testing will be performed for ACR70. Otherwise, testing will be 
stopped for this treatment group. All treatment groups will follow the same testing procedure.
In addition, the difference of the response rates between each active treatment and the placebo 
will be estimated and their corresponding 95% confidence interval will be calculated for Day 85 
visit and other applicable visits. 
The point estimate for ACR response rate along with 95% confidence interval will be calculated 
for each treatment arm for each applicable visit.
All subjects who prematurely discontinue the trial after receiving study medication will have
missing data imputed as non-responder at all scheduled protocol visits subsequent to the point of
discontinuation. The analysis will be preformed based on Efficacy Analysis Population analysis 
population. More details of imputation rule for classification of binary response status are 
provided in Sections 8.3.
A senstivity analysis of statistical testing may be preformed using the Cochram-Mantel-
Haenszel(CMH) Chi-square test with stratification factors (prior treatment failure status and 
region). The CMH Chi-square p-value will be provided for each comparison between the active 
treatment and the placebo arm along with the relative risk and its 95% CI. Similar testing 
procedure as the primary analysis will be conducted. The absolute treatment difference and its 
95% CI will be provided using the mimimum risk Weights8. In case in a given stratum, there are 
0 responders (all non-responders) in the compared treatment groups, 0.5 will be added to
(subtracted from) both treatment groups in order to avoid a variance of 0 in that stratum.  
7.5.2
Secondary Efficacy Endpoints in Double-blind Period
For each of the binary endpoints (DAS28-CRP<2.6, CDAI<=2.8 etc.), the estimate and its 
corresponding 95% confidence interval will be calculated for the difference of the proportions 
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between each active treatment arm and the placebo arm for each applicable visit, similar to the 
primary analysis except no p-values will be provided.
For each of the continuous endpoints (DAS28-CRP, CDAI, etc.), the mixed effect model will be 
fit with treatment and visit as the fixed effects and measurements within each subject as the 
repeated measurements. The baseline value will be added into the model as a covariate if 
necessary. Based on the mixed effect model, the estimate and 95% confidence interval will be 
calculated for the difference between each active treatment and the placebo at each specified 
visit. No p-values will be provided. In addition, descriptive summary statistics of mean change 
from baseline and 95% confidence interval for each treatment arm will be provided. The missing 
data in continuous measures will be handled via utilization of mixed model procedure in SAS.
7.5.2.1
Magnetic Resonance Imaging (MRI) 
Magnetic resonance imaging will be performed at baseline, Week 4 and Week 12 (or at the time 
of discontinuation, e.g., early termination visit [ET]). The independent read of MRI image data 
will be performed by two primary readers who have no knowledge of the subject’s identity, 
treatment arm or time point chronologic sequence. The readers will be presented with the image 
set(s) of the most clinically swollen hand/wrist acquired at baseline and of that same hand/wrist 
acquired at Week 4 and Week 12 for the assessment of four parameters of bone erosion, bone 
marrow edema (osteitis), synovitis, and cartilage loss (joint space narrowing). The scoring of 
four parameters will be assessed according to the OMERACT RAMRIS criteria9.
The MRI score for each parameter is the sum of scores at joints/bone ends where applicable by 
each reader. The MRI score that is used in the analyses is calculated as the average of MRI 
scores provided by the two readers for each parameter per each subject at each visit. If a MRI 
score from one of the readers is missing, then MRI score from the other reader will be used. If 
the score is missing for both readers at any given time point, the average score is considered 
missing. If a case requires adjudication, a consensus read of all four parameters will be 
performed by the two readers working together as defined in the charter. The consensus score 
will be used in the analysis in this case for each of the four parameters. 
If there are more than 20% of joints/bone ends with missing score, the MRI score of each 
parameter will be considered missing. If there are less than or equal to 20% of joints/bone ends 
with missing score, the MRI score of each parameter from the missing joints/bone ends will be 
carried forward from previous scan (e.g., baseline to Week 4, Week 4 to Week 12), or carried 
backward from later time point or early termination visit (ET) scan if previous scan is not 
available (e.g., Week 12 to Week 4). If subjects had missing complete MRI assessment at Week 
4 or 12, their assessment will be imputed via linear in/extrapolation. Imputation will require a 
subject to have available scores at minimum 2 visits (including baseline, Week 4, Week 12 or 
early termination (ET) visit). Subjects with no baseline or only baseline scores will be excluded 
from the analysis. 
The following analyses will be performed based on imputed data unless specified otherwise. In 
addition, the analysis of changes from baseline may be performed based on as-observed data to 
assess the robustness of results at the presence of missing data. 
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The summary of changes from baseline to Week 4 and 12 in each of four parameters will be 
provided by treatment group using a mixed model. The proportion of subjects with new erosion 
count (defined as erosion score =0 at baseline and erosion score >0 at post baseline) per 
hand/wrist will be also summarized at Week 4 and 12. 
In addition, the proportion of responders who show no progression of damage based on each of 
four parameters will be summarized by treatment group at Week 4 and 12 using point estimate 
and 95% CI, and point estimate and 95% CI of the difference in proportions between the 
treatment groups. The responder at Week 4 and 12 is defined as the change score from baseline 
is less than negative value of the smallest detectable change (SDC)10. The SDC is calculated by 
1.96 × ܵܦ∆(௖௛௔௡௚௘ି௦௖௢௥௘௦)/(√2 × √݇)
in 
which 
ܵܦ∆(௖௛௔௡௚௘ି௦௖௢௥௘௦)/√2
represents 
the 
measurement error of single change-scores and k=2 represents the number of readings or raters 
used for the actual analyses of the trial. The calculation of SDC will be based on the data from 
two readers excluding the cases that require adjudication.
7.5.3
Subgroup Analyses
Subgroup analyses of ACR 20/50/70 responses, and DAS28-CRP/DAS28-ESR change from 
baseline will be provided by point estimates and 95% CI by treatment group at Week 12. The 
subgroup analyses will be performed using Efficacy analysis population. Subgroup factors and 
breakdown are listed in Table 2. 
Table 2:
Subgroup Analyses Factors and Categories
Subgroup Factor
Categories
Age 
< 65 Years Old
65 Years Old
Gender 
Male
Female
Race  
White
Black
Asian
Other
Geographic Region Grouping Scheme Aa
Latin America+Eastern Europe
North America+Western Europe+ROW
Geographic Region Grouping Scheme Bb
North America
Latin America
Europe
ROW
Prior treatment 
MTX-IR
TNF-IR
# of TNFi failure
=1
=2
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Table 2:
Subgroup Analyses Factors and Categories
Subgroup Factor
Categories
Duration of Rheumatoid Arthritis
10 Years
> 10 Years
Baseline DAS28-CRP 
Baseline DAS28-CRP > 5.1
Baseline DAS28-CRP 5.1
a See region/country listin in Appendix 3.
7.5.4
Sensitivity Analyses
If more than 10% of total subjects in the efficacy analysis population discontinued due to any 
reasons other than Lack of Efficacy (LOE), AE or Unknown reason, a sensitivity analysis may 
be performed. The subjects who have missing response due to premature discontinuation with 
reasons other than LOE, AE or Unknown will be excluded from the analyses, hence defining the 
sensitivity analysis population. The sensitivity analysis will be carried out for the primary and 
selected secondary endpoints (ACR20/50/70 response, DAS28-CRP and DAS28-ESR change 
from baseline) based on the sensitivity analysis population. 
7.5.5
Per-Protocol Analyses
If at least 10% of total subjects in efficacy analysis population demonstrate relevant protocol 
deviations, a per-protocol analysis may be performed. A Per-protocol (PP) analysis population 
will exclude all subjects with at least one relevant protocol deviation (defined in Appendix 1) 
from the efficacy analysis population. A per-protocol analysis will be carried out for the primary 
and selected secondary endpoints (as defined in section 7.5.4) based on the PP analysis 
population. The grouping scheme will be the same as in the primary efficacy analysis.
7.6
Safety
Analysis of all safety data will follow the BMS standard safety data conventions11 12 and 
supplements to the standard conventions as defined in this document.
The evaluation of drug safety is based primarily on clinical AE, laboratory abnormalities and 
vital signs reported during the study. 
The summaries of AEs and laboratory marked abnormality during DB period will be provided by 
treatment groups. AEs and laboratory marked abnormalities will be included in the analysis of 
the DB period if the onset date is on or after first dose date and event occurs within 30 days post 
last dose date (DB period). 
Frequency distribution and individual listings of all AEs will be generated. Laboratory marked 
abnormality using pre-defined abnormality criteria will also be descriptively summarized. There 
will be no statistical testing of group difference with respect to frequencies of AEs or laboratory 
marked abnormalities.
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All recorded adverse events will be listed and tabulated by system organ class, preferred term, 
treatment and overall. Any physical examination findings will be listed. ECG, vital signs and 
clinical laboratory test results and corresponding change from baseline values will be listed and 
summarized by treatment. Values for ECG, vital signs and clinical laboratory test results outside 
the pre-specified criteria will also be listed and summarized. ECG readings will be evaluated by 
the Investigator and abnormalities, if present, will be listed.  
Unless otherwise specified, baseline is defined as the last non-missing result with a collection 
date-time less than the date-time of the first dose of study medication, for laboratory results, vital 
signs and ECG.
Presentations for the DB period will be provided by “as treated” treatment group for as-treated 
analysis population, unless otherwise specified.
7.6.1
Adverse Events
The investigator will determine the intensity of each AE as mild, moderate, severe, or very 
severe. In addition, the investigator will determine the relationship of the AE to the 
administration of the study drug.
All AEs are coded and grouped into Preferred Terms (PT) by System Organ Class (SOC), using 
the latest approved version of the Medical Dictionary for Regulatory Activities (MedDRA) at the 
time of database lock.  Listings and summaries will be based on the resulting SOCs and PTs.
AEs will be included in the frequency tabulations if they occur while a subject is on study 
medication up to and including 30 days after the last dose of study medication. These AE 
summaries will be based on proportions, which represent the number of subjects experiencing 
the AEs divided by the number of subjects received at least 1 dose of study medication in the 
current period.
All AE listings will indicate the unique subject identifier, age, gender, current treatment, the date 
of onset, the date of resolution, day of onset relative to the start of treatment, action taken, 
investigator’s assessment of severity and relationship to study drug. Additional listings will be 
provided for adverse events leading to discontinuation and adverse events without recorded 
resolution. Summaries of adverse events will include adverse events, adverse events by intensity
(based on CTC grade) and adverse events by relationship.  
Where a subject has the same adverse event, based on preferred terminology, reported multiple 
times in a single analysis period, the subject will only be counted once at the preferred 
terminology level in adverse event frequency tables.
Where a subject has multiple adverse events within the same system organ class in a single 
analysis period, the subject will only be counted once at the system organ class level in adverse 
event frequency tables.
When a subject has the same adverse event, based on preferred terminology, reported multiple 
times in a single analysis period, the following criteria, in order of precedence, will be used to 
select the event to be included in summary tables:
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
Relationship to study medication

Intensity of event

Onset date and time
When reporting adverse events by intensity, in addition to providing a summary table based on 
the event selection criteria detailed above, summary tables will also be provided based on the 
most intense event during the analysis period - independent of relationship to study medication. 
For these tables, the following criteria, in order of precedence, will be used to select the event to 
be included in summary tables:

Intensity of event

Onset date and time
Subjects will only be counted once in the ‘Total’ at their maximum intensity, regardless of SOC 
or PT.
Any reported AEs that occur more than 30 days after the last dose of study drug will be excluded 
from safety summaries. Any reported AEs that occur more than 30 days post the last dose of 
study drug will appear in the listing. 
Summary information (the number and percent of subjects by treatment) will be tabulated for the 
following AEs: 

All AEs including clinical and laboratory AEs

Most common AEs (reported in 5% of subjects or more in any treatment group)

All related events

Serious AEs (SAEs)

Discontinuations due to AEs
Laboratory AEs are laboratory changes identified by the investigator as AEs and thus reported on 
the AE pages of the eCRF. The intensity of all related AE will be provided if enough data 
warrants the anlysis.
7.6.2
Adverse Events of Interest 
The following adverse events of special interest will be listed and summarized by treatment 
groups during the DB period. 

Pre-specified liver function abnormalities

Infections: All reported infections and infestations within the System Organ Class (SOC): 
Infections and infestations. The severity of serious infections will be summarized.

Malignancy: All reported events defined in MedDRA Maintenance and Support Services 
Organization (MSSO) Structured MedDRA Query (SMQ) list.

Blood pressure related AE

Hypertension: All reported events defined in pre-specified MedDRA code of hypertension.
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
Neutropenia: All reported events defined in pre-specified MedDRA code of neutropenia.

Thrombocytopenia: All reported events defined in pre-specified MedDRA code of 
thrombocytopenia.

Demyelinating disorders: All reported events defined in MedDRA Maintenance and Support 
Services Organization (MSSO) Structured MedDRA Query (SMQ) list.

Autoimmune diseases: All reported events defined in pre-specified MedDRA code of 
autoimmune disorders.
7.6.3
Deaths
All AEs with the outcome of death reported during the study will be listed together with a 
clinical narrative relating to the death of the subject. All reported deaths after a subject is 
enrolled will be listed separately by subject.
7.6.4
Other Serious Adverse Events
SAEs are captured on an eCRF page. All SAEs and related SAEs will be summarized by 
treatment group and listed together with a clinical narrative.
7.6.5
Adverse Events Leading to Discontinuation of Study Therapy
AEs leading to discontinuation of study drug are identified on the eCRF will be summarized and 
listed together with a clincial narrative.
7.6.6
Multiple Occurrences of Adverse Events
Several descriptive summaries of adverse events that takes into account the number of 
occurrences that an AE was reported by individual subjects will be provided.  In order to prepare 
these summaries, the CRF data will be processed according to standard BMS algorithms to 
categorize each line of subject data as a new occurrence or a continuation of an existing event. 
This determination will be based upon onset and resolution dates. Each line of subject data will 
represent the maximum severity observed as well as the last known assessed relationship to study 
medication by the investigator.  
The number and proportion of subjects who experienced an AE once or multiple times (0 Events, 
1 Events, 2-3 Events, >=4 Events) will be summarized by treatment groups for most common 
AE (at least 5% subject in any treatment group) and event of special interest, infections.
Listing displaying the unique instances of all AEs will be provided.
Note: The unique instances of all AEs will be generated after duplicates have been eliminated 
and overlapping and contiguous occurrences of the same event have been collapsed.
7.6.7
Summaries of Laboratory Data
The results of all protocol-specified clinical laboratory tests, as well as laboratory results outside 
of the normal range, will be listed. Scheduled laboratory measurements and corresponding 
change from baseline values will be summarized by treatment and nominal visit for each
laboratory test for the MITT analysis population. 
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The frequency of subjects with any marked laboratory abnormality will be presented by 
laboratory test for the DB period. The results are based on the As-treated analysis population.
The criteria used for classifying laboratory test results as markedly abnormal will be listed. 
7.6.8
Other Safety Considerations
7.6.8.1
ECG
Summary statistics (n, mean, standard deviation, median, minimum, and maximum) will be 
presented for each ECG parameters and the corresponding changes from baseline by treatment 
and visit. The baseline value is defined as the last measurement before the first dose. ECG 
readings will be evaluated by the Investigator and abnormalities, if present, will be listed.  
The frequency distribution of subjects’ maximum recorded post-dose QTcF, PR, QRS and 
QTcF will be tabulated by treatment and summarized within the CSR text for the following 
ranges:
For QTcF:  QTcF ≤ 450 msec, 450 msec < QTcF ≤ 480 msec, 480 msec < QTcF ≤ 500 msec, 
QTcF > 500 msec
For PR: PR ≤ 200 msec, PR > 200 msec
For QRS: QRS ≤ 120 msec, QRS > 120 msec
For QTcF: QTcF ≤ 30 msec, 30 msec < QTcF ≤ 60 msec, QTcF > 60 msec
Individual QTcF, PR, QRS or QTcF values meeting these criteria will be flagged in the data 
listing.
7.6.8.2
Vital Sign
Vital signs parameters (systolic blood pressure, diastolic blood pressure, heart rate, respiratory 
rate and body temperature) will be listed. Summaries of vital sign parameters will be provided 
for each vital sign parameter at corresponding visits by treatment and respective changes from 
baseline. Subjects with vital signs outside of a pre-specified range will also be listed.
The following criteria will be used to determine vital sign results that are outside of a pre-
specified range, where changes from baseline are based on matched postural positions and are 
calculated as parameter value - baseline parameter value:
Table 3:
Vital sign parameter cut-off values
Heart Rate(bpm)
Value > 100 and change from baseline > 30, or
Value < 55 and change from baseline < -15
Systolic BP(mmHg)
Value > 140 and change from baseline > 20, or
Value < 90 and change from baseline < -20
Diastolic BP(mmHg) 
Value > 90 and change from baseline > 10, or
Value < 55 and change from baseline < -10
Respiration(breaths/min)
Value > 16 or change from baseline > 10
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Table 3:
Vital sign parameter cut-off values
Heart Rate(bpm)
Value > 100 and change from baseline > 30, or
Value < 55 and change from baseline < -15
Temperature (°C)
Value > 38.3°C or change from baseline > 1.6°C
7.6.8.3
Physical Examination Findings
All physical examination abnormal findings will be listed per subject by visit. 
7.7
Pharmacokinetic Analysis
Summary statistics of Ctrough (mean, SD, geometric mean, % CV, median, min, and max) for 
the PK analysis population by treatment and study day.
The listing of Concentration of BMS-986142 by treatment and study day will be provided as well.
 
 
 
 
 
 
 
 
7.9
Interim Analyses
After about 20 subjects per treatment arm have completed at least 4 weeks of the treatment 
period or discontinued the treatment, an interim analysis will be conducted to assess the efficacy 
of the BMS-986142 dose arms and the overall safety. The interim analysis will use pre-specified 
efficacy, safety and PK endpoints. The results of the interim analysis will be reviewed by an 
unblinded sponsor team who is not involved in the study conduct and who will provide 
recommendations with regard to the adaptive design decisions to the blinded study team. 
Population PK and exposure-response analysis may be performed to support the statistical 
Bayesian analysis and to facilitate decisions around dose selection. Population PK analysis to 
characterize the PK of BMS-986142 may be performed by pooling data from the present study 
with the Phase 1 study IMXXXXXX, in order to supplement the PK data as well as test for 
covariate effects, including but not limited to demographics, disease state, concomitant 
medications, etc. Exposure-response analysis may be performed using DAS28-CRP as the 
primary endpoint to characterize the relationship between measures of BMS-986142 exposure 
and reduction in DAS28-CRP. Details regarding the data evaluation and modeling methodology 
for interim analysis will be provided in a separate modeling and simulation analysis plan. 
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Efficacy analysis (DAS28) using Bayesian modeling and dose/exposure response analysis:
The interim analysis will be performed on all available data of DAS28 change from baseline up 
to Week 12 using a Bayesian predictive approach.13 This analysis assumes that the DAS28 at 
Week 4 and at Week 12 in the subjects who have not yet been observed will be similar to what 
was observed for the subjects included at Week 4 and Week 12, respectively. As such the 
unobserved data will be simulated from the predictive distribution conditional on the interim data 
and the prior distribution of the treatment difference (using a non-informative prior). Under the 
Bayesian framework, the posterior distribution of the treatment difference (BMS-986142 active 
dose – Placebo) will be constructed to determine the predictive probability of ΔΔDAS28 
improvement greater than a cutoff value at the planned end of the trial for each dose arm. 
Note: ΔΔDAS28 improvement: The difference of change from baseline in DAS28-CRP between 
active dose arm and placebo arm. The lower is the DAS28 score, the better is the disease status.
The Bayesian predicative analysis and the dose/exposure response analysis will determine if new 
BMS-986142 dose(s) will be needed to fully characterize dose-efficacy relationship. Pre-
specified efficacy endpoint (DAS28) will be assessed with exposure endpoints to guide the 
selection of new dose levels in different scenarios as described below. Considering the safety 
margin estimated from non-clinical studies, new dose levels based on the interim analysis will 
not be greater than 350 mg/day.
If the predictive probability of ΔΔDAS28 improvement being greater than 1.0 is high (eg, > 
80%) in all active arm(s), the BMS team may recommend to maintain the study design and 
treatment arms. In this scenario, all enrolled subjects will continue the treatments without 
modifications and also be included in the final analysis for the existing dose arm. The BMS team 
may also recommend adding an additional dose arm at lower dose level than current active doses 
to explore the suboptimal dose.  In this case, up to 41 subjects will be randomized into the 
suboptimal dose arm along with existing efficacious dose arms. The new suboptimal dose level 
may be selected based on dose/exposure response analysis. In support of adding new dose arm
(suboptimal dose or middle dose(s) as descriped below), population exposure-response analysis 
may be conducted for the time-course of DAS28-CRP scores and/or selected safety endpoints 
collected until the interim analsyis using a mixed effects inhibitory Emax model, or other 
alternative models, with respect to time and BMS-986142 exposure.
If the predictive probability of ΔΔDAS28 improvement being greater than 1.0 is high (eg, >80%) 
in 2 BMS-986142 arms (mid and high dose arms), then the BMS team may recommend to 
maintain the study design and these 2 treatment arms. The enrolled subjects will be carried over 
in the existing dose arm and also be included in the final analysis for the existing dose arm. The 
subjects enrolled in the low dose arm will continue the treatment only if they have received at 
least 1 treatment and treatment is considered safe before the interim analysis is completed. 
However, no new subjects will be enrolled in this treatment arm. Based on the dose/exposure 
response analysis, new dose levels may be added to further characterize the steep portion of the
dose-response relationship if the existing 2 consecutive dose levels show a relatively flat 
exposure response.
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If the predictive probability of ΔΔDAS28 improvement being greater than 1.0 is high (eg, > 
80%) in 1 BMS-986142 arm (high dose arm), then the BMS team may recommend to maintain 
the study design and this treatment arm. The enrolled subjects will be carried over in the existing 
dose arm and also be included in the final analysis for the existing dose arm. The subjects 
enrolled in the low and mid dose arms will continue the treatment only if they have received at 
least 1 treatment and treatment is safe before the interim analysis is completed. However, no new 
subjects will be enrolled in this treatment arm. Based on the dose/exposure response analysis, up 
to 2 new dose levels may be added to adequately characterize the dose-response relationship.
If the predictive probability of ΔΔDAS28 improvement being greater than 0.6 is low (eg, < 
20%), that dose arm is deemed futile in terms of DAS28CRP change from baseline. However, 
the final futility will also incorporate the results from other efficacy endpoints as defined below.
The proposed stopping rules at the interim analysis, based on the futility assessment and the 
overall safety assessment, are as follows:

Rule 1: If safety issues are identified in all dose arms or all dose arms are futile, stop the 
study

Rule 2: Drop the dose arm(s) with safety issues identified

Rule 3: Drop the futile dose arm(s) and the dose arm cannot be dropped until the lower 
dose arm has been dropped.
If the predictive probability of ΔΔDAS28 improvement being greater than 0.6 is lower than 20% 
in all active treatment arms, BMS team may recommend stopping further enrollment and 
continuing those subjects receiving therapy up to 12 weeks.
Descriptive efficacy analysis (other efficacy endpoints):
In addition to Bayesian predictive analysis above, the following as-observed clinical data up to 
database lock will be summarized at the time of Week 4 interim analysis to facilitate decision-
making. 

ACR20/50/70 response over time

DAS28-CRP < 2.6, DAS28-ESR < 2.6, CDAI ≤ 2.8, SDAI ≤ 3.3 and Boolean remission 
over time

Change from baseline in DAS28-CRP, DAS28-ESR, CDAI, SDAI over time.
Descriptive safety analysis:
For the following pre-specified safety endpoints:

AE/SAE (including but not limited to hypertension, diarrhea, neutropenia)

Change from baseline in vitals including systolic blood pressure (SBP) and diastolic 
blood pressure (DBP). 
The study will be stopped if intolerable safety events are identified in all treatment arms. If 
intolerable safety events are identified in 1 or 2 treatment arms, these arms will be dropped and 
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the study will be continued with caution. New dose levels may be added based on the exposure 
response analysis (not greater than 350 mg daily). If intolerable safety events show a clear 
relationship with higher exposure of BMS-986142, a lower dose will be selected where the 
predicted exposure in ~ 90% of subjects does not exceed the exposure ranges associated with 
safety findings.
Based on the totality of safety and efficacy considerations, unsafe dose arm will be stopped 
immediately. The dose arm(s) that are projected to be ineffective will continue till the end of 
double-blind period for subjects already taking at least one dose of study medication and no new 
subjects will be enrolled into ineffective dose arm(s).
 
 
 
 
 
 
8
CONVENTIONS
8.1
Calculations of Key Measures
8.1.1
Evaluation of ACR
ACR 20, the American College of Rheumatology (ACR) definition of 20% improvement is 
based on a 20% improvement (compared to baseline (Day 1) values) in tender and swollen joint 
counts and 20% improvement in 3 of the remaining 5 core set measures (subject global 
assessment of pain, subject global assessment of disease activity, physician global assessment of 
disease activity, subject assessment of physical function and one acute phase reactant value 
(CRP)). 
If ACR 20 response based on the criteria above, was not met, because no 20% improvement in 
tender and swollen joints, then the patient is an ACR20 non-responder.
If ACR 20 response, based on the criteria above was not met, because not 3 of the remaining 5 
core set measures had 20 % improvement then the number of components with 20% or more 
improvement (for the 5 remaining core components) will be tabulated in relation to the number 
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of missing components (in the remaining 5 core components) prior to the final calculation of 
ACR 20. If the sum of the number of components with 20% or more improvement and the 
number of missing components is greater than or equal to 3, then ACR 20 will be set to missing 
as there is insufficient amount of data to determine the correct status, otherwise the patient is an 
ACR20 non responder.
Higher values for each component of the ACR composite variable indicate greater severity of 
disease. Improvement from baseline in a component of the ACR composite variable will be 
computed as the difference between the baseline value and the value at a given post-baseline 
visit. A positive value for improvement from baseline for an individual component indicates 
lesser severity of disease.
Percent improvement will be computed as the ratio of improvement from baseline to the baseline 
value times 100 for an endpoint:
% Improvement = 100 * (Improvement from Baseline) / Baseline Value
                           = 100 * (Baseline Value - Post-baseline Value) / Baseline Value.
Based on the percent improvement from baseline in each of the ACR components, ACR 50 and 
ACR 70 will be similarly defined with 50% and 70% improvement, respectively.
The conventions for dealing with missing data, procedures or intra-articular injections of joints 
(has impact on tender and swollen joint counts), restricted medications and high dose of 
corticosteroids are provided in Section 8.2, 8.3, 8.5.1.
8.1.2
Evaluation of DAS28-CRP and DAS28-ESR
The DAS used in this protocol is the DAS using the 28-count subsets of tender/painful joints and 
swollen joints, together with either CRP or erythrocyte sedimentation rate ESR, to derive the, 
DAS28-CRP, and DAS28-ESR, which are calculated using the following formulae, respectively:
DAS28-CRP = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96.
DAS28-ESR = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*ln(ESR) + 0.014*GH. 
where TJC28 is number of painful joints out of 28 joints, SJC28 is number of swollen joints out 
of 28 joints, GH is the general health or patients’ global assessment of disease activity on a 100 
mm VAS, ln is the natural logarithm, ESR is in mm/hour, and CRP is in mg/L.
8.1.3
Evaluation of CDAI
Calculation of Clinical Disease Activity Index (CDAI) is the simple linear sum of the outcome 
parameters: tender joint count (TJC) and swollen joint count (SJC) based on a 28-joint 
assessment, patient global assessment of disease activity (PGA: VAS 0–10 cm), and physician 
global assessment of disease activity (EGA: VAS 0–10 cm): 
CDAI = TJC28 + SJC28 + PGA + EGA.
CDAI Remission responder is defined as a CDAI score less than or equal to 2.8.
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8.1.4
Evaluation of SDAI and Boolean-based Remission
Calculation of Simple Disease Activity Index (SDAI) is the simple linear sum of the outcome 
parameters: tender joint count (TJC) and swollen joint count (SJC) based on a 28-joint 
assessment, patient global assessment of disease activity (PGA: VAS 0–10 cm), physician global 
assessment of disease activity (EGA: VAS 0–10 cm) and C-reactive protein (CRP in mg/dL) as 
shown below:
SDAI = TJC28 + SJC28 + PGA + EGA+ CRP.
SDAI Remission responder is defined as a SDAI score less than or equal 3.3.
Remission by Boolean-based definition: Subject must satisfy all of the followings:
TJC28 <=1; SJC28<=1; PGA<=1; CRP<=1 mg/dL
8.1.5
Evaluation of HAQ Disability Index
Scoring conventions for the Standard Disability Index of HAQ will be followed. The Standard 
disability index (HAQ DI) takes into account the subject’s use of aids or devices or assistance in 
the scoring algorithm for a disability category. The score for each category is the single response 
within the category with the highest score. For each of the eight disability categories these is an 
AIDS OR DEVICES companion variable(s) that is used to record the type of assistance, if any, a 
subject uses for his/her usual activities. If aids or devices and/or assistance from another person 
are checked for a disability category, the score for this category is set to 2 (much difficulty), if 
the original score is 0 (no difficulty) or 1 (some difficulty). The HAQ DI is then calculated by 
summing the adjusted categories scores and dividing by the number of categories answered. The 
HAQ DI cannot be calculated if the patient does not have scores for at least 6 categories. Details 
of the HAQ DI scoring conventions are documented in “The Health Assessment 
Questionnaire”14.
A HAQ response for RA is defined as a subject with a reduction from baseline in HAQ DI of at 
least 0.22.
8.1.6
Evaluation of FACIT-Fatigue
The FACIT-Fatigue is a 13 item subject self-assessment tool that measures the subjects’ usual 
daily activities over the post week. Responses of ‘not at all’, ‘a little’, ‘somewhat’, ‘quite a bit’, 
and ‘very much’ are available for each question, and correspond to scores of 0, 1, 2, 3, and 4, 
respectively for the item codes An5 and An7 and correspond to scores of 4, 3, 2, 1, 0 (reversal of 
response) for the other item codes. 
The total score = (sum of scores) *13/ (number of items answered), resulting in a maximum of 
52 and a minimum of 0. The total score cannot be calculated if the patient does not have 
answered at least 7 of the 13 items (more than 50 % of the items should be answered).  
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8.1.7
Evaluation of BRAF-MDQ 
The 
BRAF 
MDQ 
(Bristol 
Rheumatoid Arthritis 
[RA] 
Fatigue 
Multi-Dimensional 
Questionnaire)15 was developed to assess the overall experience and impact of RA fatigue, and 
its different dimensions. 
Items scored 0–3, except for items 1 (scored 0–10), 2 (scored 0–7), and 3 (scored 0–2). A total 
fatigue score is obtained by summing the 20 item scores. Subscale items are summed to produce 
scores for physical fatigue, living with fatigue, cognitive fatigue, and emotional fatigue. 
Instructions for missing data are that only 3 questions may be omitted in total, questions 1 and 2 
must be completed, and only 1 question may be omitted from each subscale (replaced with 
patient’s average score for that subscale).
Higher scores reflect greater severity. Total fatigue score is 0–70; subscale scores are physical 
fatigue 0–22, living with fatigue 0–21, cognitive fatigue 0–15, and emotional fatigue 0–12.
Figure 2:
BRAF-MDQ Score table
Missing data is handled as follows:

Questions 1 and 2 are compulsory. 

Only 1 question may be missing from each dimension (maximum of 3 in the overall BRAF-
MDQ). 

Replace the missing question score with the average score for that dimension. 

For the Physical Fatigue dimension, a weighted average score is used to account for the 
varying item score ranges: Total the 3 completed scores, divide by the total max possible 
score for those 3 questions, then multiply by the maximum score possible for all 4 questions 
(22). 
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For example: 

Q1 is 10/10, Q2 is 6/7, Q3 is missing, and Q4 is 2/3. 

Total completed score =18.

Divide by total max possible for those 3 questions (10+7+3) i.e. 18/20 = 0.9 weighted 
average. 

Multiply by the max possible score for all 4 questions i.e. 0.9 x 22 = 19.8. 

Physical Function score is thus imputed as 19.8.
8.1.8
Evaluation of SF-36 Summary Functions and Components
The SF-36 is composed of 36 items measuring 8 health concepts: Physical Functioning, Role-
physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-emotional, and Mental 
Health. These 8 scales form 2 summary scores: (1) Physical Component Summary (PCS) and (2) 
Mental Component Summary (MCS).  Scoring conventions for the SF-36 scales and components 
are documented in “SF Health Outcomes TM Scoring Software User’s Guide”16.
8.2
Handling of Procedures, Conditions and Intra-articular Injections of 
Joints
Joints may have been undergone procedures (e.g., fusion/ankylosis, synovectomy, steroid 
injection, and amputation) due to worsening RA during the study. Joint status is adjusted 
according to the following rules:

If a joint undergoes procedure on or before the start of study drug, then for this joint both 
tenderness and swelling will be considered as ‘not present’ for all visits.

If a joint undergoes procedure due to RA involvement and occurs after the start of study 
drug, then for this joint both tenderness and swelling will be considered as ‘present’ for all 
visits on or after the procedure.

If a joint undergoes procedure for reason other than RA involvement and occurs after the 
start of study drug, then for this joint both tenderness and swelling will be considered as ‘not 
present’ for all visits on or after the surgery procedure date.
In addition, joint status is also adjusted for conditions and IA injection as follows:

If a joint undergoes other procedures or conditions at any visit, then for that joint both 
tenderness and swelling will be considered as ‘not present’ at that particular visit.

If an intra-articular injection occurs, then for that joint both tenderness and swelling will be 
considered as ‘present’ at that particular visit and all subsequent visits.
8.3
Determination of Responder Data 
Subjects who receive 1 or more IA or IM injection during the double-blind period of study will 
be classified as ACR non-responder on and after the time of the first IA or IM injection and up to 
the end of the double-blind period. Subjects who receive a high oral steroids course that is 
defined as the use of either any oral dose (equivalent of prednisone) higher than baseline (Day 1) 
use for >=1 day or any oral dose (equivalent of prednisone) >10mg/day for >=1 day will be 
counted as non-responder at all visits subsequent to the date of dose that is higher than the 
baseline dose.
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Subjects who increase MTX use (versus baseline) during the double-blind period will be counted 
as non-responder at all visits subsequent to the earliest date of increased MTX dose.
Subjects who receive any DMARDs (other than MTX) during the double-blind period will be 
counted as non-responder at all visits subsequent to the earliest date of DMARDs.
These rules will apply to binary endpoints including ACR20/50/70, DAS28-CRP <2.6, DAS28-
ESR <2.6 and remission status defined by CDAI, SDAI and Boolean definition.
8.4
Baseline Measures
The baseline value is the last assessment taken prior to the first dose of study medication. In 
general, baseline value is the assessment taken on study Day 1 before the administration of study 
medication. If a measurement on Day 1 is missing, the last assessment taken at the screening 
period prior to the first dose of study medication will be used. 
8.5
Missing Measurements
8.5.1
Imputation of Missing Data for Binary Variables
This imputation is applicable for all binary variables (ACR20/50/70, DAS28-CRP <2.6, DAS28-
ESR <2.6, and remission status defined by CDAI, SDAI and Boolean definition).
If the response cannot be assessed due to missing data or a subject’s early discontinuation, the 
following conventions will be implemented in a sequence:

Any subject who prematurely discontinues the trial during the double-blind period after 
receiving study medication will have data imputed as non-responder at all scheduled protocol 
visits subsequent to the point of discontinuation up to the end of the double-blind period.

After any imputation above or none, if for some reason the binary variable still can’t be 
determined, including the case where baseline data is missing, then its value will be set to 
non-responder.
For listings, missing responses will be presented as missing.
8.5.2
Imputation of Missing Data for Continuous Variables
For the analysis of changes from baseline values (e.g., individual components of ACR, DAS28-
CRP, and DAS28-ESR etc), missing values will be dealt with via the longitudinal repeated 
measures analysis assuming MAR (missingness at random). 
For all safety (including laboratory measurements), and PK measures, missing values will not be 
imputed.  
8.6
Missing, Unknown or Partial Dates
The BMS safety guidelines for conventions relating to the handling of missing or partial dates 
and the determination of appropriate default values in such cases (in particular, for concomitant 
medication dose start-dates and end-dates and AE onset dates) will be utilized.  
8.7
Day Ranges for Analysis of Time Points
Subjects who do not always adhere strictly to the visit schedule timing in the protocol. Therefore 
the designation of visits during the double-blind period of the study will be based on the day of 
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evaluation relative to the trial (day of first study medication = study Day 1) rather than the 
nominal visit recorded in the eCRF. Mutually exclusive relative day windows are defined below 
to provide derived visits that correspond to the post-baseline time points. If a visit falls outside of 
the pre-specified visit windows, then the data collected at that visit will not be assigned a derived 
visit but will remain in the derived data sets. Determination of baseline values is addressed in 
Section 8.2.
If a subject has more than 1 visit where a measurement is recorded within a window, the 
measurement closest to the target day will be used.  In case of 2 visits being equidistant from the 
target, the earlier measurement will be used in analyses. For these safety indicators, the least 
favorable value (toward a positive response) in the window will be used.
Designation of visits for efficacy assessments, and other measures during the double-blind period 
is tabulated below.
Table 4:
Days Ranges for Assessments at Every Scheduled Visits During the
Double-blind Period
Visit
Target Day
ACR20/50/70,DA
S28-CRP, DAS28-
ESR, HAQ
MRI
Fatigue, SF-
36, Stiffness, 
BRAF-MDQ
Biomarker
Baseline
/Day 1
1
1
1
1
1
D15
15
8-21
8-21
D29
29
22-43
15-57
22-43
D57
57
44-71
44-71
D85
85
72-99
58-113
43-113
72-99
9
CONTENT OF REPORTS
The results of the study conducted by Protocol IM006-016 will be presented in a standard BMS 
CSR appendix.  Key results and any unanticipated findings that are unusual for this study will be 
identified.  A meeting for the initial dissemination of study results will be held after database 
locked.  Attendees at this meeting will review all efficacy and safety summaries and listings and 
will identify key results that should be highlighted in the CSR.
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Original version
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