Clinical trial NCT05064436
Conditions: Multiple Sclerosis (MS)
Keywords: Multiple Sclerosis (MS) Healthy Participants 11C-BMS-986196 PET tracer
Sponsor: Bristol-Myers Squibb
Start date: 2021-12-10; Completion date: 2023-12-18
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, kinetics, biodistribution and central nervous system signal of 11C-BMS-986196 after intravenous (IV) administration in healthy participants and after repeat IV administration in participants with multiple sclerosis.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: 11C-BMS-986196
Intervention descriptions: intervention 1: Specified dose on specified days

Protocol documents:
Prot_000.pdf: 
Official Title of Study: 
A Phase 1, Open-label, Multi-part Study to Evaluate the Safety, Tolerability, Kinetics, Biodistribution, 
and CNS Signal of the Positron Emission Tomography Ligand 11C-BMS-986196 in Healthy 
Participants After Intravenous Administration and to Evaluate the Safety, Tolerability, Kinetics, and CNS 
Signal Repeatability of 11C-BMS-986196 After Repeat Intravenous Administration in Participants With 
Multiple Sclerosis 
 
NCT Number: NCT05064436 
Document Date (Date in which document was last revised): 30 June 2023 
 
 
 


Page:
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Protocol Number:
IM038010
Date:
16-Apr-2021
Revised Date:
30-Jun-2023
CLINICAL PROTOCOL IM038010
A Phase 1, Open-label, Multi-part Study to Evaluate the Safety, Tolerability, Kinetics,
Biodistribution and CNS Signal of the Positron Emission Tomography Ligand 11C-BMS-986196 
in Healthy Participants after Intravenous Administration and to Evaluate the Safety, Tolerability, 
Kinetics, and CNS Signal Repeatability of 11C-BMS-986196 after Repeat Intravenous 
Administration in Participants with Multiple Sclerosis
Brief Title:
Safety, Tolerability, Kinetics, and Biodistribution of the PET Ligand 11C-BMS-986196 after IV
Administration in Healthy Participants and the Evaluation of CNS Signal Repeatability after 
Repeat IV Administration in Participants with Multiple Sclerosis
Protocol Amendment Number 05
Clinical Trial Physician - Medical Monitor
Bristol-Myers Squibb Company
San Diego, CA 92121 
Telephone: 
Email: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Company
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
REGULATORY AGENCY IDENTIFIER NUMBER(S)
IND: 154386
EudraCT/EU Trial Number: 2021-001986-19
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Clinical Protocol
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BMS-986196
BTKi-CNS
Protocol Amendment No.: 05
Date: 30-Jun-2023
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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) 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. References to BMS in this protocol may apply to partners to which BMS 
has transferred obligations (eg, a Contract Research Organization [CRO]).  
© 2023 Bristol-Myers Squibb Company
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BMS-986196
BTKi-CNS
Protocol Amendment No.: 05
Date: 30-Jun-2023
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol Amendment 
05
30-Jun-2023
Revisions to:
Add a novel Part C to the protocol, to quantify free Bruton’s 
tyrosine kinase (BTK) in the brain before and approximately 
24 hours after oral administration of unlabeled BMS-986196
at doses of 15 mg, 30 mg, and 60 mg.
Protocol Amendment 
04
09-May-2022
Revisions to:

Accurately account for the radiation exposure 
resulting from a cranial computed tomography 
(CT) scan.

To facilitate operational conduct of the study by: 
o
Allowing for a shorter interval between 
positron emission tomography (PET) 
scans.
o
Allowing a third PET scan in Part B in 
case 1 PET scan procedure is not 
successful.
o
Allowing up to 6 cranial CT scans in 
Part B (1 before and 1 after each PET 
scan) to account for potential movement 
during the PET procedure.
o
Specifying that fasting requirements are 
only for Part A participants.
o
Allowing vital sign assessment in sitting 
position.
Protocol Amendment 
03
21-Feb-2022
Revisions to allow venous blood sampling during cranial 
positron emission tomography (PET). This would be 
necessary if emerging data from this ongoing study indicate 
that a (pseudo) reference region cannot be reliably 
established, therefore making future studies with 
11C-BMS-986196 without arterial input function 
challenging. 
Protocol Amendment 
02
02-Nov-2021
1)
Revisions to AE-based stopping rules
Updated the procedures for study restart after stopping rules 
have been met.
Protocol Amendment 
01
22-Oct-2021
1)
Revisions to Exclusion Criteria

Removal of required consultation with the BMS 
clinical trial physician regarding the eligibility of a 
participant with any sequelae from a prior SARS-
CoV-2 infection.

Removal of participants with malaria falciparum 
infection.

Removal of any exception granted by the Sponsor 
medical monitor regarding the use of any 
prescription drugs within 4 weeks or 5 times the 
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Protocol Amendment No.: 05
Date: 30-Jun-2023
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Document
Date of Issue
Summary of Change
elimination half-life (if known), whichever is 
longer before tracer administration. 

Removal of any exception granted by the Sponsor 
medical monitor regarding the use of any 
investigational drugs or placebo within 4 weeks or 
5 times the elimination half-life (if known), 
whichever is longer before tracer administration. 

Removal of any exception granted by the Sponsor 
medical monitor with regards to the participant’s 
participation in another clinical trial concurrent 
with this study. Addition of the investigator 
assessment on whether or not to enroll the 
participant meeting this criterion.
2)
Revisions to (S)AE-based stopping rules

Specifying stricter criteria for triggering (S)AE-
based stopping rules and specifying the procedures 
for study restart after stopping have been met.
Administrative Letter 
01
22-Aug-2021
This administrative letter addresses an inconsistency 
between different sections in the protocol regarding the site 
personnel placing arterial lines. Table 3.3.1-1 of the 
protocol specifies that arterial line placement is performed 
by experienced staff, whereas Section 3.3 (Benefit/Risk 
Assessment) and Section 9.1.1.1 (PET Assessment) state 
that the arterial line placement is performed by an 
experienced physician. This administrative letter clarifies 
that arterial line placement will be performed by 
experienced staff. Experienced staff includes technicians, 
who are not physicians. This clarification ensures that 
arterial line placement is performed according to the 
standard practice at the participating sites. 
Original Protocol
16-Apr-2021
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BTKi-CNS
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 05:
The overall rationale for Amendment 05 is to add a novel Part C to the study protocol, in which 
free Bruton’s tyrosine kinase (BTK) in the brain will be quantified in healthy participants before 
and approximately 24 hours after oral administration of unlabeled BMS-986196 at doses of 15 mg, 
30 mg, and 60 mg once daily (QD). 
These amendment changes will apply to future participants.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
Title Page
Clinical Scientist information removed. 
Administrative change to align 
with the current Bristol-Myers 
Squibb (BMS) protocol model 
document. 
Section 1, Protocol Summary
Text in protocol summary updated to reflect 
changes from protocol body.
Updated for consistency.
Section 2, Schedule of 
Activities (Table 2-1)

Table title updated to include Part C for 
screening procedures. 

Columbia-Suicide Severity Rating 
Scale (C-SSRS) and 
QuantiFERON-TB Gold Plus
procedures added as a screening for 
Part C participants only. 

Clarification added that Allen’s test 
procedure only required for Part A and 
Part B.

Clarification added that hematology, 
chemistry, urinalysis, coagulation, 
urine drug screen, and urine cotinine 
test only required for Part A and 
Part C. 
 
 
 
To account for the assessments
in the newly added Part C.
Section 2, Schedule of 
Activities (Table 2-4)
New table added for Part C.
To account for the assessments
in the newly added Part C.
Section 3, Introduction;
Section 3.3 Benefit/Risk 
Assessment; 
Section 5.4, Scientific 
Rationale for Study Design;
Section 5.5 Justification for
Dose;
Section 6.3.2 Caffeine, 
Alcohol, and Tobacco;
Additional information for Part C added.
To account for the newly added 
Part C.
Protocol Amendment No.: 05
Date: 30-Jun-2023
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
Section 7.4 Dosage 
Modification;
Section 9.2.5 Pregnancy
Section 3.1 Study Rationale
Removed “in patients with MS” from first 
bullet. 
Clarification made to facilitate 
the broader population and not 
only the specific population. 
Section 3.2.7, BMS-986196 
Clinical Experience;
Section 3.2.8, 
11C-BMS-986196 Clinical 
Experience
New sections added.
To provide newly available 
clinical information for 
BMS-986196 and 
11C-BMS-986196.
Section 3.3 Benefit/Risk 
Assessment;
Section 9.1.1.1 PET 
Assessments
Site information updated. 
Site information has been 
updated to include more sites for 
Part C.
Section 4 Objectives and 
Endpoints
Additional primary 
 
objectives and endpoints added for 
unlabeled BMS-986196. 
To account for the newly added 
Part C.
Section 5, Study Design
Additional information for Part C added:

Study design updated to include Part C.

Total number of participants updated 
from 16 to 28.

Treatment period and safety follow-up 
updated with additional information 
relevant to Part C. 
To account for the newly added 
Part C.
Section 5.2, Number of 
Participants
Total number of participants updated from 
16 to 28. Additional information for the 
participants to be considered in Part C 
added. 
To account for the study 
participants in the newly added 
Part C.
Section 6.1 Inclusion Criteria
New criteria added for Part C participants 
in 2) and 4). 
To account for the inclusion 
criteria in the newly added 
Part C.
Section 6.2 Exclusion Criteria

Two new criteria added for Part C 
participants in 1). 

Added “Part C” in criteria 1) a), 1) g), 
1) w), 3) b), 4) b), and 4) c). 

Added “Part A and Part B” in criterion 
1) t). 
To account for the exclusion 
criteria in the newly added 
Part C.
Section 7.1 Study Interventions 
Administered
New information on Part C added in 
Table 7.1-1.
To account for study 
interventions in the newly added 
Part C.
Section 7.2 Method of Study 
Intervention Assignment
Additional details for assignment of 
participants in Part C added.
To account for the newly added 
Part C.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
Section 7.5 
Preparation/Handing/Storage/
Accountability 
Added statement: “Only participants 
enrolled in the study may receive study 
intervention, and only authorized staff may 
supply, prepare, or administer study 
intervention.”
Statement added to align with 
the current BMS protocol model 
document. 
Section 7.6 Treatment 
Compliance
Additional Part C information added.
To account for the assessment of 
compliance in the newly added 
Part C.
Section 7.7.1 Prohibited and/or 
Restricted Treatments
Added clarification text “or 5 times the 
elimination half-life (if known), whichever 
is longer,” to bullet 6). 
Added for consistency.
Section 9.1.1.1 PET 
Assessments
Additional Part C information added under 
PET assessment.
To account for the assessments 
in the newly added Part C.
Section 9.2.1 Time Period and 
Frequency for Collecting AE 
and SAE Information
Part C serious adverse event collection time 
period added. 
To account for the assessments 
in the newly added Part C.
Section 9.4.1: Physical 
Examinations

Added “Part C”. 
To account for the assessments 
in the newly added Part C.
Section 9.4.4: Allen's Test 
(Part A and Part B only)

Added “Part A and Part B only” to 
section heading. 
To account for the assessments 
in the newly added Part C.
Section 9.4.6: Clinical Safety 
Laboratory Assessments

Added “Part C”. 

Added TB test for Part C under “Other 
Analyses”. 
To account for the assessments 
in the newly added Part C.
Section 9.4.7 Suicidal Risk 
Monitoring (Part C only) 
New section added.
To specify C-SSRS assessments 
in the newly added Part C.
Section 9.8 Biomarkers
Section updated to include Part C sampling 
schedule. 
To specify biomarker 
assessments in the newly added 
Part C.
Section 10.3: Analysis Sets;
Section 10.4.2: Primary 
Endpoint(s);
 
Updated to include Part C.
To address statistical 
considerations for the newly 
added Part C.
Throughout the protocol
Minor language and formatting changes.
To improve clarity of the 
protocol.
Protocol Amendment No.: 05
Date: 30-Jun-2023
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 05: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 PROTOCOL SUMMARY ......................................................................................... 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.2 Background ....................................................................................................... 
 
3.2.1 11C-BMS-986196 .................................................................................... 
 
3.2.2 Multiple Sclerosis ..................................................................................... 
 
3.2.3 BMS-986196 Nonclinical Pharmacology ................................................ 
 
3.2.4 BMS-986196 Nonclinical Pharmacokinetics ........................................... 
 
3.2.5 Preclinical BMS-986196 PET Tracer Studies ......................................... 
 
3.2.6 BMS-986196 Nonclinical Toxicology ...................................................... 
 
3.2.7 BMS-986196 Clinical Experience ............................................................ 
 
3.2.8 11C-BMS-986196 Clinical Experience .................................................... 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
3.3.1 Risk Assessment ....................................................................................... 
 
3.3.2 Benefit Assessment ................................................................................... 
 
3.3.3 Overall Benefit/Risk Conclusion .............................................................. 
 
3.3.4 COVID-19-related Risk Mitigation Measures ......................................... 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Data Monitoring Committee and Other Committees ............................... 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.5 Justification for Dose ........................................................................................ 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.3.1 Meals and Dietary Restrictions ............................................................... 
 
6.3.2 Caffeine, Alcohol, and Tobacco ............................................................... 
 
6.3.3 Activity ..................................................................................................... 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening ..................................................................... 
 
7 STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ....................... 
 
7.1 Study Interventions Administered .................................................................... 
 
7.2 Method of Study Intervention Assignment ....................................................... 
 
7.3 Blinding............................................................................................................. 
 
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7.4 Dosage Modification ......................................................................................... 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Other Restrictions and Precautions ......................................................... 
 
7.7.2.1 Imaging Restriction and Precautions ............................................. 
 
7.8 Continued Access to Study Intervention after the End of the Study ................ 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Intervention ......................................................... 
 
8.1.1 Post-study Intervention Study Follow-up................................................. 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.2.1 Individual Discontinuation Criteria ........................................................ 
 
8.3 Lost to Follow-up .............................................................................................. 
 
8.4 AE-defined Stopping Rules .............................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Imaging Assessments ............................................................................... 
 
9.1.1.1 PET Assessments ............................................................................. 
 
9.1.1.2 MRI Imaging During Screening ...................................................... 
 
9.1.1.3 Central Image Analysis ................................................................... 
 
 
 
9.2 Adverse Events ................................................................................................. 
 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
 
9.2.5 Pregnancy ................................................................................................ 
 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.7 Potential Drug-induced Liver Injury ....................................................... 
 
9.2.8 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Physical Examinations ............................................................................. 
 
9.4.2 Height and Weight ................................................................................... 
 
9.4.3 Vital Signs ................................................................................................ 
 
9.4.4 Allen’s Test (Part A and Part B only) ...................................................... 
 
9.4.5 Electrocardiograms ................................................................................. 
 
9.4.6 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.7 Suicidal Risk Monitoring (Part C only) ................................................... 
 
9.4.8 Other Safety Assessment .......................................................................... 
 
 
 
9.6 Immunogenicity Assessments ........................................................................... 
 
9.7 Genetics............................................................................................................. 
 
9.8 Biomarkers ........................................................................................................ 
 
9.9 Additional Research .......................................................................................... 
 
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9.10 Other Assessments .......................................................................................... 
 
9.11 Health Economics OR Medical Resource Utilization and Health Economics
........................................................................................................................... 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Statistical Hypotheses ..................................................................................... 
 
10.2 Sample Size Determination ............................................................................. 
 
10.3 Analysis Sets ................................................................................................... 
 
10.4 Statistical Analyses ......................................................................................... 
 
10.4.1 General Considerations ......................................................................... 
 
10.4.2 Primary Endpoint(s) .............................................................................. 
 
10.4.3 Secondary Endpoint(s) ........................................................................... 
 
 
 
10.4.5 Other Safety Analysis ............................................................................. 
 
10.4.6 Other Analyses ....................................................................................... 
 
10.5 Interim Analyses ............................................................................................. 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING ....................................................................... 
 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 COCKCROFT GAULT FORMULA .................................................... 
 
APPENDIX 6 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
................................................................................................................................. 
 
 
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BTKi-CNS
1
PROTOCOL SUMMARY
Protocol Title:
A Phase 1, Open-label, Multi-part Study to Evaluate the Safety, Tolerability, Kinetics, 
Biodistribution, and CNS Signal of the Positron Emission Tomography Ligand 11C-BMS-986196 
in Healthy Participants after Intravenous Administration and to Evaluate the Safety, Tolerability, 
Kinetics, and CNS Signal Repeatability of 11C-BMS-986196 after Repeat Intravenous 
Administration in Participants with Multiple Sclerosis
Brief Title:
Safety, Tolerability, Kinetics, and Biodistribution of the PET Ligand 11C-BMS-986196 after IV 
Administration in Healthy Participants and the Evaluation of CNS Signal Repeatability after 
Repeat IV Administration in Participants with Multiple Sclerosis
Rationale:
11C-BMS-986196 covalently binds and inhibits Bruton’s tyrosine kinase (BTK), a kinase 
expressed in B-cells, monocytes, macrophages, microglia, dendritic cells, natural killer cells, 
granulocytes, mast cells, basophils, eosinophils, osteoclasts, and platelets. BTK plays a role in 
intracellular signaling cascades downstream of the B-cell receptor, activating immunoglobulin G 
immune complex receptors (FCγRIIa and FCγRIIIa), the high affinity immunoglobulin E receptor 
(FcεRI), and the receptor activator of nuclear factor kappa-Β (RANK).
BTK is not expressed in neurons, astrocytes, or oligodendrocytes and is not known to have 
functions in a healthy central nervous system (CNS) without inflammatory conditions. Based on 
the cellular expression profile of BTK, the known presence of B-cells, macrophages, and microglia 
in multiple sclerosis (MS) lesions, and the short half-life of [C-11], 11C-BMS-986196 has the 
potential to be a Positron Emission Tomography (PET) tracer for the detection of (chronic) 
microglial inflammation, (acute) lesions with infiltrating macrophages, and B-cell infiltrates in the 
brain or meninges of patients with MS. Preclinical experiments in experimental autoimmune 
encephalitis (EAE) mice support that 11C-BMS-986196 has the potential to detect MS.
This is the first study testing 11C-BMS-986196 as a PET ligand in humans. This study is supported 
by preclinical Good Laboratory Practices (GLP) toxicity and safety studies, including in rats and 
cynomolgus monkeys, in the context of an Investigational New Drug (IND) submission. There is 
no formal primary research hypothesis for this study to be statistically tested. The purpose of this 
study is to assess 11C-BMS-986196, a novel PET tracer for BTK in healthy participants and in 
participants with MS to facilitate its use for:

Assessment of CNS 
 in future clinical studies

Dose selection of compounds that target the BTK receptor in the CNS, including dose selection 
for unlabeled BMS-986196

Assessing the presence of BTK-expressing cells in participants with inflammatory CNS 
diseases, including MS
Protocol Amendment No.: 05
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Clinical Protocol
IM038010
BMS-986196
BTKi-CNS
Overall, the data from this study will contribute to general research and the development of a novel 
means to visualize CNS inflammation, and are expected to facilitate development of therapies for 
progressive MS.
Objectives and Endpoints:
Objectives
Endpoints
Primary
Primary

To assess safety, tolerability, kinetics, and CNS 
signal repeatability of the novel tracer 
11C-BMS-986196 in healthy participants and in 
participants with MS

To assess the safety of BMS-986196

Incidence, severity, seriousness, and type of AEs; 
clinically significant abnormalities in ECG, VS, 
laboratory values, physical examination, and C-SSRS

Radiation dosimetry calculated from PET-CT images 
in healthy participants

Image acquisition window after administration of 
11C-BMS-986196 

Test-retest repeatability based on quantitative 
analysis of CNS PET-MRI images (eg, SUV and/or 
VT) in participants with MS 

To quantify the proportion of free BTK in the 
brain after administration of unlabeled 
BMS-986196

% Free brain BTK relative to baseline
Secondary
Secondary

To assess 11C-BMS-986196 signal 
characterization

Calculated SUV and VT in the brain
Abbreviations: AE, adverse event; BTK, Bruton’s tyrosine kinase; CNS, central nervous system; C-SSRS, Columbia-
Suicide Severity Rating Scale; ECG, electrocardiogram; MS, multiple sclerosis; PET-CT, positron emission 
tomography - computed tomography; PET-MRI, positron emission tomography - magnetic resonance imaging; SUV, 
standardized uptake value; VS, vital signs; VT, volume of distribution.
Overall Design:
This is a Phase 1, open-label study in healthy participants and participants with MS to evaluate a 
novel, positron-emitting ligand 11C-BMS-986196, for measurement of free BTK. The study will 
include up to 28 evaluable participants (Part A: up to 8 healthy participants; Part B: up to 
8 participants with MS; Part C: up to 12 healthy participants). The study consists of 3 periods: 
screening, treatment, and safety follow up. See Figure 1.
All participants will undergo PET scanning with 11C-BMS-986196. An initial dose of 
11C-BMS-986196 will be administered at doses up to 20 μg with the radioactivity of the dose at 
approximately 370 MBq (10 mCi). In Part B and Part C, the radioactive dose and participant 
preparation may be revised based on results of radiation dosimetry obtained in Part A, but 
administered mass will not exceed 20 μg.

Part A (Whole-Body Radiation Dosimetry and Cranial PET Imaging): Up to 6 evaluable 
healthy adult participants (at least 2 male and 2 female participants are planned) will complete 
whole-body positron emission tomography - computed tomography (PET-CT) imaging after a 
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bolus intravenous (IV) administration of 11C-BMS-986196 under fasting conditions, to 
confirm tracer safety, assess image acquisition window, determine radiation dosimetry of the 
administered radiotracer, and assess optimal imaging time. The PET scan will last 
approximately 2 hours. At least 2 hours and at most 6 days after the first tracer administration, 
participants will receive a second tracer administration and undergo cranial PET imaging using 
either PET-CT or positron emission tomography - magnetic resonance imaging (PET-MRI), 
depending on the availability of equipment. If the interval between the first and second PET 
scan is 4 days or more, the study site staff must contact the participant remotely (eg, by phone) 
on Day 4 (ie, 3 days after the first PET scan) and record adverse events (AEs) and any 
concomitant medications. Following an observation period of approximately 1 hour after 
completion of all PET scanning procedures, participants will be discharged from the PET 
center and enter the safety follow-up period. Up to 6 healthy participants will complete Part A 
before initiation of Part B. If emerging data from Part B indicate that venous blood sampling 
is likely to be required in future studies using 11C-BMS-986196 without arterial blood sampling 
(eg, because a [pseudo]-reference region cannot be reliably established), 2 additional 
participants can be enrolled in Part A at the discretion of the Sponsor. These additional 
2 participants will only undergo cranial PET imaging using either PET-CT or PET-MRI, 
depending on the availability of equipment (ie, not whole body PET-CT).

Part B (Characterization of 11C-BMS-986196 binding in the human brain): Up to 
8 participants with MS will complete 2 evaluable cranial PET-CT or PET-MRI scans 
(depending on equipment availability) after a bolus IV administration of 11C-BMS-986196, 
separated by at least 2 hours and at most 6 days to determine the optimal quantification 
parameters, including within-participant variability under test and retest conditions. Following 
an observation period of approximately 1 hour after completion of PET scanning procedures, 
participants will be discharged from the PET center and enter the safety follow-up period. If 
the interval between the first and second PET scan is 4 days or more, the study site staff must 
contact the participant remotely (eg, by phone) on Day 4 (ie, 3 days after the first PET scan) 
and record AEs and any concomitant medications. Participants who had a MS relapse within 
30 days prior to Day 1 must start Scan 2 on Day 1 or Day 2. Up to 8 participants with MS will 
complete Part B.

Part C (Quantification of free BTK availability in the human brain): Up to 12 evaluable 
healthy adult participants will complete 2 evaluable cranial PET-CT or PET-MRI scans 
(depending on equipment availability). The first cranial PET scan will occur on Day 1 after a 
bolus IV administration of 11C-BMS-986196. After completion of the first evaluable PET scan
(on the same day or the day following the PET scan), participants will receive orally 
administered unlabeled BMS-986196 on-site or at home once daily (QD) for preferably 1 day; 
and approximately 24 hours after the (last) dose of BMS-986196, participants will undergo the 
second cranial PET scan after a bolus IV administration of 11C-BMS-986196. If the second 
PET scan cannot be performed in this time frame, it is permissible to administer a single dose 
of unlabeled BMS-986196 up to 7 days after the Day 1 PET (eg, in case of scheduling 
conflicts). In addition, in case of synthesis failure of PET tracer it is permissible to administered 
multiple doses of unlabeled BMS-986196 in order to have BMS-986196 administered 24 hours 
prior to the second PET scan, if Sponsor agrees. No more than 7 doses can be administered.
Up to 3 dose levels of (unlabeled) BMS-986196 will be tested (15 mg, 30 mg, and 60 mg QD) 
and approximately 4 participants per dose level will be tested. Initially, participants will be 
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assigned to the 30 mg dose level. After an interim review of PET results from 2 to 4 evaluable 
participants, the next dose level (15 mg or 60 mg) will be determined. At least 2 evaluable 
participants should have completed PET imaging at the second dose level before participants 
are assigned to the last dose level.
Figure 1:
Study Design Schema
Part A - Safety, Tolerability, and Dosimetry in Healthy Participantsa
Part B - Repeatability of 11C-BMS-986196 PET in Participants with MS
Part C - Quantification of Free BTK Availability in Healthy Participants
Abbreviations: BTK, Bruton’s tyrosine kinase; IV, intravenous; hr, hour; MS, multiple sclerosis; PET, positron 
emission tomography; QD, once daily.
a Prior to initiation of Part B, all Part A participants will undergo Visits 1 and 2. After initiation of Part B, up to 
2 participants may be added to Part A and will not undergo Visit 1, only Visit 2. For these participants only, Visit 
2 will be regarded as Day 1.
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b Visit 2 tracer administration must be done at least 2 hours and at most 6 days after Visit 1 tracer administration (ie, 
Day 2 to Day 7).
c Participants who had a MS relapse within 30 days prior to Day 1 must start Scan 2 on Day 1 or Day 2.
d After completion of the first evaluable PET scan (on the same day or the day following the PET scan), participants 
will receive orally administered unlabeled BMS-986196 QD for preferably 1 day; and approximately 24 hours after 
the (last) dose of BMS-986196, participants will undergo the second cranial PET scan. If the second PET scan 
cannot be performed in this time frame, it is permissible to administer a single dose of unlabeled BMS-986196 up 
to 7 days after the Day 1 PET (eg, in case of scheduling conflicts) or to dose unlabeled BMS-986196 QD for up to 
7 days (eg, in case of synthesis failure of the PET tracer), if the Sponsor agrees.
Number of Participants:
Up to 28 evaluable participants are planned to be enrolled, up to 8, 8, and 12 in Parts A, B, and C, 
respectively. In Part A, evaluable participants for dosimetry outcomes are defined as those with 
adequate PET-CT whole-body scans collected over > 60 minutes. Part A evaluable participants for 
cranial PET are defined as those with cranial scans of adequate quality to be evaluable. In Part B, 
participants must have 2 cranial PET-CT/PET-MRI scans of adequate quality to be evaluable. To 
be evaluable in Part C, participants must have 1 cranial PET-CT/PET-MRI scan of adequate 
quality before administration of (unlabeled) BMS-986196 and 1 cranial PET-CT/PET-MRI scan 
of adequate quality after administration of (unlabeled) BMS-986196. Participants with non-
evaluable PET images may be substituted with new study participants.
Study Population:
Key Inclusion Criteria:
Women of childbearing potential (WOCBP) and men, 18 to 55 years of age, inclusive. (Parts A 
and B).
Women not of childbearing potential (WNOCBP) and men, 18 to 55 years of age, inclusive (Part C 
only).
Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP 
on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the 
potential of fetal toxicity occurring due to transmission of 11C-BMS-986196, present in seminal 
fluid, to a developing fetus even if the participant has undergone a successful vasectomy or if the 
partner is pregnant.

Type of Participant and Target Disease Characteristics

For Part A and Part B:
Body mass index (BMI) of 18 to 34 kg/m2, inclusive, and total body weight ≥50 kg 
(BMI may be rounded, eg, a participant with a BMI of 34.4 would qualify).
Documentation of normal Allen’s test result at Screening and on PET scanning days in 
the arm that will be used for arterial line placement.

Part A only:
Healthy male and female participants without clinically significant deviation from 
normal in medical history, physical examination (PE), electrocardiograms (ECGs), and 
clinical laboratory determinations.
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
Part B only:
Male or female participant diagnosed with MS according to the 2017 revisions of the 
McDonald diagnostic criteria.
Expanded Disability Status Scale (EDSS) score between 0 to 6.5, inclusive, at 
Screening.

For Part C: 
Body mass index (BMI) of 18 to 34 kg/m2, inclusive, and total body weight ≥50 kg 
(BMI may be rounded, eg, a participant with a BMI of 34.4 would qualify). 
Healthy male and WNOCBP participants without clinically significant deviation from 
normal in medical history, physical examination (PE), ECGs, and clinical laboratory 
determinations.
Key Exclusion Criteria:

Medical Conditions

Any significant acute or chronic medical illness (Part A and Part C). Any significant acute 
or chronic medical illness (other than MS) posing a risk to the participant’s safety or 
negatively affecting the ability to detect CNS PET signal (Part B only).

Benign MS defined as a baseline EDSS of 2.0 with MS diagnosis ≥ 10 years prior to Day 1. 
Spinal MS without clinical or radiological evidence of brain lesions. Any other 
combination of clinical and radiological data suggestive of an absence of inflammatory 
brain lesions.

MS relapse within 14 days prior to Day 1. Participants with a MS relapse within 30 days 
prior to Day 1 must agree to have their second PET scan scheduled on Day 1 or Day 2 
(Part B only).

Any major surgery within 4 weeks of study treatment administration and/or any minor 
surgery within 2 weeks of tracer administration.

A history of pancreatitis.

A history of prolonged bleeding or excessive bruising.

Known or suspected autoimmune disorder, including but not limited to rheumatoid 
arthritis, fibromyalgia, systemic lupus erythematosis, polymyalgia rheumatica, giant cell 
arteritis, Behcet’s disease, dermatomyositis, severe asthma, any autoimmune vasculitis, 
autoimmune hepatitis, or any other active autoimmune disease for which a participant 
requires medical follow-up or medical treatment. Participants in Part A and Part C must 
not have a diagnosis of MS.

Any history of known or suspected congenital or acquired immunodeficiency state or 
condition that would compromise the participant’s immune status and/or confound tracer 
dosimetry and signal detection (eg, splenectomy).

Presence of any factors that would predispose the participant to develop infection (eg, 
rectal fissures, poor dentition, open skin lesions, and presence of pre-existing skin 
conditions that increase risks for injection site complications [eg, Behcet’s disease, 
psoriasis, pustular dermatoses]).
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
Known currently active tuberculosis (TB) (Part A and Part B).

Any serious acute or chronic bacterial or viral infection (eg, pneumonia, septicemia) within 
3 months prior to Screening.

In the case of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection, symptoms must have completely resolved and based on investigator assessment, 
there are no sequelae (eg, shortness of breath, persistent cough, excessive fatigue, loss of 
smell) that would place the participant at a higher risk of receiving investigational 
treatment.

Positive test result for the presence of SARS-CoV-2 virus (eg, polymerase chain reaction 
[PCR] test) within 14 days of Day 1.

Any recent infection requiring antibiotic treatment within 4 weeks of Day 1.

Active herpes infection, including herpes simplex 1 and 2 and herpes zoster.

Known active malaria.

History or any evidence of active infection or febrile illness within 7 days of tracer 
administration (eg, bronchopulmonary, urinary, or gastrointestinal).

Donation of blood to a blood bank or to another clinical study within 4 weeks of tracer 
administration (within 2 weeks for plasma only).

Inability to be venipunctured and/or tolerate venous access.

Have any contraindication to arterial line insertion, including but not limited to, an 
abnormal Allen’s test result, coagulation profile, allergy to local anesthetics, or other 
medical history or examination findings that in the opinion of the Investigator would make 
radial artery cannulation contraindicated (international normalized ratio [INR]/partial 
thromboplastin time [PTT]) at Screening (Part A and Part B).

Contraindications against MRI imaging, including non-MRI compatible metal implants, 
cardiac pacemakers, cochlear implants, ventricular shunt systems; metal particles in the 
body that pose a risk to the participant, including large tattoos in regions affected by cranial 
MRI scanning; severe claustrophobia. Contraindications against gadolinium-based contrast 
agents including known hypersensitivity to gadolinium-based contrast agents (Part B only).

Recent (within 6 months of study intervention administration) drug or alcohol abuse as 
defined in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5), 
Diagnostic Criteria for Drug and Alcohol Abuse.

Use of any tobacco- or nicotine-containing products (including but not limited to cigarettes, 
pipes, cigars, electronic cigarettes, chewing tobacco, nicotine patches, nicotine lozenges, 
or nicotine gum) within 3 months prior to the first dose of tracer administration (Part A and 
Part C).

Any other sound medical, psychiatric, and/or social reason as determined by the 
investigator.

Inability to lie on the scanner for the duration of a PET scan acquisition.

Current clinical or laboratory evidence of active TB. Participants with a positive 
QuantiFERON-TB Gold Plus test or 2 successive indeterminate QuantiFERON-TB Gold 
Plus tests at Screening will be excluded (Part C only).
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
Participants who answer “yes” to items 4 or 5 of the Columbia-Suicide Severity Rating 
Scale (C-SSRS) or who answer “yes” to any suicidal behavior item (excluding non-suicidal 
self-injurious behavior) within 6 months prior to Day 1 or at Day -1 (See Section 9.4.7 for 
details on suicidal risk monitoring) (Part C only).

Reproductive Status

Women who are pregnant 

Women who are breastfeeding

Physical and Laboratory Test Findings

Evidence of organ dysfunction or any clinically significant deviation from normal in PE, 
vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the 
target population, in the opinion of the investigator

Positive urine screen for drugs of abuse (Part A and Part C)

Positive cotinine test (Part A and Part C)

Positive blood screen for hepatitis C antibody, hepatitis B core antibody, hepatitis B surface 
antigen, or human immunodeficiency virus (HIV)-1 and -2 antibody 

Estimated renal creatinine clearance < 30 ml/min based on the Cockgroft-Gault formula

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 x upper limit 
of normal (ULN)

Total bilirubin > 2 x ULN (unless in the context of Gilbert syndrome)
Intervention Groups and Duration:
Study intervention: 
Study Intervention for IM038010
Medication 
Potency 
IP/Non-IP/AxMP
11C-BMS-986196
Approximately 370 MBq, 
equivalent to up to 20 μg
IP
BMS-986196 tablet
15 mg, 30 mg, or 60 mg
IP
AxMP, auxiliary medicinal product; IP, investigational product; MBq, megabecquerel.
Study duration:
The estimated duration from screening through safety follow-up phone call (or in-person study site 
visit) is up to approximately 6 weeks for Part A, approximately 6 weeks for Part B, and up to 
10 weeks for Part C.

Screening: Within 30 days prior to administration of 11C-BMS-986196
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
Treatment Period:

Part A: After the first tracer administration (Day 1), participants will receive a second tracer 
administration at least 2 hours and at most 6 days and undergo cranial PET imaging using 
either PET-CT or PET-MRI, depending on the availability of equipment

Part B: After the first tracer administration (Day 1), participants will receive a second tracer 
administration at least 2 hours and at most 6 days, and undergo cranial PET imaging using 
either PET-CT or PET-MRI, depending on the availability of equipment

Part C: After the first tracer administration and cranial PET imaging (Day 1), participants 
will receive unlabeled BMS-986196 for oral administration on-site or at home QD for 
approximately 1 day (at least 1 and at most 7 days), and will undergo a second cranial PET 
procedure approximately 24 hours after the last dose of unlabeled BMS-986196. PET 
imaging will be performed with PET-CT or PET-MRI, depending on the availability of 
equipment

Safety Follow-up: 

Parts A and B: Participants will be contacted remotely by phone 3 days (± 1 day) after 
completion of all PET scanning procedures. An in-person visit is optional.

Part C: Participants will have 1 in-person visit 7 days after Visit 2 after completion of all 
PET scanning procedures and will be contacted remotely by phone 28 days (+ 3 days) after 
Visit 2.
Statistical Methods:
Statistical analyses in this study will be detailed in the statistical analysis plan (SAP). There are no 
formal statistical hypotheses for this Phase 1, open-label study. Descriptive statistics or frequency 
summary, as appropriate, will be used to analyze most all primary endpoints (ie, incidence, 
severity, seriousness, and type of adverse events; incidence of clinically significant abnormal 
findings; radiation dosimetry [Part A only]; test-retest repeatability [Part B only]; proportion of 
free brain BTK relative to baseline [Part C only]; C-SSRS [Part C only]).
Data Monitoring Committee: No
A Data Monitoring Committee will not be used in the study.
Other Committee: No
Other review committees will not be used in the study.
Brief Summary:
The purpose of this study is to evaluate the safety, tolerability, kinetics, biodistribution, and central 
nervous system (CNS) signal of the positron emission tomography (PET) ligand 11C-BMS-986196 
in healthy participants after intravenous administration and to evaluate the safety, tolerability, 
kinetics, and CNS signal repeatability of 11C-BMS-986196 after repeat intravenous administration 
in participants with multiple sclerosis. In Part C, the purpose is to quantify the amount of free BTK 
in the brain before and after administration of unlabeled BMS-986196. 11C-BMS-986196 is a 
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novel PET tracer for Bruton’s tyrosine kinase (BTK), and this study will facilitate its future use 
for:

Assessment of CNS 
 in future clinical studies in patients with multiple 
sclerosis (MS)

Dose selection of compounds that target the BTK receptor in the CNS, including dose selection 
for unlabeled BMS-986196

Assessing the presence of BTK-expressing cells in participants with inflammatory CNS 
diseases, including MS
Study details include:
Study Duration: For Part A and Part B, up to approximately 6 weeks; for Part C, up to 
approximately 10 weeks
Study Intervention Duration: For Part A and Part B, up to 6 days; for Part C, up to 9 days
Study Visit Frequency: For Part A and Part B, up to two visits in 1 week and a safety follow-up 
phone call or study site visit 3 days (± 1 day) after the last visit; for Part C, up to two visits in up 
to 2 weeks, one safety follow-up study site visit 7 days after the last visit, and one safety follow-
up phone call 28 days (+ 3 days) after the last visit.
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2
SCHEDULE OF ACTIVITIES
Study assessments and procedures are presented for screening in Table 2-1 and are presented for 
imaging assessments and procedures in Table 2-2 (Part A), Table 2-3 (Part B), and Table 2-4
(Part C).
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Table 2-1:
Screening Procedural Outline for Parts A, B, and C (IM038010)
Procedure
Screening
Visit(s)
(Day -30 to
Day -1)
Notes
Eligibility Assessments and Related 
Procedures
Informed Consent
X
A participant is considered enrolled only when a protocol-specific informed consent is signed. 
Must be obtained prior to performing any screening procedures.
Inclusion/Exclusion Criteria
X
Demographics
X
Medical History
X
Include any toxicities or allergies related to previous treatments. 
For Part B, all medical history relevant to MS should be obtained. 
Safety Assessments
Height, Weight, and BMI
X
BMI will be calculated. 
Complete PE
X
If the Screening PE is performed within 24 hrs prior to tracer administration on Day 1, then a 
single complete PE is sufficient for both the Screening and Day 1 PE. See Section 9.4.1.
12-Lead ECG
X
ECGs should be recorded after the participant has been supine for at least 5 min. 
If the Screening ECG is performed within 24 hrs prior to tracer administration on Day 1, then a 
single ECG is sufficient for both the Screening and Day 1 ECG. See Section 9.4.5.
Vital Signs
X
VS (including body temperature, respiration rate, seated BP, and HR) should be measured after 
the participant has been resting quietly in a supine position for at least 5 min. 
See Section 9.4.3.
Allen’s Test
X
Parts A and B only. Normal result must be documented in at least 1 arm.
C-SSRS
X
Part C only. Screening/baseline version with lifetime and 6 months review interval.
SAE Assessment
X
All SAEs must be collected from the time of signing the consent until 10 days after the last tracer 
administration or the final visit, whichever is later.
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Table 2-1:
Screening Procedural Outline for Parts A, B, and C (IM038010)
Procedure
Screening
Visit(s)
(Day -30 to
Day -1)
Notes
All AEs (SAEs and non-serious AEs) associated with SARS-CoV-2 infection must be collected 
from the date of participant’s written consent. See Section 9.2.1.
Prior and Concomitant Medication 
Use
X
Includes prescription, over-the-counter medications, and herbal supplements. 
See Section 7.7.1 for Prohibited and/or Restricted Treatments.
Laboratory Tests
HBsAg, anti-HBc, HCV Ab, HIV 
Serology
X
Results must be confirmed as negative prior to tracer administration on Day 1.
Hematology, Chemistry, Urinalysis, 
and Coagulation
X
Parts A and C participants: Participants are required to fast for at least 10 hrs prior to specimen 
collection. 
Screening results must be reviewed for eligibility prior to tracer administration on Day 1. See 
Section 9.4.6 for full list of clinical laboratory safety tests/assessments.
Urine Drug Screen 
X
Parts A and C only. Includes amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, and opiates.
Urine or Breath Alcohol Test
X
Urine Cotinine Test
X
Parts A and C only.
Pregnancy Test (WOCBP only)
X
Urine or serum test. Result must be confirmed as negative prior to tracer administration on 
Day 1. Acceptable methods of contraception are specified in Appendix 4. 
FSH Test
X
Women < 55 years for confirmation of postmenopausal status. Refer to Appendix 4.
QuantiFERON-TB Gold Plus
X
Part C only. 
Imaging
Cranial MRI Scan
X
Part B only. MRI scan should only be performed after all Screening assessments for safety, 
clinical laboratory tests, and medical history have established eligibility for the study. See 
Section 9.1.1.2.
MRI scan with and without gadolinium contrast agent. If gadolinium contrast agent will be used 
during PET-MRI, gadolinium-based contrast agent is not required during Screening MRI. 
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Table 2-1:
Screening Procedural Outline for Parts A, B, and C (IM038010)
Procedure
Screening
Visit(s)
(Day -30 to
Day -1)
Notes
MRI scan should be performed within 14 days of Day 1. 
Abbreviations: AE, adverse event; anti-HBc, anti-hepatitis B core antibody; BMI, body mass index; BP, blood pressure; C-SSRS, Columbia-suicide severity rating 
scale; ECG, electrocardiogram; 
 FSH, follicle-stimulating hormone; HBsAG, hepatitis B surface antigen; 
HCV Ab, hepatitis C antibody; HIV, human immunodeficiency virus; HR, heart rate; hrs, hours; MRI, magnetic resonance imaging; MS, multiple sclerosis; min,
minutes; PE, physical examination; PET, positron emission tomography; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 
2; VS, vital signs; WOCBP, women of childbearing potential.
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Table 2-2:
Imaging Procedural Outline for Part A (IM038010)
Procedure
Visit 1
Day 1a
Visit 2 
(2 hrs to 6 days 
after Visit 1 
tracer 
administration)b
Safety Follow-up 
3 days (± 1 day) 
after most 
recent PET 
Scanc/Early 
Terminationd
Notes
Safety Assessments
Weight Measurement 
X
X
Partial PE
X
X
PE must be done within 24 hrs of tracer administration. 
Symptom-based PE only.
12-Lead ECG 
X
X
ECGs should be recorded after the participant has been 
supine for at least 5 min.
ECG will be conducted prior to tracer administration and 
after completion of the PET scan. See Section 9.4.5.
Vital Signs
X
X
VS will be obtained before tracer administration, after 
PET scan completion, and prior to discharge on Visits 1 
and 2. See Section 9.4.3.
Allen’s Test
X
Normal result (in the arm that will be used for arterial line 
placement) must be documented prior to arterial line 
placement.
Hematology, Chemistry, 
Urinalysis
X
X
Participants are required to fast for at least 10 hrs prior to 
specimen collection. Specimens will be collected at least 
1.5 hrs after the first tracer administration and at least 1.5 
hours after the second tracer administration.
See Section 9.4.6 for full list of clinical laboratory safety 
tests/assessments.
Pregnancy Test (WOCBP only)
X
X
Urine or serum test. Result must be confirmed as negative 
prior to tracer administration on Day 1.
Review of Emergency Contact 
Instructions
X
X
Prior to discharge on Visits 1 and 2.
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BTKi-CNS
Table 2-2:
Imaging Procedural Outline for Part A (IM038010)
Procedure
Visit 1
Day 1a
Visit 2 
(2 hrs to 6 days 
after Visit 1 
tracer 
administration)b
Safety Follow-up 
3 days (± 1 day) 
after most 
recent PET 
Scanc/Early 
Terminationd
Notes
Non-serious AE and SAE 
Assessments
X
X
X
All SAEs must be collected from the time of signing the 
consent until 10 days after the last tracer administration or 
the final visit, whichever is later.
All AEs (SAEs and non-serious AEs) associated with 
SARS-CoV-2 infection must be collected from the date of 
participant’s written consent. See Section 9.2.1.
Concomitant Medication Use
X
X
X
Imaging Assessments and Subsequent Procedures
Arterial Line Placement
X
Prior to tracer administration.
Venous Line Placement for 
Venous Blood Sampling 
(During Visit 2 PET Scan)
X
Prior to tracer administration (on the arm opposite to the 
tracer administration). 
Only in up to 2 participants (added to Part A after 
initiation of Part B) undergoing simultaneous arterial and 
venous blood sampling.
Whole-body PET-CT Scan
X
Whole-body PET-CT scan is from apex to the upper-thigh 
level. 
Cranial PET-CT Scan or PET-
MRI Scan
X
PET-CT or PET-MRI is performed, depending on 
equipment availability. The cranial PET scan is 
performed after the whole-body PET-CT scan. 
If scans are performed on the same day, participants are 
allowed to have a light meal between the whole-body 
PET scan and the cranial PET scan. 
Check Pressure Dressing, Hand 
and Finger Circulation
X
After arterial line placement, throughout the PET 
procedure, following removal of the arterial line, and 
before discharge
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BMS-986196
BTKi-CNS
Table 2-2:
Imaging Procedural Outline for Part A (IM038010)
Procedure
Visit 1
Day 1a
Visit 2 
(2 hrs to 6 days 
after Visit 1 
tracer 
administration)b
Safety Follow-up 
3 days (± 1 day) 
after most 
recent PET 
Scanc/Early 
Terminationd
Notes
Radiotracer Administration
Overnight and Post-dose Fasting
X
X
The night before tracer administration, participants will 
fast for at least 8.5 hrs before tracer administration and 
will remain fasted until at least 1.5 hrs after tracer 
administration. 
If 2 tracer administrations are performed on the same day, 
participants can have a light meal after the first tracer 
administration.
11C-BMS-986196 Tracer 
Administration 
Xa
Xa
Tracer is administered by a slow IV bolus prior to the 
whole-body PET scan and again prior to the cranial PET 
scan. 
Abbreviations: AE, adverse event; ECG, electrocardiogram; hr, hour; IV, intravenous; min, minute; PE, physical examination; PET, positron emission tomography; 
PET-CT, positron emission tomography - computed tomography; PET-MRI, positron emission tomography - magnetic resonance imaging; SAE, serious adverse 
event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VS, vital signs; WOCBP, women of childbearing potential.
a Prior to initiation of Part B, all Part A participants undergo Visits 1 and 2. After initiation of Part B, up to 2 participants may be added to Part A, and will not 
undergo Visit 1, only Visit 2. For these participants only, Visit 2 will be regarded as Day 1.
b Visit 2 tracer administration must be done at least 2 hours after and at most 6 days after Visit 1 tracer administration. If Visit 2 is performed on Days 5, 6, or 7, 
the site staff must contact the participant remotely (ie, by phone) on Day 4 and record AEs and concomitant medications. If 2 scans are performed on the same 
day, hematology and clinical chemistry sample collection, VS measurement, ECG, and review of AEs and concomitant medications are the only safety 
assessments that must be assessed in duplicate, and the same arterial line may be used for both scans.
c If the interval between Visit 1 (PET Scan 1) and Visit 2 (PET Scan 2) is ≥ 4 days, 2 follow up remote contacts (ie, phone calls) must be performed. In this case, 
each follow up contact will be performed 3 days (± 1 day) after the most recent PET procedure. 
d For participants who are prematurely discontinued from the study.
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BTKi-CNS
Table 2-3:
Imaging Procedural Outline for Part B (IM038010)
Procedure
Visit 1
Day 1
Visit 2 
(2 hrs to 6 days 
after Visit 1 tracer 
administration)a
Safety Follow-up 
3 days (± 1 day) 
after most recent 
PET Scanb/Early 
Terminationc
Notes
Safety Assessments
Weight Measurement 
X
Partial PE
X
X
On Visits 1 and 2, PE must be done within 24 
hrs of tracer administration. 
Symptom-based PE only.
12-Lead ECG 
X
X
ECGs should be recorded after the participant 
has been supine for at least 5 min.
On days with tracer administration, ECG should 
be conducted prior to tracer administration and 
after completion of the PET scan. 
See Section 9.4.5.
Vital Signs
X
X
VS will be obtained before tracer 
administration, after PET scan completion, and 
prior to discharge on Visits 1 and 2. 
See Section 9.4.3.
Allen’s Test
X
X
Normal result (in the arm that will be used for 
arterial line placement) must be documented 
prior to arterial line placement.
Hematology, Chemistry, and 
Urinalysis
X
X
For Visits 1 and 2, specimens will be collected 
at least 1.5 hours after tracer administration.
See Section 9.4.6 for full list of clinical 
laboratory safety tests/assessments.
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BTKi-CNS
Table 2-3:
Imaging Procedural Outline for Part B (IM038010)
Procedure
Visit 1
Day 1
Visit 2 
(2 hrs to 6 days 
after Visit 1 tracer 
administration)a
Safety Follow-up 
3 days (± 1 day) 
after most recent 
PET Scanb/Early 
Terminationc
Notes
Pregnancy Test (WOCBP only)
X
X
Urine or serum test. Result must be confirmed 
as negative prior to tracer administration on 
Day 1.
Review of Emergency Contact 
Instructions
X
X
Prior to discharge on Visits 1 and 2.
Non-serious AE and SAE 
Assessments
X
X
X
All SAEs must be collected from the date of 
participant’s written consent until 10 days after 
the last tracer administration or the final visit, 
whichever is later.
All AEs (SAEs and non-serious AEs) associated 
with SARS-CoV-2 infection must be collected 
from the date of participant’s written consent. 
See Section 9.2.1
Concomitant Medication Use
X
X
X
Imaging Assessments and Subsequent Procedures
Arterial Line Placement
X
X
Prior to tracer administration.
Venous Line Placement for 
Venous Blood Sampling
X
Prior to tracer administration (on the arm 
opposite to the tracer administration). 
Only in up to 6 participants if requested by 
Sponsor, and only during one cranial PET scan, 
preferably during Visit 1.
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BTKi-CNS
Table 2-3:
Imaging Procedural Outline for Part B (IM038010)
Procedure
Visit 1
Day 1
Visit 2 
(2 hrs to 6 days 
after Visit 1 tracer 
administration)a
Safety Follow-up 
3 days (± 1 day) 
after most recent 
PET Scanb/Early 
Terminationc
Notes
Cranial PET-MRI Scan or PET-CT 
Scan
Xd
Xb,d
PET-MRI or PET-CT is performed, depending 
on equipment availability. Same scan type (ie, 
PET-MRI or PET-CT) should be performed for 
both Visits 1 and 2.
Check Pressure Dressing, Hand 
and Finger Circulation
X
X
After arterial line placement, throughout the 
PET procedure, following removal of the 
arterial line, and before discharge.
Radiotracer Administration 
11C-BMS-986196 Tracer 
Administration 
X
Xe
Tracer is administered by a slow IV bolus prior 
to each PET scan.
Abbreviations: AE, adverse event; ECG, electrocardiogram; 
 hr, hour; IV, intravenous; min, minute; 
 
 PE, physical examination; PET, positron emission tomography; PET-CT, positron emission tomography computed tomography; PET-MRI, positron 
emission tomography magnetic resonance imaging; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VS, vital signs; 
WOCBP, women of childbearing potential.
a Visit 2 tracer administration must be done at least 2 hours after and at most 6 days after Visit 1 tracer administration. If Visit 2 is performed on Days 5, 6, or 7, 
the site staff must contact the participant remotely (ie, by phone) on Day 4 and record AEs and concomitant medications. Participants who had a 
 
within 30 days prior to Day 1 must start Scan 2 on Day 1 or Day 2. If 2 scans are performed on the same day, VS measurement, ECG, and review of AEs and 
concomitant medications are the only safety assessments that must be assessed in duplicate, and the same arterial line may be used for both scans. 
b If the interval between Visit 1 (PET Scan 1) and Visit 2 (PET Scan 2) is ≥ 4 days, 2 follow up remote contacts (ie, phone calls) must be performed. In this case, 
each follow up contact will be performed 3 days (± 1 day) after the most recent PET scan. 
c For participants who are prematurely discontinued from the study.
d Dynamic PET image acquisition.
e A third administration is permissible if a PET scan has to be repeated (eg, due to failure of a prior scan).
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BTKi-CNS
Table 2-4:
Imaging Procedural Outline for Part C (IM038010)
Procedure
Visit 1 
Day 1
Visit 2
approximately 
24 hrs after 
the last dose of 
BMS-986196
(Days 2-9)
Visit 3 
7 Days (±2) 
after Visit 
2/ET
Visit 4 
(28 - 31 
days 
after 
Visit 3)
Notes
In-person Visit to 
Clinical Site
X
X
X
Phone call/Telemedicine 
visit
X
In-person visit is optional. 
Email or text messaging is 
not sufficient.
Safety Assessments
Weight Measurement
X
Partial PE
X
X
X
12-lead ECG
X
X
X
Vital Signs
X
X
X
Hematology, Clinical 
Chemistry, Urine 
analysis
X
X
Participants are required to 
fast for at least 10 hrs prior to 
specimen collection. 
Specimens will be collected 
prior to tracer administration 
on Visits 1 and 2. 
See Section 9.4.6 for full list 
of clinical laboratory safety 
tests/assessments.
C-SSRS
X
X
X
Since last visit version of 
C-SSRS.
Review Emergency 
Contact Information
X
X
X
AE and SAE assessment
X
X
X
X
All AEs and SAEs must be 
collected from the time of 
signing the informed consent 
form, including those thought 
to be associated with 
protocol-specified procedures 
and until 28 days following 
discontinuation of dosing.
Concomitant Medication 
Use
X
X
X
X
Imaging Assessments and Procedures
Venous Line Placement 
for Blood Sampling
X
X
Prior to tracer administration 
(on the arm opposite to the 
tracer administration).
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BTKi-CNS
Table 2-4:
Imaging Procedural Outline for Part C (IM038010)
Procedure
Visit 1 
Day 1
Visit 2
approximately 
24 hrs after 
the last dose of 
BMS-986196
(Days 2-9)
Visit 3 
7 Days (±2) 
after Visit 
2/ET
Visit 4 
(28 - 31 
days 
after 
Visit 3)
Notes
Cranial PET/CT or 
PET/MRI
X
X
PET-CT or PET-MRI is 
performed, depending on 
equipment availability.
11C-BMS-986196 Tracer 
Administration
X
X
Tracer is administered by a 
slow IV bolus prior to each 
PET scan.
 PD Assessments
PD Sample for 
 
X
X
At Visit 2, collected prior to 
radiotracer administration
Administration of Unlabeled BMS-986196
Dispensing and Oral 
Administration of 
Unlabeled BMS-
986196a
X
Unlabeled BMS-986196 is 
administered orally with 
food. Administration starts on 
Day 1 after completion of the 
PET procedure or on Day 2.
BMS-986196 is preferably 
administered once;
approximately 24 hrs after 
the (last) dose of 
BMS-986196, participants 
will undergo the second 
cranial PET scan. If the 
second PET scan cannot be 
performed in this time frame, 
it is permissible to administer 
a single dose of unlabeled 
BMS-986196 up to 7 days 
after the Day 1 PET (eg, in 
case of scheduling conflicts) 
or to dose unlabeled 
BMS-986196 QD for up to 7 
days (eg, in case of synthesis 
failure of the PET tracer), if 
the Sponsor agrees.
Administration must be 
documented and can occur 
on-site and/or at home 
according to site preference
Reconciliation of 
Unlabeled BMS-986196
X
See Section 7.6 for additional 
information on reconciliation 
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BTKi-CNS
Table 2-4:
Imaging Procedural Outline for Part C (IM038010)
Procedure
Visit 1 
Day 1
Visit 2
approximately 
24 hrs after 
the last dose of 
BMS-986196
(Days 2-9)
Visit 3 
7 Days (±2) 
after Visit 
2/ET
Visit 4 
(28 - 31 
days 
after 
Visit 3)
Notes
of study intervention, drug 
accountability, and review of 
dosing diary.
Abbreviations: AE, adverse event; 
 C-SSRS, Columbia-Suicide Severity Rating Scale; 
ECG, electrocardiogram; ET, end of treatment; hr, hour; PD, pharmacodynamic; PE, physical examination; PET-CT, 
positron emission tomography - computed tomography; PET-MRI, positron emission tomography - magnetic 
resonance imaging; 
 SAE, serious adverse event; QD, once daily.
a BMS-986196 will be supplied by BMS and dispensed by the site before the participant leaves on Day 1. Participants 
should return the BMS-986196 container and any unused tablets to the facility for drug reconciliation if they take 
the medication home.
In the event that multiple procedures are required at a single time point, the following is a list of 
procedures from highest to lowest priority to minimize the effect of procedures on vital signs and 
electrocardiogram (ECG) evaluations:
Safety (12-lead ECG)
Safety (vital signs measurements)
Safety (clinical labs)
Safety assessment in response to AEs are not impacted by this priority list.
If the scheduled time for a 12-lead ECG coincides with any blood collection (ie, clinical safety 
labs), the blood draw should be performed as scheduled, with the 12-lead ECG being performed 
prior to any blood collection (up to 15 minutes earlier). ECGs will also be collected prior to the 
vital sign measurements.
3
INTRODUCTION
This is the first study characterizing 11C-BMS-986196 as a positron emission tomography (PET) 
tracer in humans.
11C-BMS-986196 is a radiolabeled version of BMS-986196, a central nervous system
(CNS)-penetrant Bruton’s tyrosine kinase inhibitor (BTKi) which is being developed for the 
treatment of multiple sclerosis (MS). 11C-BMS-986196 is intended to facilitate clinical 
development of unlabeled, therapeutically dosed BMS-986196 by enabling quantification of 
Bruton’s tyrosine kinase (BTK) receptor occupancy in the CNS of patients with MS. Measuring 
BTK receptor occupancy in the CNS is relevant for dose selection of BTKi, which generally 
requires > 95% receptor occupancy for efficacy.1,2,3 While BTK occupancy in white blood cells 
can be measured ex vivo, no tools exist for in vivo measurement of BTK occupancy in the human 
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BTKi-CNS
CNS, which is the tissue affected in MS. The current study is intended to characterize 
11C-BMS-986196 as a suitable PET ligand for detection of free BTK in the CNS. 
In mice with experimental autoimmune encephalitis (EAE), a preclinical model of MS, 
BMS-986196 labelled inflammatory lesions (confirmed by 
11C-BMS-986196 PET and 
[3H]BMS-986196 autoradiography) and demonstrated in vivo dose-dependent target engagement 
in mice pretreated with unlabeled BMS-986196 (see Investigator Brochure [IB] for details). In 
healthy non-human primates without inflammatory CNS lesions, 11C-BMS-986196 elicits a 
transient, diffuse signal in the CNS that is believed to reflect diffusion of 11C-BMS-986196 into 
the CNS without target engagement and is followed by rapid wash-out (see IB for details).
In this study, 11C-BMS-986196 will be dosed at microdoses of up to 20 μg, which is below the 
general microdose criterion of 100 μg for small molecule PET ligands. At doses of up to 20 μg, 
11C-BMS-986196 is not expected to elicit meaningful biological or pharmacological effects. 
Concurrent with this study, Study IM038008 is testing the safety, tolerability, pharmacokinetics, 
and target engagement as pharmacodynamics of BMS-986196 in healthy participants. In Study 
IM038008, the starting dose of unlabeled, orally administered BMS-986196 is 1 mg, which is 
projected to not have biologically meaningful effects and result in area under the plasma 
concentration-time curve (AUC) exposure more than 1,000-fold below that at the no-observed-
adverse-effect level (NOAEL) from the 1-month toxicology studies. The AUC exposure associated 
with single intravenous (IV) administration of 20 μg 11C-BMS-986196 is projected to be 
approximately 7.5-fold below the exposure associated with an oral dose of 1 mg. Orally 
administered doses ≥10 mg are projected to result in peak BTK occupancy > 95% in blood, and 
therefore, are projected to approach therapeutic levels. 
In Part C of this study, non-radioactively labeled (unlabeled) BMS-986196 will be administered 
at dose levels up to 60 mg once daily (QD) up to 7 days. Hence, in Part C, (unlabeled) BMS-986196 
will be administered at therapeutic dose levels and is expected to result in near maximum BTK 
occupancy. In Study IM038008, the first-in-human study testing unlabeled BMS-986196 at 
therapeutically relevant doses, administration of BMS-986196 at doses up to 90 mg QD for 14 
days was shown to be safe and tolerated. 
3.1
Study Rationale
This is the first study testing 11C-BMS-986196 as a PET ligand in humans. This study is supported 
by preclinical Good Laboratory Practices (GLP) toxicity and safety studies, including in rats and 
cynomolgus monkeys, in the context of an Investigational New Drug (IND) submission. There is 
no formal primary research hypothesis for this study to be statistically tested. The purpose of this 
study is to assess 11C-BMS-986196, a novel PET tracer for BTK in healthy participants and in 
participants with MS to facilitate its use for:

Assessment of CNS 
 in future clinical studies

Dose selection of compounds that target the BTK receptor in the CNS, including dose selection 
for unlabeled BMS-986196

Assessing the presence of BTK-expressing cells in participants with inflammatory CNS 
diseases, including MS
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BTKi-CNS
Overall, the data from this study will contribute to general research and the development of a novel 
means to visualize CNS inflammation, and are expected to facilitate development of therapies for 
progressive MS.
3.2
Background
A detailed description of the chemistry, pharmacology, preclinical efficacy, and safety of 
BMS-986196 and its PET ligand 11C-BMS-986196 are provided in the Investigator’s Brochure 
(IB).4
3.2.1
11C-BMS-986196
11C-BMS-986196 covalently binds, and inhibits BTK, a kinase expressed in B-cells, monocytes, 
macrophages, microglia, dendritic cells, natural killer cells, granulocytes, mast cells, basophils, 
eosinophils, osteoclasts, and platelets.5,6,7,8 BTK plays a role in intracellular signaling cascades 
downstream of the B-cell receptor, activating immunoglobulin G (IgG) immune complex receptors 
(FCγRIIa and FCγRIIIa), the high affinity immunoglobulin E receptor (FcεRI), and the receptor 
activator of nuclear factor kappa-Β (RANK).9
BTK is not expressed in neurons, astrocytes, or oligodendrocytes and is not known to have 
functions in a healthy CNS without inflammatory conditions. Based on the cellular expression 
profile of BTK, the known presence of B-cells, macrophages, and microglia in MS lesions, 10 and 
the short half-life of C-11, 11C-BMS-986196 has the potential to be a PET tracer for the detection 
of (chronic) microglial inflammation, (acute) lesions with infiltrating macrophages, and B-cell 
infiltrates in the brain or meninges of patients with MS. Preclinical experiments in EAE mice 
support that 11C-BMS-986196 has the potential to detect MS lesions (see Section 3.2.5 and IB for 
details).
BMS-986196 is blood-brain barrier penetrant in rats and cynomolgus monkeys and has high in-
vitro selectivity over other kinases (for details see the IB).
3.2.2
Multiple Sclerosis
MS is a chronic inflammatory disease; its pathology is characterized by lesions with acute bulk 
invasion of peripheral white blood cells to plaques and by chronic compartmentalized 
inflammatory lesions containing microglia and macrophages that are typically at some distance to 
perivascular or meningeal lymphocyte infiltrates.10 Within the continuum of relapsing and 
progressive MS, acute lesions are the predominant pathology in relapsing remitting MS, whereas 
chronic compartmentalized lesions are predominant in progressive MS. Approved treatments for 
MS, including anti-cluster of differentiation 20 (CD20) monoclonal antibodies, predominantly 
address the pathology associated with acute lesions. Importantly, none of the approved 
disease-modifying therapies for MS have the potential for exerting robust anti-inflammatory 
effects directly in the CNS or the meninges. Accordingly, the efficacy of approved 
disease-modifying therapies in MS has predominantly been demonstrated in relapsing forms of 
MS and is either absent or comparatively weaker in nonrelapsing progressive forms of MS.11
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BMS-986196
BTKi-CNS
Therefore, an unmet need exists for MS therapies that can exert robust anti-inflammatory effects 
in the CNS and have robust efficacy in nonrelapsing progressive forms of MS.  
3.2.3
BMS-986196 Nonclinical Pharmacology
BMS-986196 administered as an oral (PO) dose to mice potently inactivated BTK in peripheral 
blood, spleens, and brains of mice with EAE. The inactivation was durable, with recovery of 
available active sites due to new protein synthesis measured at a rate of approximately 15% per 
day after the drug was cleared. BMS-986196 provided robust inhibition of disease in the 
FcR-dependent, B cell independent collagen antibody-induced arthritis. In the EAE model, 
BMS-986196 provided efficacy against both clinically-evident disease and histological damage in
the brain. BMS-986196 also blocked antigen-dependent germinal center B cell production, a 
model of the ectopic follicles and CNS draining cervical lymph nodes, critical in driving MS 
immunopathology.
3.2.4
BMS-986196 Nonclinical Pharmacokinetics
 
 
 
 
 
 
 
 In vitro data indicated that hepatic uptake of 
BMS-986196 involved both passive diffusion and active transport, but organic anion transporting 
polypeptides (OATPs) and sodium taurocholate co-transporting polypeptide (NTCP) do not play 
a role in the uptake.
In vitro, BMS-986196 was extensively metabolized in liver microsomes and hepatocytes across 
species. Major metabolic pathways in human hepatocytes included oxidation of different moieties 
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BTKi-CNS
and hydrolysis of the vinyl amide moiety. Glutathione (GSH)-adduct formation was low in human 
and monkey hepatocytes, but substantially higher in rodent and dog hepatocytes. No unique 
metabolite was observed in human in vitro systems. In plasma samples of mice and rats 
administered with BMS-986196, the parent compound was the predominant drug-related 
component. Consistent with the results from in vitro data, the metabolic profiles of BMS-986196 
in mouse and rat plasma samples revealed the presence of several low level oxidative metabolites, 
downstream products of GSH-conjugates, and a hydrolysis product. Renal clearance of 
BMS-986196 was minimal in animals (< 0.1% of the overall clearance).
In vitro, there were few cysteine adducts detected in microsomal incubations fortified with 
cysteine, suggesting low intrinsic chemical reactivity of BMS-986196 to thiol. There was minimal 
to no covalent binding to off-target cysteinyl residues in BTK, human hemoglobin, or human 
serum albumin. Based on the in vitro protein covalent binding in hepatocytes and serum, the 
estimated daily covalent binding burden (DCBB) of BMS-986196 in humans is 0.95 mg/day at the 
projected efficacious dose of 66 mg once daily (QD), which is much lower than the literature 
suggested- upper limit of DCBB (10 mg/day)12 for clinically safe drugs that are designed as 
covalent enzyme inhibitors. 
3.2.5
Preclinical BMS-986196 PET Tracer Studies
[3H]BMS-986196 distribution in EAE mouse brain was examined by autoradiography at 1 hour 
and 24 hours after a single IV administration of 0.15 mg/kg or 1.5 mg/kg. [3H]BMS-986196 
binding was observed to align with the presence of disease in the sample, with over 3-fold 
increased radiotracer retention in lesion areas of EAE mice (1.43 nCi/mg) compared to brains of 
naïve animals (0.41 nCi/mg). In PET studies, 11C-BMS-986196 labelled suspected inflammatory 
lesions and demonstrated in vivo dose-dependent target engagement in EAE mice pretreated with 
oral doses of unlabeled BMS-986196 at 0.5 mg/kg or 5 mg/kg. In healthy non-human primates 
without inflammatory CNS lesions, 11C-BMS-986196 elicits a transient, diffuse signal in the CNS 
that is believed to reflect diffusion of 11C-BMS-986196 into the CNS without target engagement 
and is followed by rapid wash-out (see IB for details). Radiation dosimetry of 11C-BMS-986196 
was performed in healthy cynomolgus monkeys (2 male and 2 female) to estimate the absorbed 
radiation dose to human participants. Whole-body BMS-986196 distribution was assessed by 
serial imaging up to approximately 2 hours following radiotracer administration, covering 
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BMS-986196
BTKi-CNS
approximately 6 radioactive half-lives of the C-11 isotope. Individual organs with visual tracer 
signal (eg, brain, heart, lung, liver, spleen, kidney, muscle, bladder, etc.) were identified from the 
resulting scans. These identified organs were used as source organs for further dosimetry analysis. 
For additional details, see the IB. 
3.2.6
BMS-986196 Nonclinical Toxicology
A battery of nonclinical studies, including single- and/or repeat-dose oral toxicity studies 
(≤1-month) in rats, monkeys, and dogs; in vitro and in vivo genetic toxicology studies; in vitro 
and in vivo safety pharmacology assessments; and in vitro phototoxicity study have been 
completed to assess the toxicologic profile of BMS-986196. Rats and monkeys were selected as 
the species for toxicity evaluation because BMS-986196 is pharmacologically active in both 
species. Additionally, monkey was selected as the non-rodent species based on the ability to 
achieve acceptable exposure and tolerability between rats and monkeys. Since there were no sex 
differences in BMS-986196 exposures in either rats or monkeys, all exposures below are presented 
as sex-combined mean values. Safety multiples below are calculated relative to either the projected 
maximum observed plasma concentrations (Cmax) or exposures (AUC) of BMS-986196 at the 
proposed starting (1 mg) and ending (60 mg) doses in the single ascending dose (SAD)/multiple 
ascending dose (MAD) clinical study.
BMS-986196 was not phototoxic, mutagenic, or clastogenic in vitro. While it was genotoxic via 
an aneugenic (indirect) mechanism in vitro and in vivo as part of the 2-week exploratory 
toxicology study in rats at 300 mg/kg (Day 1 female mean area under the plasma concentration-
time curve from time zero to 24 hours postdose [AUC(0-24h)] ≤17.177 gh/mL), it was not 
genotoxic when administered to female rats at daily doses up to 200 mg/kg/day (Day 1 mean 
AUC[0-24h] ≤25.2 gh/mL; AUC multiple of > 40,000-fold over the projected associated with 
a 20 μg IV dose proposed in this study) for 4 days in the definitive in vivo micronucleus study 
with comet evaluation. Based on the overall weight of evidence, BMS-986196 is considered 
non-genotoxic.
In vitro screening against a panel of receptors, ion channels, transporters, and enzymes 
demonstrated that BMS-986196 did not significantly alter ligand binding or functional activity and 
was considered to have a low potential to produce effects related to secondary pharmacology. 
BMS-986196 did demonstrate weak to moderate inhibitory effects on cardiac human 
ether-a-go-go-related gene (hERG)/rapid delayed rectifier potassium channel current (IKr) 
potassium, cardiac SCN5A sodium channel, and L-type calcium channel currents. The cardiac 
hERG/IKr potassium channel IC50 was 9.1 μM (3.56 μg/mL). BMS-986196 at 1 and 4 Hz 
stimulation frequency inhibited cardiac sodium currents by 23.7 ± 2.1% and 29.4 ± 2.4%, 
respectively, at 10 μM (3.91 μg/mL). BMS-986196 inhibited cardiac calcium currents by 
46.3 ± 0.7% at 10 μM (3.91 μg/mL). There were no BMS-986196-related adverse cardiovascular 
changes in exploratory or definitive single-dose monkey telemetry studies at doses up to 
100 mg/kg (sex-combined mean plasma concentrations of ≤ 569 ng/mL 6 hours after dose; Cmax 
multiple of > 1,500-fold over the projected associated with a 20 μg IV dose proposed in this study). 
In addition, there were no BMS-986196-related effects on the CNS in the neurologic safety 
pharmacology study in male Sprague-Dawley rats at doses up to 200 mg/kg (mean AUC[0-24h] 
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≤23.9 g•h/mL; AUC multiple of > 40,000-fold over the projected associated with a 20 μg IV 
dose proposed in this study). Overall, BMS-986196 was considered to have low potential for 
cardiovascular, neurologic, and other off-target pharmacology, at clinically relevant doses and 
exposures.
In the pivotal, repeat-dose 1-month toxicity study in rats with 2-week recovery, daily oral doses of 
20, 75, or 200 mg/kg/day of BMS-986196 were clinically well tolerated at all doses. 
Pharmacologic activity of BMS-986196 was noted at all doses, including BTK inactivation and 
suppression of T cell-dependent antibody response to a keyhole limpet hemocyanin (KLH) peptide 
antigen. The primary target organ of toxicity was the pancreas at all doses (adverse findings of 
islet/peri-islet congestion/hemorrhage, pigment, inflammation/fibrosis; interstitial hemorrhage, 
pigment, and inflammation; and peri-islet/lobular acinar cell atrophy). By the end of the 2-week 
postdose recovery period, partial recovery of the pancreatic findings was observed. However, 
based on the literature evidence, internal data with BMS-986196, and other BTK inhibitors, the 
pancreatic findings are considered rat-specific and unlikely to be relevant to humans.13 Therefore, 
the NOAEL is considered to be 200 mg/kg/day (mean sex-combined AUC[0-24h] 46.1 gh/mL; 
AUC multiple of > 70,000-fold over the projected associated with a 20 μg IV dose proposed in 
this study) when excluding the pancreatic findings.
In the pivotal, repeat-dose 1-month toxicity study in cynomolgus monkeys with 2-week recovery, 
daily oral doses of 10, 30, and 60 mg/kg/day of BMS-986196 were clinically well tolerated at all 
doses. Decreases in B cells, suppression of IgG antibody response, and BTK inactivation at all 
doses were considered related to the pharmacologic activity of BMS-986196. Based on the 
minimal clinical effects and the absence of adverse findings at any dose tested, the NOAEL was 
considered to be 60 mg/kg/day (mean sex-combined AUC[0-24h] 6.26 gh/mL; AUC multiple 
of > 10,000-fold over the projected associated with a 20 μg IV dose proposed in this study).
The totality of the nonclinical toxicity assessments demonstrate that BMS-986196 has a favorable 
nonclinical safety profile with NOAELs in rodents (excluding pancreatic findings) and nonrodents 
providing acceptable exposure margins relative to the planned clinical doses. Exposure multiples 
at the highest dose tested in the pivotal rat and monkey studies are > 10,000-fold over the projected 
associated with a 20 μg IV dose proposed in this study. Additional details for the toxicology profile 
and the full range of exposure margins are provided in Section 4.3 and Section 7.2 of the IB.4
Overall, the nonclinical studies established a dose-related pharmacologic, PK, and toxicologic 
profile for BMS-986196 and its PET ligand that support its early clinical development. 
3.2.7
BMS-986196 Clinical Experience
BMS-986196 was evaluated in the first-in-human clinical study IM038008. 
IM038008 is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) and 
multiple ascending dose (MAD) study evaluating the safety, tolerability, PK, and target 
engagement as pharmacodynamics of BMS-986196 in healthy participants. In addition, it includes 
an open-label assessment of both food and formulation effects on the relative bioavailability of 
BMS-986196. 
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In the SAD, BMS-986196 was administered as single dose ranging from 1 mg to 90 mg. In the 
MAD, BMS-986196 was administered at dose levels ranging from 20 mg QD to 90 mg QD for 
14 days. To evaluate food and formulation effects, 25 mg BMS-986196 was administered in a 
4-way crossover design as solution or suspension, and each formulation was administered in the 
fasted state and after a meal. 
BMS-986196 was safe and tolerated at all doses. No SAEs or severe AEs were reported, and no 
participants discontinued study drug due to AEs. 
Following single and multiple oral doses of solution formulation in the fasted state, BMS-986196 
was absorbed with a median time of maximum observed concentration (Tmax) of ~1 hour. The 
terminal elimination half-life (T-HALF) ranged from approximately 1 to 5 hours. Cmax and AUC 
of BMS-986196 increased in a slightly greater than dose-proportional manner over a dose range 
of 1 mg to 90 mg. 
After 14 doses of BMS-986196 60 mg QD, the observed geometric mean Cmax and AUC(TAU) 
were approximately 81.4 ng/mL and 227 ng•hr/mL, respectively. At the 90 mg QD dose (Day 14), 
the observed geometric mean Cmax and AUC(TAU) were approximately 178 ng/mL and 
431 ng•hr/mL, respectively. Little to no accumulation was observed after repeat dosing. Apparent 
mean total body clearance (CLT/F) was approximately 265 L/hr; mean volume of distribution at 
terminal phase (Vz/F) was approximately 1600 L, and T-HALF ranged from approximately 3 to 
5 hours. 
When BMS-986196 25 mg was administered as suspension formulation in the fasted state, the 
geometric mean Cmax and AUC(0-T) were reduced by approximately 84% and 22%, respectively, 
relative to solution formulation administered in the fasted state. 
In comparison to solution in fasted state, the suspension fed Cmax decreased ~64% (43.7 ng/mL
vs. 15.8 ng/mL) while AUC(INF) increased 25% (81.5 ng*hr/mL vs. 102 ng*hr/mL). 
In Part C of this study, BMS-986196 will be administered in tablet form with food, and the 
 
profile is expected to be between the solution and suspension formulations. 
At doses used in this study (15 mg, 30 mg, and 60 mg), near maximal 
 is expected 
over the treatment period, and 
 will be approximately 50% at 7 days after the last 
dose.  
3.2.8
11C-BMS-986196 Clinical Experience
Clinical experience with 11C-BMS-986196 is based on this current ongoing study, IM038010. As 
of 21-Mar-2023, the time of Protocol Amendment 05 preparation, no serious or severe AEs were 
reported in the ongoing study and no participants discontinued due to an AE. Preliminary data 
indicated that 11C-BMS-986196 binding in the human brain was fairly homogeneous, with no 
evidence of notable differences between healthy participants and participants with MS. Based on 
preliminary data, modeling and quantification of 
when using venous blood 
appears feasible.
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3.3
Benefit/Risk Assessment
BMS-986196 is currently under evaluation in a first-in-human study; limited, if any, human 
experience is available to date. The 11C‑BMS-986196 PET ligand has not been administered in 
humans prior to this study; therefore, the overall safety profile for 11C‑BMS‑986196 is based on 
data from a full battery of the nonclinical toxicology, pharmacology, and PK BMS-986196 studies 
and nonclinical 11C‑BMS‑986196 dosimetry. 
Risks Associated with Radiation and PET Procedure:
The planned radioactivity administered with a single administration (ie, IV infusion) of 
11C-BMS-986196 is approximately 370 MBq (10 mCi), and is projected to result in a radiation 
effective dose maximum of 1.37 mSv for an average human participant, estimated from nonhuman 
primate radiation dosimetry studies. The estimated dose from a low-dose apex to upper -thigh (in 
this document referred to as whole-body scan) computed tomography (CT; for co-registration with 
PET and attenuation correction) is approximately 2.3 mSv (0.23 rem). Thus, in Part A, total 
radiation exposure from one 11C-BMS-986196 PET scan and a single whole-body attenuation CT 
scan is expected to be approximately 3.67 mSv (0.367 rem).
In Part A, the cranial PET is performed either as positron emission tomography - computed 
tomography (PET-CT) or positron emission tomography - magnetic resonance imaging 
(PET-MRI), depending on availability of equipment. For each cranial PET scan, up to 2 CT scans 
(1 predose and 1 postdose) are allowed to account for potential movement during the scan. The 
tracer administration for cranial PET in Part A adds 1.37 mSv effective dose from the tracer and 
approximately 0.6 mSv if 2 cranial CT scans are performed. Hence, the maximal effective dose in 
Part A is approximately 5.64 mSv (0.564 rem). If the cranial PET is performed via PET-MRI, the 
total effective dose in Part A is approximately 5.04 mSv (0.504 rem). In Part B and Part C, either 
PET-CT scans or PET-MRI scans of the head will be performed, depending on availability of 
equipment. The estimated dose from a low-dose attenuation CT scan of the head is approximately 
0.3 mSv. For each cranial PET scan, up to 6 total CT scans (2 required CT scans [1 predose and 
1 postdose] + additional if a repeat scan is necessary at either timepoint) are allowed to account 
for potential movement during the scan. The total effective dose from 2 administrations of 
11C-BMS-986196 with 2 CT scans of the head is expected to be approximately 3.34 mSv 
(0.334 rem) for participants undergoing PET-CT and approximately 2.74 mSv (0.274 rem) for 
participants undergoing PET-MRI. However, because participants with MS, more so than healthy 
participants, may be prone to movement artifacts (eg, due to spasticity) or scan interruptions due 
to urinary bladder symptoms, in Part B, up to 3 PET tracer administrations and up to 6 cranial CT 
scans (1 before and 1 after each PET scan) are permissible, for a total cumulative dose of 
approximately 5.91 mSv (0.591 rem). The same rules also apply to Part C participants for repeat 
scans. 
The  Radiation Safety Committees (RSC) at each site will review the use of radiation in this 
research study, and no participants will be enrolled until RSC approval is obtained. This research 
study involves exposure to radiation from 11C-BMS-986196 PET-CT scanning. This radiation 
exposure is not necessary for medical care and is for research purposes only.
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In Parts A, B, and C, the expected radiation effective dose does not exceed 6 mSv (0.6 rem). This 
is below the relevant 10 mSv (1 rem) limit in the UK, based on the standard established by the 
International Commission on Radiological Protection (ICRP) in Publication 62 of the annals of 
the ICRP 22 (3) in 1992. The effective dose is also below the United States (US)-applicable annual 
effective dose limit of 5 rem (50 mSv) below which radiation exposure can be considered generally 
safe according to the Code of Federal Regulations (CFR), Title 21, Part 361.1(b)(3)(i). At such 
low radiation exposures, scientists disagree about the amount of health risk, and there may be very 
little risk, if any.
All PET scans will be done in the presence of medical supervision and nursing staff in an institution 
specifically designed to support imaging studies. In the event of serious medical complications, 
the PET scan facilities have immediate access to or consultation with specialized medical units. 
Preparation of radiopharmaceuticals and execution of PET scans will be performed by 
radiochemists, physicians, and technologists at the clinical sites. These professionals are qualified 
by training and experience in the safe use and handling of radionuclides. Where required, 
participants will be asked about their previous radiation exposure, and those who have had research 
exposure within the past year will be excluded if their cumulative annual exposure (including the 
present study) exceeds applicable limits.
Risk associated with 11C-BMS-986196-derived BTK inhibition
Pharmacologically, 11C-BMS-986196 belongs to the class of BTK inhibitors. In this study, the IV 
administered dose of 11C-BMS-986196 is up to 20 μg, which is projected to cause approximately 
up to 2.7% 
 in blood with single IV administration and 5.4% with repeat 
administration during a 24-hour interval and up to approximately 8.1% 
 with 
3 administrations. For therapeutic efficacy, BTKi generally must be chronically dosed to 
 
 of approximately 95%.1 Female carriers of BTK null mutations are asymptomatic. A 
single oral dose of 10 mg BMS-986196 is projected to cause peak 
 of 95% in 
blood, ie, approach therapeutic efficacy. The AUC associated with a single dose IV dose of 20 μg 
is projected to be approximately 75-fold lower than the AUC associated with a single, orally 
administered dose of 10 mg. The pharmacological half-life of 11C-BMS-986196 in humans is 
projected to be approximately 6 hours. Therefore, at the doses and frequency administered in this 
study, 11C-BMS-986196 is not considered to have pharmacologically or biologically relevant 
activity. 
Risk associated with unlabeled BMS-986196-derived BTK inhibition
In Part C, unlabeled BMS-986196 is administered orally at doses up to 60 mg for up to 7 days in 
healthy participants. The dose levels tested in Part C are considered therapeutically relevant. In 
preclinical rat studies, BMS-986196 causes pancreatic injury in rats. However, based on the 
literature evidence, internal data with BMS-986196, and other BTK inhibitors, the pancreatic 
findings are considered rat-specific and unlikely to be relevant to humans.13 Other BTKi have been 
approved for the treatment of multiple myeloma and other hematological malignancies. At the 
approved doses, these BTKi typically result in chronic 
 > 95% (eg, acalabrutinib 
US prescribing information14). Approved BTKi are associated with increased risk for infections, 
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bleeding, arrhythmias, cytopenia, tumor lysis syndrome, secondary malignancies, and embryofetal 
toxicity (eg, acalabrutinib14 and ibrutinib15 US prescribing information). Additional risks
associated with therapeutically relevant doses of BMS-986196 are listed in Table 3.3.1-1.
Risks Associated with Use of an Arterial Catheter (Part A and Part B): Participants will have 
a radial arterial catheter inserted on the day(s) of PET scan to facilitate arterial blood draws
(150 mL blood volume) during the cranial PET scanning sessions. Risks associated with placing a 
radial arterial catheter include mild-to-moderate pain, bruising at the puncture site, bleeding, 
hematoma, inflammation, infection, arterial occlusion, ischemic damage to the hand, and 
development of a pseudoaneurysm. Severe complications may require additional treatment. Major 
complications occur in less than 1% of procedures and permanent ischemic damage or 
pseudoaneurysm each occur in 0.09% of procedures, according to a meta-review.16 Risk 
minimization measures in this protocol include:
1) Laboratory testing for blood coagulation at Screening prior to arterial line placement. Results 
must be within normal limits.
2) Normal results of the Allen’s test must be documented at Screening and on PET scanning days 
prior to arterial line placement 
3) The procedure will be performed by experienced staff
4) Applying skin disinfectant prior to skin puncture
5) Manual compression of the puncture site for ≥ 15 minutes after removal of the arterial catheter
6) Application of a pressure dressing (eg, Coban™)
7) Examination of hand and finger blood supply after arterial cannulation, throughout the PET 
procedure, following catheter removal, and before discharge
8) Providing participants with a 24-hour emergency physician telephone number to call if they 
encounter pain, discoloration, numbness, tingling, coolness, hematoma, inflammation, or any 
other unusual symptoms in the wrist or hand, or fever, chills, or drainage from the vascular 
puncture sites
9) Excluding fish oil, aspirin, platelet aggregation inhibitors (including nonsteroidal anti-
inflammatory drugs with such activity) and anticoagulants for at least 10 days prior to arterial 
line insertion and at least 7 days following arterial line removal
10) Excluding participants who have donated blood within 4 weeks prior to radial artery puncture 
Risk Associated with MRI
In Part A and Part C, participants may undergo cranial PET-MRI, depending on availability of 
equipment. In Part B, participants will undergo a cranial MRI scan during the screening period, 
and participants may undergo MRI scans as part of the PET-MRI scans. Participants must have 
completed all other Screening assessments first and remain eligible for the study before undergoing 
a Screening MRI scan. MRI scans are generally considered safe procedures and severe 
complications are very rare. Risks include heat sensations, anxiety in claustrophobic individuals, 
hearing damage if adequate ear protection is not worn, heating or moving of magnetic 
devices/particles in the body, magnetic objects in the scanner becoming projectiles, electric 
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devices being damaged in/near the scanner, and allergic reactions to gadolinium-based contrast 
agents. While gadolinium-based contrast agents are retained in the body long term, no AEs have 
been associated with retention of gadolinium-based contrast agents, to date. Risk mitigation 
measures include:
1) Screening for and exclusion of participants with contra-indications to MRI, including, but not 
limited to individuals with severe claustrophobia, metal implants, pacemakers, electronic 
devices, or any other implants deemed unsafe
2) Exclusion of individuals with known hypersensitivity to gadolinium-based contrast agents
3) Exclusion of individuals with an estimated creatinine clearance of < 30 mL/min at Screening 
based on the Cockgroft-Gault formula
4) Removal of magnetic and electric devices prior to entering the scanner
5) Wearing of adequate ear protection during the procedure
6) Sites should use gadolinium-based contrast agents resulting in lowest retention in the body 
(gadoterate meglumine, gadobutrol, gadoteridol) 
Should incidental findings be observed, the investigator will discuss them with the participant and 
determine if follow up is warranted.
Risk associated with severe acute respiratory syndrome coronavirus 2 infection
As long as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic 
continues, interactions with site staff as required per the protocol potentially increase the risk for 
SARS-CoV-2 infection relative to more socially distanced behavior. To reduce the risk of 
SARS-CoV-2 infection, general risk mitigation against coronavirus disease 2019 (COVID-19) will 
be implemented in accordance with the site monitoring and prevention control procedures, and 
relevant governmental and Institutional Review Board (IRB)-associated requirements. Such 
measures aim to minimize the prevalence and transmission of SARS-CoV-2 amongst site staff and 
study participants, and may include distancing, sanitization, testing, and the use of personal 
protective equipment. The risk mitigation measures are part of the site’s generic informed consent 
form (ICF), when and where applicable, will be amended based on emerging guidance. The ICF 
and any other documentation regarding these general measures are independent of this protocol 
and will be entered into this study’s trial master file (TMF) if used for participants in this study. 
In Parts A and B, serum samples will be collected for 
 
. These 
 titers will not be automatically determined 
in participants at Screening and the results will not be used to determine study eligibility, but 
information may be helpful for potential evaluation of 
 if warranted, eg, if 
participants develop symptoms compatible with a diagnosis of 
. Participants with 
known active 
 are excluded from the study. 
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3.3.1
Risk Assessment
Table 3.3.1-1:
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk 
Mitigation Strategy
Study Intervention(s)
Nonclinical Risk BMS-986196-
induced pancreatic toxicity
Pancreatic toxicity of BTK 
inhibitors is considered rat-specific, 
(IB Section 7.1.1 and Erickson, et 
al, 201713). 
Dose and frequency of 
administration in Parts A and B is 
not considered to result in 
pharmacologically or biologically 
relevant activity. Testing amylase, 
lipase, glucose in laboratory panel. 
Excluding participants with history 
of pancreatitis (Parts A, B, and C).
Nonclinical Risk BMS-986196-
induced immune suppression
No evidence of infection in non-
clinical studies, but BTKi MoA is 
consistent with immune 
suppression. (IB Section 7.1.2). 
Dose and frequency of 
administration in Parts A and B is 
not considered to result in immune 
suppression or to have 
pharmacologically or biologically 
relevant activity. Exclusion of 
participants with recent or recurrent 
infections (Parts A, B, andC). 
Nonclinical Risk 11C-BMS-986196-
induced liver injury
In GLP 1-month toxicology study, 
no liver injury in monkeys and rats. 
Combined preclinical in vivo and in 
vitro assessment suggest low risk 
for liver injury (IB Section 7.1.3). 
Dose and frequency of 
administration in this study is not 
considered to result in 
pharmacologically or biologically 
relevant activity in Part A and B. 
Exclusion of participants with 
active hepatitis, ALT or AST > 1.5-
fold ULN, total bilirubin > 2-fold 
ULN (unless in the context of 
Gilbert Syndrome) (Parts A, B, and 
C). 
Risk associated with BMS-986196 
CNS penetrance/suicidal ideation 
and behavior
(Part C)
IB Section 7.1.1.4
Exclusion of participants who 
answer "yes" to item 4 or 5 or who 
answer “yes”to any suicidal 
behavior item of the C-SSRS 
(excluding non-suicidal 
self-injurious behavior) at screening 
or Day -1. Suicidality will be 
assessed by the C-SSRS during the 
study in Part C.
Physical examination, including 
neurological examination, will be 
performed at screening and during 
the study.
Nonclinical Risk associated with 
BMS-986196 for developmental 
toxicity (Part C)
IB Section 7.1.1.2
Exclusion of WOCBP from Part C, 
contraception requirements for 
male participants.
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Table 3.3.1-1:
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk 
Mitigation Strategy
Clinical risks associated with 
therapeutic doses of approved 
BTKi, including infection, 
bleeding, arrhythmia, cytopenia, 
tumor lysis syndrome, secondary 
malignancy, embryofetal toxicity
Acalabrutinib and Ibrutinib US 
prescribing information
At the dose and frequency of 
administration used in the study 
population, the pharmacological 
risks associated with BMS-986196 
and BTK inhibition are not 
considered relevant.
11C-BMS-986196-associated 
radiation exposure
CFR, Title 21, Part 361.1(b)(3)(i)
Publication 62 of the annals of the 
ICRP 22 (3), 1992
Risk mitigation by limiting 
estimated effective dose to < 6 mSv 
(0.6 rem), below the relevant 
10 mSv (1 rem) limit in the UK, 
based on ICRP standard and below 
the US-applicable annual effective 
dose limit of 5 rem (50 mSv), 
below which radiation exposure can 
be considered generally safe 
according to the CFR. 
Study Procedures
Arterial line placement
Major complications associated 
with arterial line placement occur in 
less than 1% of procedures; 
permanent ischemic damage and 
pseudoaneurysm occur in 0.09% of 
procedures16
Allen’s test performed before 
arterial line placement. Blood 
coagulation tested at Screening. 
Arterial line placement performed 
by experienced staff. Examination 
of hand/finger circulation after 
arterial line placement and before 
discharge. Examination of pressure 
dressing prior to discharge. 
Provision of 24 hr emergency 
phone number. Exclusion of fish 
oil, aspirin, platelet aggregation 
inhibitors (including nonsteroidal 
anti-inflammatory drugs with such 
activity) and anticoagulants for at 
least 10 days prior to arterial line 
insertion and at least 7 days 
following arterial line removal. 
(Parts A and B)
MRI and administration of 
gadolinium-based contrast agent
Body heat sensation, noise, 
claustrophobia. Magnetic particles 
inside the MRI may become 
projectiles. Electric devices inside 
the MRI may be damaged. 
Magnetic implants or particles 
inside the body may move and/or 
generate heat. Allergic reactions to 
gadolinium-based contrast 
agents.17
Exclusion of individuals with 
estimated creatinine clearance 
< 30 mL/min. Providing adequate 
ear protection, excluding 
participants with contraindications 
to MRI (including non-MRI 
compatible metal
implants/particles, pacemakers, 
cochlear implants, ventricular 
shunts, large tattoos in the area 
affected by the MRI, severe 
claustrophobia), removing magnetic 
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Table 3.3.1-1:
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk 
Mitigation Strategy
objects prior to entering the MRI 
scanner, excluding participants with 
known allergy to gadolinium-based 
contrast agent.
Other (if applicable)
SARS-CoV-2 infection risk
During SARS-CoV-2 pandemic, 
study visits and procedures may 
increase the risk for infection 
relative to more socially distanced 
behavior. 
Site-mandated measures for 
minimization of SARS-CoV-2 
transmission. Exclusion of 
participants with known active 
SARS-CoV-2 infection.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BTK, Bruton’s tyrosine kinase; 
BTKi, Bruton’s tyrosine kinase inhibitor; CFR, Code of Federal Regulations; CNS, central nervous system; C-SSRS,
Columbia-Suicide Severity Rating Scale; GLP, Good Laboratory Practices; hr, hour; IB, Investigator’s Brochure; 
ICRP, International Commission on Radiological Protection; MoA, mechanism of action; MRI, magnet resonance 
imaging; mSv, millisievert; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; UK, United Kingdom; 
ULN, upper limit of normal; US, United States.
3.3.2
Benefit Assessment
Administration of 11C-BMS-986196 does not confer any therapeutic benefit to study participants. 
Participating in this study contributes to research and to the development of a compound that can 
visualize inflammation in the CNS in a novel way and that can help develop therapies for 
progressive MS. Participants will undergo medical evaluations including a physical examination, 
ECGs, and clinical laboratory safety tests, and a cranial PET scan. 
 
 
3.3.3
Overall Benefit/Risk Conclusion
The protocol was designed to mitigate the risk associated with the study-defined assessments and 
procedures. The Sponsor will evaluate the risk/benefit profile of the study on an ongoing basis. 
This evaluation will be based on all available data – with particular attention to: AEs or other safety 
trends in this study of 11C-BMS-986196 whose character, severity, and/or frequency suggest that 
participants would be exposed to an unreasonable and significant risk of illness or injury.
If such evaluation suggests that the risk/benefit profile of the study has become unfavorable to 
participants, the Sponsor will pause enrollment and/or tracer administration until further evaluation 
of data, and interaction with the appropriate Health Authority(ies) can take place on potential 
actions. Such actions may include (but are not limited to) study continuation, substantial 
amendment, or termination of the study.
3.3.4
COVID-19-related Risk Mitigation Measures
Serum samples will be collected for 
 testing in Parts A and B (see Section 9.8
for biomarker collections). These antibody titers will not be automatically determined in 
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participants at Screening, but information may be helpful for potential evaluation of 
 
 if warranted. 
General risk mitigation against COVID-19 will be implemented in accordance with the clinical 
research unit (CRU’s) monitoring and prevention control procedures and relevant governmental 
and Institutional Review Board (IRB)-associated requirements. Such measures aim to minimize 
the prevalence and transmission of SARS-CoV-2 amongst site staff and participants and may 
include distancing, sanitization, testing, and the use of personal protective equipment. The risk 
mitigation measures are part of the CRU’s generic informed consent and, when and where 
applicable, will be amended based on emerging guidance. The ICF and any other documentation 
regarding these general measures are independent of this protocol and will be entered into this 
study’s trial master file (TMF) if used for participants in this study.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
Primary

To assess safety, tolerability, kinetics, and CNS 
signal 
repeatability 
of 
the 
novel 
tracer 
11C-BMS-986196 in healthy participants and in 
participants with MS

To assess the safety of BMS-986196

Incidence, severity, seriousness, and type of AEs; 
clinically significant abnormalities in ECG, VS, 
laboratory values, physical examination, and 
C-SSRS

Radiation dosimetry calculated from PET-CT 
images in healthy participants

Image acquisition window after administration of 
11C-BMS-986196 

Test-retest repeatability based on quantitative 
analysis of CNS PET-MRI images (eg, SUV and/or 
VT) in participants with MS

To quantify the proportion of free BTK in the brain 
after administration of unlabeled BMS-986196

% Free brain BTK relative to baseline
Secondary
Secondary
To assess 11C-BMS-986196 signal characterization
Calculated SUV and VT in the brain
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Abbreviations: AE, adverse event; BTK, Bruton’s tyrosine kinase; CNS, central nervous system; C-SSRS, Columbia-
Suicide Severity Rating Scale; ECG, electrocardiogram;
 MS, multiple sclerosis; PET, positron emission tomography; PET-CT, positron emission 
tomography - computed tomography; PET-MRI, positron emission tomography - magnetic resonance imaging; 
 SUV, standardized uptake value; VS, vital signs; VT, 
volume of distribution.
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 1, open-label study in healthy participants and participants with MS to evaluate a 
novel, positron-emitting ligand 11C-BMS-986196, for measurement of free BTK. The study will 
include up to 28 evaluable participants (Part A: up to 8 healthy participants; Part B: up to 
8 participants with MS; Part C: up to 12 healthy participants).
All participants will undergo PET scanning with 11C-BMS-986196. An initial dose of 
11C-BMS-986196 will be administered at doses up to 20 μg with the radioactivity of the dose at 
approximately 370 MBq (10 mCi). In Part B and Part C, the radioactive dose and participant 
preparation may be revised based on results of radiation dosimetry obtained in Part A but 
administered mass will not exceed 20 μg.
The study consists of 3 periods: screening, treatment, and safety follow-up. The estimated duration 
from screening through safety follow-up phone call (or in-person study site visit) is up to 
approximately 6 weeks for Part A, approximately 6 weeks for Part B, and approximately 10 weeks 
for Part C.
Screening Period
Before any study procedures or assessments are performed, study participants must sign and date 
the informed consent form, after which participants undergo screening assessments within 30 days 
prior to administration of 11C-BMS-986196. Participants in Part B must undergo a screening 
cranial MRI scan. Eligible participants will be enrolled to the treatment period.
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Treatment Period
Part A (Whole-Body Radiation Dosimetry and Cranial PET Imaging): Up to 6 evaluable 
healthy adult participants (at least 2 male and 2 female participants are planned) will complete 
whole-body PET-CT imaging after a bolus IV administration of 11C-BMS-986196 under fasting 
conditions, to confirm tracer safety, assess image acquisition window, determine radiation 
dosimetry of the administered radiotracer, and assess optimal imaging time. The PET scan will 
last approximately 2 hours. At least 2 hours and at most 6 days after the first tracer administration, 
participants will receive a second tracer administration and undergo cranial PET imaging using 
either PET-CT or PET-MRI, depending on the availability of equipment. If the interval between 
the first and second PET scan is 4 days or more, the study site staff must contact the participant 
remotely (eg, by phone) on Day 4 (ie, 3 days after the first PET scan) and record adverse events 
(AEs) and any concomitant medications. Following an observation period of approximately 1 hour 
after completion of all PET scanning procedures, participants will be discharged from the PET 
center and enter the safety follow-up period. Up to 6 healthy participants will complete Part A 
before initiation of Part B.
If emerging data from Part B indicate that venous blood sampling is likely to be required in future 
studies using 11C-BMS-986196 without arterial blood sampling (eg, because a [pseudo]-reference 
region cannot be reliably established), 2 additional participants can be enrolled in Part A at the 
discretion of the Sponsor. These additional 2 participants will only undergo cranial PET imaging 
using either PET-CT or PET-MRI, depending on the availability of equipment (ie, not whole body 
PET-CT).
Part B (Characterization of 11C-BMS-986196 binding in the human brain): Up to 
8 participants with MS will complete 2 evaluable cranial PET-CT or PET-MRI scans (depending 
on equipment availability) after a bolus IV administration of 11C-BMS-986196, separated by at 
least 2 hours and at most 6 days to determine the optimal quantification parameters, including 
within-participant variability under test and retest conditions.  Following an observation period of 
approximately 1 hour after completion of PET scanning procedures, participants will be 
discharged from the PET center and enter the safety follow-up period. If the interval between the 
first and second PET scan is 4 days or more, the study site staff must contact the participant 
remotely (eg, by phone) on Day 4 (ie, 3 days after the first PET scan) and record AEs and any 
concomitant medications. Participants who had a MS relapse within 30 days prior to Day 1 must 
start Scan 2 on Day 1 or Day 2. Up to 8 participants with MS will complete Part B. 
Part C (Quantification of free BTK availability in the human brain): Up to 12 evaluable 
healthy adult participants will complete 2 evaluable cranial PET-CT or PET-MRI scans 
(depending on equipment availability). The first cranial PET scan will occur on Day 1 after a bolus 
IV administration of 11C-BMS-986196. After completion of the first evaluable PET scan (on the 
same day or the day following the PET scan), participants will receive orally administered 
unlabeled BMS-986196 on-site or at home once daily (QD) for preferably 1 day; approximately 
24 hours after the (last) dose of BMS-986196, participants will undergo the second cranial PET 
scan after a bolus IV administration of 11C-BMS-986196. If the second PET scan cannot be 
performed in this time frame, it is permissible to administer a single dose of unlabeled BMS-
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986196 up to 7 days after the Day 1 PET (eg, in case of scheduling conflicts).  In addition, in case 
of synthesis failure of PET tracer it is permissible to administered multiple doses of unlabeled 
BMS-986196 in order to have BMS-986196 administered 24 hours prior to the second PET scan, 
if Sponsor agrees. No more than 7 doses can be administered. Up to 3 dose levels of (unlabeled) 
BMS-986196 will be tested (15 mg, 30 mg, and 60 mg QD) and approximately 4 participants per 
dose level will be tested. Initially, participants will be assigned to the 30 mg dose level. After an 
interim review of PET results from 2 to 4 evaluable participants, the next dose level (15 mg or 
60 mg) will be determined. At least 2 evaluable participants should have completed PET imaging 
at the second dose level before participants are assigned to the last dose level.
Safety Follow-up Period
For Part A and Part B, participants will be contacted remotely by phone (or web-call; email or text 
contact without verbal contact is not sufficient) 3 days (± 1 day) after completion of all PET 
scanning procedures and will be asked about AEs and concomitant medications. An in-person visit 
is optional. For Part C, participants will attend one in-person follow-up visit (Visit 3) 7 days after 
completion of all PET scanning procedures on Visit 2. During Visit 3, participants will undergo 
clinical assessments, have blood collected for laboratory tests, and will be asked about AEs and 
concomitant medications. For Visit 4, participants will be contacted remotely by phone (or web-
call; email or text contact without verbal contact is not sufficient) 28 days (+ 3 days) after 
completion of Visit 2 and will be asked about AEs and concomitant medications. At the discretion 
of the investigator, Visit 4 can be conducted in-person.
Upon completion of Visit 4 participants will have completed the study. 
Safety will be assessed throughout the study by the recording of any AEs experienced during study 
participation.
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schema
Part A - Safety, Tolerability, and Dosimetry in Healthy Participantsa
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Part B - Repeatability of 11C-BMS-986196 PET in Participants with MS
Part C - Quantification of Free BTK Availability in Healthy Participants
Abbreviations: BTK, Bruton’s tyrosine kinase; IV, intravenous; MS, multiple sclerosis; PET, positron emission 
tomography; QD, once daily.
a Prior to initiation of Part B, all Part A participants will undergo Visits 1 and 2. After initiation of Part B, up to 
2 participants may be added to Part A and will not undergo Visit 1, only Visit 2. For these participants only, Visit 2 
will be regarded as Day 1.
b Visit 2 tracer administration must be done at least 2 hours and at most 6 days after Visit 1 tracer administration (ie, 
Day 2 to Day 7).
c Participants who had a MS relapse within 30 days prior to Day 1 must start Scan 2 on Day 1 or Day 2.
d After completion of the first evaluable PET scan (on the same day or the day following the PET scan), participants 
will receive orally administered unlabeled BMS-986196 QD for preferably 1 day; and approximately 24 hours after 
the (last) dose of BMS-986196, participants will undergo the second cranial PET scan. If the second PET scan 
cannot be performed in this time frame, it is permissible to administer a single dose of unlabeled BMS-986196 up 
to 7 days after the Day 1 PET (eg, in case of scheduling conflicts) or to dose unlabeled BMS-986196 once per day 
for up to 7 days (eg, in case of synthesis failure of the PET tracer) if the Sponsor agrees.
Physical examinations, vital sign measurements, 12-lead ECGs, and clinical laboratory evaluations 
will be performed at selected times throughout the study. Participants will be closely monitored 
for AEs throughout the study.
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In Part A, the maximum volume of blood drawn from a participant is approximately 340 mL 
(40 mL clinical safety labs + up to 150 mL during the PET scan procedure for participants 
undergoing Visits 1 and 2 or up to 250 mL for participants only undergoing Visit 2). 
In Part B, up to 445 mL of blood will be drawn from participants undergoing 2 PET scans and 
undergoing simultaneous arterial and venous sampling during 1 scan; approximately 345 mL will 
be drawn in participants undergoing only arterial sampling. The maximum volume of blood drawn 
in a period of 24 hours is approximately 420 mL. 
In Part C, up to approximately 360 mL of blood will be drawn from participants (up to 150 mL 
during each of 2 PET scan procedures + 40 mL clinical safety labs + 6 mL QuantiFERON-TB + 
10 mL for 
 biomarker testing). 
Participants who undergo repeat PET scans will not exceed a cumulative blood draw volume of 
approximately 500 mL. 
5.1.1
Data Monitoring Committee and Other Committees
A Data Monitoring Committee will not be used in the study.
5.2
Number of Participants
Up to 28 evaluable participants are planned to be enrolled. In Part A, evaluable participants for 
dosimetry outcomes are defined as those with adequate PET-CT whole-body scans collected over 
> 60 minutes. Part A evaluable participants for cranial PET scans are defined as those with cranial 
scans of adequate quality to be evaluable. In Part B, participants must have 2 cranial 
PET-CT/PET-MRI scans of adequate quality to be evaluable. To be evaluable in Part C, 
participants must have 2 cranial PET-CT/PET-MRI scans of adequate quality, one before and one 
after administration of (unlabeled) BMS-986196. Participants with non-evaluable PET images 
may be replaced, ie, the total number of enrolled participants may exceed 28 if participants have 
to be replaced.
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened.
End of trial is defined as the last participant last visit or scheduled procedure.
Study completion is defined as the final date on which data for the primary endpoint were or are 
expected to be collected, if this is not the same.
A participant is considered to have completed the study if he/she has completed the last 
assessment/procedure shown in the Schedule of Activities. 
5.4
Scientific Rationale for Study Design
This study is designed to assess the safety, tolerability, repeatability, and feasibility of 
11C-BMS-986196 as a PET imaging tracer in healthy participants and participants with MS.
Part A is conducted in healthy adult volunteers. A healthy adult volunteer population facilitates 
the interpretation of AEs and the characterization of the 11C-BMS-986196 safety profile including 
11C-BMS-986196 dosimetry in this first study testing the PET tracer in humans. Part A is planned 
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to include up to 8 total participants. Up to 6 participants will undergo whole-body PET-CT, 
including at least 2 male and at least 2 female participants to enable radiation dosimetry calculation 
in organ tissue, including in reproductive organs. The 
 in Part A will allow 
determination of the 
 of healthy individuals and comparison with brain 
signal in patients with MS. Part B is conducted in patients with MS, because characterization of 
BTK expression in inflammatory CNS lesions containing microglia, macrophages, and/or B-cells 
is a key objective for the development and use of 11C-BMS-986196. Adult patients with MS are 
the expected population in which 11C-BMS-986196 will be utilized- in future studies. Part C has 
been added to the study via Protocol Amendment 05, after preliminary results of the current study 
indicated that 11C-BMS-986196 resulted similar brain PET images in Part A (healthy participants) 
and Part B (participants with MS) and results from the first-in-human study (IM038008) 
demonstrated that BMS-986196 was safe and well tolerated at dose levels up to 90 mg QD for 14 
days. In Part C, PET imaging allows characterization of brain 
 after treatment with 
unlabeled BMS-986196 at therapeutically relevant doses. For this purpose, an uncontrolled 
open-label design is adequate and typical. Open-label design without a control group is considered 
adequate for the purpose of this study, because a blinded study design with a control group is not 
expected to improve dosimetry or CNS signal detection. Based on the short treatment duration and 
microdose administered, safety evaluation in an open-label fashion without a control group is 
considered acceptable in Parts A and B. Based on the results of the first-in-human study 
(IM038008), safety evaluation is also considered acceptable in Part C. An open-label, uncontrolled 
study design is common for studies characterizing PET tracers and studies evaluating 
 
 by PET.18
5.5
Justification for Dose
A single dose of 11C-BMS-986196 is administered at up to 20 μg in this study. Participants will 
receive up to 2 doses of 11C-BMS-986196 in Part A and up to 3 doses of 11C-BMS-986196 in 
Parts B and C. A third administration in Parts B and C is permissible if a PET scan has to be 
repeated (eg, due to failure of a prior scan). This is consistent with general practice in similar PET 
studies, in which small molecule tracers are generally administered at doses < 100 µg. The 
exposure associated with 2 administrations in a 24-hour period is projected to result in up to 
approximately 5.4% 
, and 3 administrations are projected to result in up to 
approximately 8.1% 
. At the dose and frequency administered in the study 
population, 11C-BMS-986196 exposure is not considered pharmacologically or biologically 
relevant (see Section 3.3, Benefit/Risk Assessment for additional details). In Part C, unlabeled 
BMS-986196 is expected to result in near maximal 
. 
The administered radioactive dose was selected on the basis of nonclinical radiation dosimetry 
studies. The radioactivity of a single administration of 11C-BMS-986196 is equivalent to
approximately 370 MBq (10 mCi) and in terms of radiation exposure results in an effective dose 
of approximately 1.37 mSv (0.137 rem). In Part A, a single whole-body CT scan (ie, scan from 
apex to upper-thigh level) results in an effective dose of approximately 2.3 mSv (0.23 rem). Based 
on feedback provided by the participating clinical sites, the cranial CT scan sequences used in this 
study result in an effective dose of approximately 0.3 mSv (0.03 rem). The effective dose derived 
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from 11C-BMS-986196 administration and CT scans in Parts A, B, and C and total combined dose 
is shown in Table 5.5-1. Of note, the total dose depends on whether PET-CT or PET-MRI is used. 
Table 5.5-1:
Radiation Exposure from PET Tracer Administration and CT 
Scans
Study 
Part
Number of 
11C-BMS-986196 
Administrations 
(Effective Dose)
Number of CT Scans 
(Effective Dose)
Total Effective 
Dose from 
Tracer 
Administration 
and CT Scan
Notes
A
2 (2.74 mSv)
3 (2.3 mSv + 0.6 mSv)
5.64 mSv
Whole-body PET-CT scan + 2 
cranial PET-CT scans 
A
2 (2.74 mSv)
1 (2.3 mSv)
5.04 mSv
Whole-body PET-CT scan + 
cranial PET-MRI scan
A
2 (2.74 mSv)
4 (1.2 mSv)
3.94 mSv
Part A participants who only 
undergo Visit 2 and need a repeat 
PET scan with pre- and post-CT 
scans for each PET scan
B+C
2 (2.74 mSv)
0 (0 mSv) 
2.74 mSv
Cranial PET-MRI scan if no 
additional scan is required
B+C
3 (4.11 mSv)
0 (0 mSv)
4.11 mSv
Cranial PET-MRI scan if a third 
scan is necessary 
B+C
2 (2.74 mSv)
2 (0.6 mSv) 
3.34 mSv
Cranial PET-CT scan if no 
additional scans are required
B+C
3 (4.11 mSv)
6 (1.8 mSv)
5.91 mSv
Cranial PET-CT scan if a third 
PET scan is necessary with pre-
and post-PET cranial CT scans 
for each PET scan
Abbreviations: CT, computed tomography; MRI, magnet resonance imaging; mSv, millisievert; PET-CT, positron 
emission tomography - computed tomography; PET-MRI, positron emission tomography - magnetic resonance 
imaging.
The maximum effective dose in Part A is 5.64 mSv (0.564 rem), and the maximum effective dose 
in Parts B and C (in participants undergoing 2 cranial PET-CT scans) is 5.91 mSv (0.591 rem),
which is below the relevant limit of 10 mSv (1 rem) in the UK, based on ICRP standard 
(Publication 62 of the annals of the ICRP 22 (3), 1992). It is also below 50 mSv (5 rem), the annual 
effective dose limit below which radiation exposure can be considered generally safe according to 
the CFR, Title 21, Part 361.1(b)(3)(i). At such low radiation exposures, scientists disagree about 
the amount of health risk, and there may be very little risk, if any.
All of the exposures required by the study are additional to routine clinical care. The maximum 
total protocol dose in participants is 5.91 mSv. This is equivalent to 2.5 years of average natural 
background radiation in the UK.
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Ionizing radiation can cause cancer which manifests itself after many years or decades. The risk 
of developing cancer as a consequence of taking part in this study is estimated as 0.03%. For 
comparison, the natural lifetime cancer incidence in the general population is about 50%.
6
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply: 
1) Signed Written Informed Consent
Participants must have signed and dated an IRB/Independent Ethics Committee 
(IEC)-approved written ICF in accordance with regulatory, local, and institutional guidelines. 
This must be obtained before the performance of any protocol-related procedures that are not 
part of normal patient care.
2) Type of Participant and Target Disease Characteristics
For Part A and Part B:

Body mass index (BMI) of 18 to 34 kg/m2, inclusive, and total body weight ≥50 kg (BMI 
may be rounded, eg, a participant with a BMI of 34.4 would qualify). 

Documentation of normal Allen’s test result at Screening and on PET scanning days in the 
arm that will be used for arterial line placement. 
a) Part A only: 

Healthy male and female participants without clinically significant deviation from normal 
in medical history, physical examination (PE), ECGs, and clinical laboratory 
determinations
b) Part B only: 

Male or female participant diagnosed with MS according to the 2017 revisions of the 
McDonald diagnostic criteria19

EDSS score between 0 to 6.5, inclusive, at Screening
c) For Part C: 

Body mass index (BMI) of 18 to 34 kg/m2, inclusive, and total body weight ≥50 kg (BMI 
may be rounded, eg, a participant with a BMI of 34.4 would qualify). 

Healthy male and WNOCBP participants without clinically significant deviation from 
normal in medical history, physical examination (PE), ECGs, and clinical laboratory 
determinations
3) Age of Participant
Participant must be 18 to 55 years of age, inclusive, at the time of signing the informed consent.
4) Reproductive Status
Investigators shall counsel women of childbearing potential (WOCBP) and male participants who 
are sexually active with WOCBP on the importance of pregnancy prevention, the implications of 
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an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of 
11C-BMS-986196 present in seminal fluid to a developing fetus, even if the participant has 
undergone a successful vasectomy or if the partner is pregnant.
The investigator shall evaluate the effectiveness of the contraceptive method in relationship to the 
first dose of tracer administration.
Local laws and regulations may require the use of alternative and/or additional contraception 
methods. 
Women who are not of childbearing potential are exempt from contraceptive requirements.
a) Female Participants:
i)
Female participants must have documented proof that they are not of childbearing 
potential. 
ii) WOCBP must have a negative highly sensitive urine or serum pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin 
[HCG]) at Screening and within 24 hours prior to tracer administration.
o
Additional requirements for pregnancy testing during and after study intervention 
are located in Section 2, Schedule of Activities.
o
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
iii) WOCBP must agree to follow instructions for method(s) of contraception defined in 
Appendix 4 and as described below and included in the ICF.
(1) WOCBP are permitted to use hormonal contraception methods (as described in 
Appendix 4).
iv) A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 of the following conditions applies:
(1) Is not a WOCBP
OR
(2) Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year), preferably with low user dependency, as described 
in Appendix 4 during the intervention period and for at least 30 hours and agrees 
not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time 
period
v) In Part C only, WOCBP are not eligible.
b) Male Participants:

Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception as defined in Appendix 4 and as described below.
i)
Azoospermic males are not exempt from contraceptive requirements and will be 
required to always use a latex or other synthetic condom during any sexual activity 
(eg, vaginal, anal, oral) with WOCBP, even if the participant has undergone a 
successful vasectomy or if the partner is pregnant.
ii) Male participants will be required to always use a latex or other synthetic condom 
during any sexual activity (eg, vaginal, anal, oral) with WOCBP, even if the 
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participants have undergone a successful vasectomy or if their partner is already 
pregnant or breastfeeding. Males should continue to use a condom during the study 
intervention period and for at least 30 hours after the last dose of tracer administration
in Parts A and B and at least 10 days after the last dose of unlabeled study drug 
administration in Part C. 
iii) Female partners of males participating in the study should be advised to use highly 
effective methods of contraception during the study intervention period and for at least 
30 hours after the last dose of tracer administration in Parts A and B and at least 10
days after the last dose of unlabeled study drug administration in Part C in the male 
participant.
iv) Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from sexual activity or use a male condom during any sexual activity 
(eg, vaginal, anal, oral), even if the participants have undergone a successful 
vasectomy, during the study intervention period and for at least 30 hours after the last 
dose of tracer administration in Parts A and B and at least 10 days after the last dose of 
unlabeled study drug administration in Part C.
v) Male participants must refrain from donating sperm during the study intervention 
period and for at least 30 hours after the last dose of tracer administration in Parts A 
and B and at least 10 days after the last dose of unlabeled study drug administration in 
Part C.
vi) Breastfeeding partners should be advised to consult their health care providers about 
using appropriate highly effective contraception during the time the participant is 
required to use condoms.
6.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1) Medical Conditions
a) Any significant acute or chronic medical illness (Part A and Part C). Any significant acute 
or chronic medical illness (other than MS) posing a risk to the participant’s safety or 
negatively affecting the ability to detect CNS PET signal (Part B only).
b) Benign MS defined as a baseline EDSS of 2.0 with MS diagnosis ≥ 10 years prior to Day 1. 
Spinal MS without clinical or radiological evidence of brain lesions. Any other 
combination of clinical and radiological data suggestive of an absence of inflammatory 
brain lesions.
c) MS relapse within 14 days prior to Day 1. Participants with a MS relapse within 30 days 
prior to Day 1 must agree to have their second PET scan scheduled on Day 1 or Day 2 
(Part B only). 
d) Any major surgery within 4 weeks of study treatment administration and/or any minor 
surgery within 2 weeks of tracer administration
e) A history of pancreatitis
f)
A history of prolonged bleeding or excessive bruising
g) Known or suspected autoimmune disorder, including but not limited to rheumatoid 
arthritis, fibromyalgia, systemic lupus erythematosis, polymyalgia rheumatica, giant cell 
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arteritis, Behcet’s disease, dermatomyositis, severe asthma, any autoimmune vasculitis, 
autoimmune hepatitis, or any other active autoimmune disease for which a participant 
requires medical follow-up or medical treatment. Participants in Part A and Part C must 
not have a diagnosis of MS.
h) Any history of known or suspected congenital or acquired immunodeficiency state or 
condition that would compromise the participant’s immune status and/or confound tracer 
dosimetry and signal detection (eg, splenectomy).
i)
Presence of any factors that would predispose the participant to develop infection (eg, 
rectal fissures, poor dentition, open skin lesions, and presence of pre-existing skin 
conditions that increase risks for injection site complications [eg, Behcet’s disease, 
psoriasis, pustular dermatoses])
j)
Known currently active tuberculosis (TB) (Part A and Part B).
k) Any serious acute or chronic bacterial or viral infection (eg, pneumonia, septicemia) within 
3 months prior to Screening
l)
In the case of prior SARS-CoV-2 infection, symptoms must have completely resolved and, 
based on investigator assessment, there are no sequelae (eg, shortness of breath, persistent 
cough, excessive fatigue, loss of smell) that would place the participant at a higher risk of 
receiving investigational treatment
m) Positive test result for the presence of SARS-CoV-2 virus (eg, polymerase chain reaction 
[PCR] test) within 14 days of Day 1 
n) Any recent infection requiring antibiotic treatment within 4 weeks of Day 1
o) Active herpes infection, including herpes simplex 1 and 2 and herpes zoster
p) Known active malaria
q) History or any evidence of active infection or febrile illness within 7 days of tracer 
administration (eg, bronchopulmonary, urinary, or gastrointestinal)
r)
Donation of blood to a blood bank or to another clinical study within 4 weeks of tracer 
administration (within 2 weeks for plasma only)
s) Inability to be venipunctured and/or tolerate venous access 
t)
Have any contraindication to arterial line insertion, including but not limited to, an 
abnormal Allen’s test result, coagulation profile, allergy to local anesthetics, or other 
medical history or examination findings that in the opinion of the Investigator would make 
radial artery cannulation contraindicated (international normalized ratio [INR]/partial 
thromboplastin time [PTT]) at Screening (Part A and Part B)
u) Contraindications against MRI imaging, including non-MRI compatible metal implants, 
cardiac pacemakers, cochlear implants, ventricular shunt systems; metal particles in the 
body that pose a risk to the participant, including large tattoos in regions affected by cranial 
MRI scanning and severe claustrophobia. Contraindications against gadolinium-based 
contrast agents including known hypersensitivity to gadolinium-based contrast agents 
(Part B only).
v) Recent (within 6 months of study intervention administration) drug or alcohol abuse as 
defined in Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM 5), 
Diagnostic Criteria for Drug and Alcohol Abuse
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w) Use of any tobacco- or nicotine-containing products (including but not limited to cigarettes, 
pipes, cigars, electronic cigarettes, chewing tobacco, nicotine patches, nicotine lozenges, 
or nicotine gum) within 3 months prior to the first dose of tracer administration (Part A and 
Part C)
x) Any other sound medical, psychiatric, and/or social reason as determined by the 
investigator.
y) Inability to lie on the scanner for the duration of a PET scan acquisition
z) Current clinical or laboratory evidence of active TB. Participants with a positive 
QuantiFERON-TB Gold Plus test or 2 successive indeterminate QuantiFERON-TB Gold 
Plus tests at Screening will be excluded (Part C only).
aa) Participants who answer “yes” to items 4 or 5 of the C-SSRS or who answer “yes” to any 
suicidal behavior item (excluding non-suicidal self-injurious behavior) within 6 months 
prior to Day 1 or at Day -1 (See Section 9.4.7 for details on suicidal risk monitoring) (Part C 
only).
2) Reproductive Status
a) Women who are pregnant 
b) Women who are breastfeeding
3) Prior/Concomitant Therapy
a) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7
Concomitant Therapy
b) Use of any prescription drugs within 4 weeks or 5 times the elimination half-life (if known), 
whichever is longer before tracer administration (Part A and Part C)
c) Use of any investigational drugs or placebo within 4 weeks or 5 times the elimination half-
life (if known), whichever is longer before tracer administration 
d) Systemic steroid medication within 4 weeks prior to tracer administration
e) Disease-modifying therapies for MS (approved, off label, or experimental) except for 
glatiramer acetate, interferon-β1a, or interferon-β1b (Part B only)
4) Physical and Laboratory Test Findings
a) Evidence of organ dysfunction or any clinically significant deviation from normal in PE, 
vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the 
target population, in the opinion of the investigator
b) Positive urine screen for drugs of abuse (Part A and Part C)
c) Positive cotinine test (Part A and Part C)
d) Positive blood screen for hepatitis C antibody, hepatitis B core antibody, hepatitis B surface 
antigen, or human immunodeficiency virus (HIV)-1 and -2 antibody 
e) Estimated renal creatinine clearance < 30 mL/min based on the Cockgroft-Gault formula 
(Appendix 5)
f)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 x upper limit 
of normal (ULN)
g) Total bilirubin > 2 x ULN (unless in the context of Gilbert syndrome)
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5) Allergies and Adverse Drug Reaction
a) History of allergy to BMS-986196 or BTKi
b) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity)
c) Known hypersensitivity to 11C-BMS-986196
d) Hypersensitivity to gadolinium-based contrast agents (Part B only)
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: Under certain specific 
circumstances and only in countries where local regulations permit, a person who has been 
imprisoned may be included or permitted to continue as a participant. Strict conditions 
apply and BMS approval is required.)
b) Inability to comply with the study protocol including restrictions as listed in Section 6.3, 
Lifestyle Restrictions
c) Participation in another clinical trial concurrent with this study. Participation in certain 
non-interventional studies (eg, longitudinal cohort observational studies) or lifestyle and 
dietary intervention studies (eg, studies testing interventions such as mild to moderate 
exercise, diets low in carbohydrates, and/or cognitive training) is permitted if, in the 
assessment of the investigator, concurrent study participation does not pose a safety risk 
and is not expected to affect the imaging outcomes of the current study.
d) For Participants in the UK (at the London site): Previous participation in another clinical 
trial involving radiation exposure, which in combination with the radiation exposure from 
this study, would result in an effective dose of more than 10 mSv in a 1-year period.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Restrictions for meals, diet, and lifestyle/activity are described in detail in the following sections.
6.3.1
Meals and Dietary Restrictions
Study participants in Part A and C are required to fast for at least 8.5 hours prior to tracer 
administration and remain fasted during the PET scan procedure and until at least 1.5 hours after 
tracer administration. After completion of the PET procedure, meals will be provided by the PET 
center on the day of each PET scan. Participants who undergo 2 PET scans on 1 day do not have 
to remain fasted for the second PET scan and can have a light meal after the first tracer 
administration.
6.3.2
Caffeine, Alcohol, and Tobacco
Part A and Part C participants must meet the eligibility criteria related to alcohol, tobacco, and 
nicotine use. 
1) Participants are not permitted to consume alcohol-containing beverages from 3 days prior to 
Day 1 until the end of the safety follow-up period. 
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2) Participants are not permitted to smoke or use electronic cigarettes, vaporizers, or any nicotine-
containing products on tracer administration days. 
There are no restrictions on caffeine use outside of the required fasting times.
6.3.3
Activity
Participants are required to remain at the PET center on scanning days until they are discharged. 
Participants are to refrain from strenuous exercise and contact sports from at least 3 day(s) prior 
to the first tracer administration until discharge.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently entered in the study/included in the analysis population. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, as applicable, and to respond to queries from regulatory authorities. 
Minimal information includes date of consent, demography, screen failure details, eligibility 
criteria, and any serious AEs.
6.4.1
Retesting During Screening
Participant Re-enrollment: This study permits one-time re-enrollment of a participant who has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized/has not 
been treated) due to reasons that can be reasonably assumed to be of temporary nature. If
re-enrolled, the participant must be re-consented.
A one-time retesting of laboratory parameters and/or other assessments within any single 
Screening period will be permitted (in addition to any parameters that require a confirmatory 
value). Consultation with the medical monitor may be needed to identify whether repeat testing of 
any particular parameter is clinically relevant.
The most current result prior to 11C-BMS-986196 tracer administration on Day 1 is the value by 
which study inclusion will be assessed, because it represents the participant’s most current clinical 
state.
7
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
procedure(s) or medical device intended to be administered to a study participant according to the 
study protocol.
Study intervention includes both Investigational [Medicinal] Product (IP/IMP) and 
Non-investigational/Auxiliary [Medicinal] Product (Non-IP/Non-IMP/AxMP) as indicated in 
Table 7.1-1.
An IP, also known as IMP 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 
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a marketing authorization but used or assembled (formulated or packaged) differently from the 
authorized form, or used for an unauthorized indication, or when used to gain further information 
about the authorized form.
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 
IPs/AxMPs. Not applicable for this study.
7.1
Study Interventions Administered
Table 7.1-1:
Study Interventions
Arm Name
Part A
Part B
Part C
Intervention Name
11C-BMS-986196 
11C-BMS-986196
11C-BMS-986196
BMS-986196
Type 
Small molecule 
PET tracer
Small molecule 
PET Tracer
Small molecule PET 
Tracer
Small 
molecule/OSD
Dose Formulation
Solution for IV 
injection
Solution for IV 
injection
Solution for IV 
injection
Tablet
Unit Dose 
Strength(s)
Approximately 370 
MBq, equivalent to 
up to 20 μg
Approximately 370 
MBq, equivalent to 
up to 20 μg
Approximately 370 
MBq, equivalent to 
up to 20 μg
15 mg, 30 mg, and 
60 mg
Dosage Level(s)
One dose level. Up 
to 2 doses 
administered with 
an interdose 
interval between 
2 hours to 6 days.
One dose level. 
Two doses 
administered with 
an interdose 
interval between 
2 hours to 6 days. 
One dose level. Two 
doses administered 
with an interdose 
interval between 
2 hours to 6 days. 
One tablet per day.
Route of 
Administration
IV injection
IV injection
IV injection
Oral
Use
Experimental
Experimental
Experimental
Experimental
IMP and Non-
IMP/AxMP
IMP 
IMP 
IMP 
IMP
Sourcing
Locally synthesized 
by the trial site
Locally 
synthesized by the 
trial site
Locally synthesized 
by the trial site
Provided centrally 
by the Sponsor
Packaging and 
Labeling
Study intervention 
will be provided in 
a sterile glass vial 
with rubber stopper 
and aluminum seal. 
Each container will 
be labeled as 
required per 
country 
requirement.
Study intervention 
will be provided in 
a sterile glass vial 
with rubber stopper 
and aluminum seal. 
Each container will 
be labeled as 
required per 
country 
requirement.
Study intervention 
will be provided in a 
sterile glass vial with 
rubber stopper and 
aluminum seal. Each 
container will be 
labeled as required 
per country
requirement.
15 mg or 30 mg or 
60 mg tablets 
packaged in bottles 
of 35 tablets. Single 
bottles will only 
contain one dose 
strength level of 
tablets. Each bottle 
will be labeled as 
required per country 
requirements.
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Table 7.1-1:
Study Interventions
Arm Name
Part A
Part B
Part C
Current/Former 
Name(s) or 
Alias(es)
11C-BMS-986196
11C-BMS-986196
11C-BMS-986196
BMS-986196
Abbreviations: AxMP, auxiliary medicinal product; IMP, Investigational Medicinal Product; IV, intravenous; MBq, 
megabecquerel; OSD, oral solid dose; PET, positron emission tomography.
The time of dose administration will be called “0” hour.
Restrictions related to food and fluid intake are described in Section 6.3.
7.2
Method of Study Intervention Assignment
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
starting with 
 (eg, 
). Sequential numbering may restart at 
 for each participating site as the distinct patient identification number will ultimately be 
comprised of the site number and participant number (eg, 
). Those enrolled participants 
meeting inclusion and exclusion criteria will be eligible to be dosed.
In Part C, up to 12 evaluable participants will be enrolled and will receive (unlabeled) BMS986196 
at dose levels of 15 mg, 30 mg, or 60 mg QD. Up to 4 evaluable participants will be assigned to 
each dose level. Initially, participants will be assigned to the 30 mg dose level. After an interim 
review of PET results from 2 to 4 evaluable participants, the next dose level (15 mg or 60 mg) will 
be determined. At least 2 evaluable participants should have completed PET imaging at the second 
dose level before participants are assigned to the last dose level. 
Study intervention will be administered at the study visits as listed in Schedule of Activities 
(Section 2). Participants will not be replaced if they are discontinued due to an AE unless the AE 
can be determined to be unrelated to treatment. If a participant is replaced after dosing, then the 
replacement participant will be assigned the original participant’s number plus 100. The 
replacement participant will receive the same treatment as the participant being replaced, but a 
new participant number will be assigned to him/her. For example, Participant 4 would be replaced 
by Participant 104. Participants with non-evaluable PET images may be replaced, ie, the total 
number of enrolled participants may exceed 28 if participants have to be replaced.
7.3
Blinding
This is a nonrandomized, open-label study, and blinding procedures are not applicable.
7.4
Dosage Modification
No dose modifications are allowed in Part A.
In Parts B and C, an initial dose of 11C-BMS-986196 will be administered at approximately 370 
MBq (10 mCi) and up to 20 μg, but the radioactive dose and participant preparation may be revised 
based on results of radiation dosimetry obtained in Part A. 
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7.5
Preparation/Handling/Storage/Accountability
The IP/AxMP must be stored in a secure area according to local regulations. It is the responsibility 
of the investigator, or designee where permitted, to ensure that IP/AxMP is only dispensed to study 
participants. The IP/AxMP must be dispensed only from official study sites by authorized 
personnel according to local regulations.
The product storage manager should ensure that the study intervention 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 intervention arise, the study intervention 
should not be dispensed, and BMS should be contacted immediately.
Study intervention not supplied by BMS will be stored in accordance with the package insert.
IP/AxMP documentation (whether supplied by BMS or not) must be maintained that includes all 
processes required to ensure the 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).
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention.
The investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study intervention accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).
Only participants enrolled in the study may receive study intervention, and only authorized staff 
may supply, prepare, or administer study intervention.
Further guidance and information for the final disposition of unused study interventions are 
provided in Appendix 2.
Radiosynthesis instructions will be provided separately to the site.
7.6
Treatment Compliance
When participants are dosed at the site, they will receive study intervention directly from qualified 
site staff under medical supervision. The date and time of each dose administered at the site will 
be recorded in the source documents and recorded in the case report form (CRF). The specific dose 
of study intervention and study participant identification will be confirmed at the time of tracer 
administration by a member of the study site staff other than the person administering the study 
intervention. 
For Part C only, BMS-986196 (unlabeled) study intervention compliance will be periodically 
monitored by drug accountability (including review of dosing diary). Drug accountability should 
be reviewed by the site study staff at each visit to confirm treatment compliance. Site staff should 
discuss discrepancies with each participant at Visit 2. 

When participants are dosed at the site with BMS-986196 (unlabeled), they will receive study 
intervention directly from authorized site staff. The date and time of each dose received in the 
clinic will be recorded in the source documents and in the CRF. The dose of study intervention 
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and study participant identification will be confirmed at the time of dosing by a member of the 
study site staff. 

When participants self-administer BMS-986196 (unlabeled) at home, compliance with study 
intervention will be assessed at Visit 2. Compliance will be assessed by direct questioning, 
counting of the remaining tablets, and review of the Participant Diary (supplied by the Sponsor) 
and documented in the source documents and the CRF. Deviations from the prescribed dosage 
regimen should be recorded in the CRF.

A record of the quantity of BMS-986196 (unlabeled) dispensed to and administered by each 
participant must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates will also be recorded in the CRF.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to tracer administration in the study are 
described below. Medications taken within 4 weeks prior to tracer administration must be recorded 
on the CRF.
1) Prior exposure to BMS-986196 within 4 weeks of 11C-BMS-986196 tracer administration 
2) Exposure to any investigational drug or placebo within 4 weeks or 5 times the elimination 
half - life (if known), whichever is longer of 11C-BMS-986196 tracer administration
3) Fish oil, aspirin, platelet aggregation inhibitors (including nonsteroidal anti-inflammatory 
drugs with such activity) and anticoagulants within 10 days prior to and within 7 days after 
11C-BMS-986196 tracer administration
4) Use of disease-modifying therapies for MS (approved, off label, or experimental), except for 
glatiramer acetate, interferon-β1a and interferon-β1b (Part B only)
5) Systemic steroid medication within 4 weeks prior to 11C-BMS-986196 tracer administration. 
6) Use of any prescription drugs within 4 weeks or 5 times the elimination half-life (if known), 
whichever is longer, prior to 
11C-BMS-986196 tracer administration. Contraceptive 
medication is permitted. In Part B, symptomatic therapy for MS (eg, against spasticity) is 
permitted.
7) Use of any other drugs, including over-the-counter medications and herbal preparations, within 
1 week prior to 11C-BMS-986196 tracer administration, except those medications cleared by 
the medical monitor. Paracetamol (acetaminophen) at daily doses up to 2000 mg for up to 
3 days is permissible.
Administration of investigational SARS-CoV-2 vaccines is not allowed during the study. 
Participants may receive approved SARS-CoV-2 vaccines while continuing on study treatment at 
the discretion of the investigator.
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Treatment of active SARS-CoV-2 infections or high risk exposures, including use of 
investigational therapies, is allowed and should be discussed with the medical monitor.
The investigator should contact and confirm agreement with the medical monitor prior to the 
administration of any concomitant medications that are not explicitly permitted and are not used 
for the emergency treatment of AEs.
7.7.2
Other Restrictions and Precautions
Participants are prohibited from joining another clinical trial while they are participating in this 
study. Participation in certain observational studies or lifestyle or dietary intervention studies may 
be permissible if, in the assessment of the investigator, concurrent study participation does not 
pose a safety risk and is not expected to affect the imaging outcomes of the current study.
7.7.2.1
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes (eg, 
allergy history, diabetic history, and renal status), the appropriate imaging modality and contrast 
regimen per imaging study. Imaging contraindications and contrast risks are to be considered in 
this assessment. Renal function should be assessed in study participants receiving gadolinium-
based contrast agent with regard to contrast agent dose and appropriateness of any administered 
contrast agent. Specific to MRI, participants with severe renal insufficiency, defined as estimated 
glomerular filtration rate (eGFR) < 30 mL/min based on the Cockcroft-Gault formula20
(Appendix 5), are excluded from the study. In addition, participants may be excluded from MRI 
and study participation in Part B if they have tattoos, non-MRI compatible metallic implants, 
pacemakers, etc. This will be outlined in the Imaging Manual. A local safety read of the MRI 
should be performed and shared with the investigator.
Gentle hydration before and after IV contrast should follow local standard of care. The ultimate 
decision to perform MRI in an individual participant in this study rests with the site radiologist, 
the investigator, and standards set by the local Ethics Committee.
7.8
Continued Access to Study Intervention after the End of the Study
At the end of the study, BMS will not continue to provide BMS-supplied study intervention to 
participants/investigators. The investigator should ensure that any patient with MS receives 
appropriate standard of care to treat the condition under study.
BMS reserves the right to terminate access to BMS-supplied study intervention if any of the 
following occur: a) the study is terminated due to safety concerns; b) the development of 
11C-BMS-986196 is terminated for other reasons, including, but not limited to not meeting the 
study objectives. In all cases, BMS will follow local regulations.
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8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Intervention
Participants MUST discontinue IP (and Non-IP/AxMP at the discretion of the investigator) for any 
of the following reasons:

Participant’s request to stop study intervention. Participants who request to discontinue study 
intervention 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 participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by the participant 
to provide this information

Any clinical 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 
participant

Termination of the study by 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. (Note: Under 
specific circumstances and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply, and 
BMS approval is required.)

Pregnancy (study treatment must be discontinued immediately. Refer to Section 9.2.5). 

Significant noncompliance with protocol (eg, procedures, assessments, medications, etc). The
investigator should discuss such issues with the medical monitor.

Abnormal liver tests suggestive of potential drug-induced liver injury (DILI) as defined in 
Section 9.2.7.

A participant has reported an adverse event meeting the stopping rule defined in Section 8.4. 

A participant has experienced a protocol-defined MS relapse after administration of 
11C-BMS-986196 at the Day 1 Visit.
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation, 
follow up, and for any further evaluations that can be completed.
All participants who discontinue study intervention should comply with protocol-specified follow-
up procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures, including post-treatment study follow-up, or loses the 
ability to consent freely (eg, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study intervention is discontinued prior to the participant’s completion of the study, the reason 
for the discontinuation must be documented in the participant’s medical records per local 
regulatory requirements in each region/country and entered on the appropriate CRF page.
8.1.1
Post-study Intervention Study Follow-up
Participants who discontinue study intervention may continue to be followed.
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8.2
Discontinuation from the Study
Participants who request to discontinue study intervention 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 participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up.

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 intervention 
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 participant 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.

If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.2.1
Individual Discontinuation Criteria

A participant may withdraw completely from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon.

At the time of discontinuing from the study, if possible, an early termination visit should be 
conducted, as shown in the Schedule of Activities. See the Schedule of Activities for data to 
be collected at the time of study discontinuation and follow-up and for any further evaluations 
that need to be completed.

The participant will be permanently discontinued both from the study intervention and from 
the study at that time.

If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-up
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:

All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.

Lost to follow-up is defined by the inability to reach the participant after a minimum of 
three (3) documented phone calls, faxes, or emails, as well as lack of response by participant 
to one (1) registered mail letter. All attempts should be documented in the participant’s medical 
records.
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
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.

If the investigator’s use of third-party representative to assist in the follow-up portion of the 
study has been included in the participant’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining the participant’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 participant remains lost to follow-up, then the last known alive date 
as determined by the investigator should be reported and documented in the participant’s 
medical records.
8.4
AE-defined Stopping Rules
AE-based stopping rules are triggered if an AE of sufficient significance (as judged by the 
investigator) warrants halting further enrollment and tracer administration. The AE must be 
considered related to study treatment and must not be an underlying condition of the study 
participant.
In addition, the following criteria trigger stopping rules: 

One participant experiences a serious adverse event (SAE) that is considered related to 
11C-BMS-986196 or BMS-986196.

Two participants experience severe AEs that are related to 11C-BMS-986196 or BMS-986196.
If either above listed criteria for stopping rules are met, a review of the safety data will be initiated 
to assess if the initial assessment of the relevant safety events was accurate.
If the review of the safety data concludes that the stopping rules were not met, then a justification 
for study restart will be submitted to the IEC/IRB and the study will only restart after IEC/IRB 
approval for restart has been obtained. If review of the safety data concludes that the stopping rules 
were met, the study will only restart after submission of a substantial amendment providing the 
data and justification for the restart.
9
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and timing are summarized in the Schedule of Activities (Section 2).

Protocol waivers or exemptions are not allowed in this study.

All safety concerns must be discussed with the medical monitor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 2), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before enrollment and tracer administration. 
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9.1
Efficacy Assessments
Not applicable; efficacy will not be assessed in this study. 
9.1.1
Imaging Assessments
9.1.1.1
PET Assessments
PET procedures will be conducted at the  PET center at each site. Female participants will be given 
a pregnancy test prior to the initiation of any imaging procedures. If the test is positive, the scans 
will not be conducted.
Participant preparation for PET scanning consists of placement of venous lines and placement of
arterial lines. In Part C, no arterial lines will be placed. IV line placement will be performed by the 
research nurse, certified nuclear medicine technologist, or investigator. The arterial and venous 
catheters will be placed by experienced staff, before the PET scan. One IV line will be used for 
tracer administration. The arterial line and, if applicable, a second IV line will be used to draw 
arterial and venous blood samples, respectively, for metabolite analysis and for determination of 
the fraction of plasma radioactivity unbound to protein.
The goal of arterial and venous lines is to be able to measure absolute physiological functions by 
mathematically relating the signal (from the PET scanner) to the tracer availability (from the 
blood). This approach provides the gold-standard data. If an arterial line cannot be placed, a second 
IV line may be placed for IV blood sampling. IV blood sampling should occur on the arm opposite 
of the arm used for 11C-BMS-986196 tracer administration. All processing of blood samples for 
11C-BMS-986196 input function determination should occur promptly at the PET center due to the 
short half-life of C-11 (20 min).
PET scans will be performed and acquired as participants lie supine on the scanner bed. 
For each PET scan, approximately 370 MBq (10 mCi) of 11C-BMS-986196 will be administered 
by a slow IV bolus. Acquisition of emission data will begin shortly after administration and
continue for a period of up to 120 minutes. Vital signs (blood pressure, heart rate, respiration rate, 
and body temperature) will be obtained before 11C-BMS-986196 administration, after completion 
of the PET scan procedure, and prior to discharge on each scan day. An ECG will be completed 
before each PET scan and prior to discharge on each scan day. 
Part A
Two tracer administrations of 11C-BMS-986196 are each followed by a PET scan. The interval 
between the first and second tracer administrations must be at least 2 hours and at most 6 days. If 
the second tracer administration is done on Days 5, 6, or 7, the study site staff must contact the 
participant remotely (ie, by phone) on Day 4 (ie, 3 days after the first PET scan) and record AEs 
and concomitant medications.
Before or after the first PET scan, a low-dose whole-body CT scan (from apex to upper-thigh level) 
will be acquired for attenuation correction. No contrast agent is administered for the CT scan.
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Before and/or after the cranial PET scan, a low-dose cranial CT scan or MRI scan will be acquired 
(depending on availability of equipment). No contrast agent is administered for the CT or the MRI 
scan.
The maximal number of tracer administrations in Part A is 2 and the maximal number of whole-
body CT scans in Part A is 1. The maximum number of cranial CT scans in Part A is 2 per cranial 
PET (1 before and 1 after the PET scan). Hence, the maximum number of cranial CT scans is 4 
for participants who will not undergo whole-body CT scans. For all other participants in Part A, 
the maximum number of cranial CT scans is 2. If 2 PET scans are performed on the same day, 
hematology and clinical chemistry samples, VS, ECG, AEs, and review of concomitant 
medications are the only safety assessments that must be assessed in duplicate, and the same 
arterial line may be used for both scans.
If, after completion of dosimetry in Part A participants and based on emerging data from Part B, 
2 additional participants are enrolled to Part A, then these 2 participants will only undergo the 
cranial PET scan of Visit 2, and these participants will have arterial and venous blood samples 
drawn during the Visit 2 PET scan. For these 2 participants, Visit 2 will be regarded as Day 1.
Part B
Two administrations of 11C-BMS-986196 are each followed by a cranial PET scan. The interval 
between the first and second tracer administration must be at least 2 hours and at most 6 days. If 
the second tracer administration is done on Days 5, 6, or 7, the study site staff must contact the 
participant remotely (ie, by phone) on Day 4 (ie, 3 days after the first PET scan) and record AEs 
and concomitant medications. Participants who had a MS relapse within 30 days prior to Day 1 
must start Scan 2 on Day 1 or Day 2.
Before or after each tracer administration, a low-dose cranial PET-CT or PET-MRI scan will be 
performed (depending on equipment availability). No contrast agent will be administered for the 
PET-CT scan. To account for potential significant movement during the PET scan, it is permissible 
to perform 1 cranial CT or MRI scan before and 1 CT or MRI scan after a cranial PET scan. At 
the discretion of the investigator, gadolinium-based contrast agents may be administered if a 
PET-MRI is performed. Participants in Part B must have at least one cranial PET-MRI scan 
performed with gadolinium-based contrast agent. Gadolinium-based contrast agent may be 
administered either at Screening or during PET-MRI.  
Before a PET-MRI scan, participants will be asked for the presence of contra-indications against 
MRI or application of gadolinium-based contrast agents and asked to remove magnetic objects 
before entering the scanner. 
The maximal number of tracer administrations in Part B is 3 and the maximal number of CT scans 
in Part B is 6. If 2 PET scan visits are performed on the same day, vital signs (VS), ECG, AEs, 
and review of concomitant medications are the only safety assessments that must be assessed in 
duplicate, and the same arterial line may be used for both scans.
In Part B, every effort must be made to perform the re-test PET scan under identical conditions as 
the test scan (eg, same scanning machines, same imaging procedures).
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If, based on emerging data from Part B, simultaneous sampling of venous and arterial blood 
sampling is considered warranted to facilitate future studies without arterial blood sampling, up to 
6 participants in Part B may undergo simultaneous venous and arterial blood sampling only during 
one PET scan procedure. Preferably, the simultaneous and arterial blood sampling is performed 
during Visit 1.
Part C
Two administrations of 11C-BMS-986196 will each be followed by a cranial PET scan. The second 
tracer administration will occur approximately 24 hours after the last administration of (unlabeled) 
BMS-986196. 
Before or after each tracer administration, a low-dose cranial PET-CT or PET-MRI scan will be 
performed (depending on equipment availability). No contrast agent will be administered for the 
PET-CT scan. To account for potential significant movement during the PET scan, it is permissible 
to perform 1 cranial CT or MRI scan before and 1 CT or MRI scan after a cranial PET scan. No 
gadolinium-based contrast agents will be administered if a PET-MRI is performed.  
Before a PET-MRI scan, participants will be asked for the presence of contraindications against 
MRI and asked to remove magnetic objects before entering the scanner. 
The maximal number of tracer administrations in Part C is 3, and the maximal number of CT scans 
in Part C is 6. 
In Part C, every effort must be made to perform the second PET scan under identical conditions 
as the first scan (eg, same scanning machine, same imaging procedures).
9.1.1.2
MRI Imaging During Screening
Participants in Part B will undergo cranial MRI scanning during the Screening period. Participants 
will only undergo cranial MRI scanning if they are eligible for the study based on the other 
assessments performed during screening. A Screening MRI should be performed within 14 days 
of Day 1. Imaging should be performed on a 3T MRI machine and at a minimum T1 and T2 
sequences are performed, including T1 sequences with and without enhancement by gadolinium-
based contrast agent. However, if use of gadolinium-based contrast agent is planned during 
PET-MRI, gadolinium-based contrast agent is not required during screening MRI. Before 
screening, MRI participants will be asked for the presence of contra-indications against MRI or 
application of gadolinium-based contrast agents and asked to remove magnetic objects before 
entering the scanner. The details of the MRI scanning conditions will be detailed in an Imaging 
Charter. A local safety read of the MRI should be performed and provided to the investigator for 
review.
9.1.1.3
Central Image Analysis
PET, CT, and MRI images will be submitted to a central imaging vendor for independent central 
review at any time during the study. Prior to scanning the first participant, sites should be qualified 
and understand the image acquisition guidelines and submission process as outlined in the Imaging 
Manual provided by the central imaging vendor.  
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9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, or a surrogate, (or 
the participant’s legally acceptable representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following up 
on AEs that are serious, considered related to the study intervention or the study, or that caused 
the participant to discontinue before completing the study. 
Refer to Appendix 3 for SAE reporting.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures, and within 10 days following discontinuation of 
dosing in Parts A and B, and within 28 days following discontinuation of dosing in Part C.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study intervention or protocol-specified procedure (eg, a follow-up skin biopsy).

Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the appropriate section of the CRF module.

All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3.

The investigator will submit any updated SAE data to the sponsor or designee within 24 hours
of updated information being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
intervention or study participation, the investigator must promptly notify the Sponsor.
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
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9.2.2
Method of Detecting AEs and SAEs
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. Care should be taken not to introduce bias when collecting AEs and/or 
SAEs. Inquiry about specific AEs should be guided by clinical judgement in the context of known 
AEs, when appropriate for the program or protocol.
9.2.3
Follow-up of AEs and SAEs

Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study intervention and for those present at the end of study intervention 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.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
The Sponsor or designee must report AEs to regulatory authorities and ethics committees 
according to local applicable laws and regulations. A SUSAR (suspected, unexpected serious 
adverse reaction) is a subset of SAEs and must be reported to the appropriate regulatory authorities 
and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
This section is not applicable for WNOCBP in Part C.
If, following initiation of the study intervention in Parts A or B, it is subsequently discovered that 
a participant is pregnant or may have been pregnant at the time of study drug exposure, including 
at least 30 hours after study product administration, the investigator must immediately notify the 
BMS medical monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to the BMS designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3.
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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. Protocol-required procedures for study discontinuation and follow-up must be 
performed on the participant.
If any sexual activity involving penile intercourse (eg, vaginal, anal, oral) has occurred between a 
male participant and a pregnant partner(s) without the use of a condom during and at least for 
30 hours after tracer administration in Parts A and B and at least for 10 days after the last dose of
unlabeled study drug administration in Part C, the information should be reported to the Sponsor 
or designee, even if the male participant has undergone a successful vasectomy.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE CRF, as appropriate. Paper forms are only intended as a back-up option when the 
electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE

Any laboratory test result abnormality that required the participant to have study intervention
discontinued or interrupted

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that, wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia vs low hemoglobin value).
9.2.7
Potential Drug-induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences 
of potential DILIs meeting the defined criteria must be reported as SAEs (see Section 9.2 and 
Appendix 3 for reporting details).
Potential DILI is defined as 1 of the following 3 conditions: 

Condition 1:

Aminotransaminase (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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
Condition 2

AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) in the presence of 
clinical symptoms (eg, upper abdominal quadrant pain, brown colored urine)
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.

Condition 3

Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) and clinical symptoms (eg, icteric conjunctiva or skin)
AND

No other immediately apparent possible causes of aminotransaminase (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.
9.2.8
Other Safety Considerations
Any significant worsening of conditions noted during interim or final physical examinations, ECG, 
x-ray filming, or any other potential safety assessment required or not required by the protocol 
should also be recorded as a nonserious AE or SAE, as appropriate, and reported accordingly.
9.3
Overdose
For this study, any dose of 11C-BMS-986196 greater than 100 μg within a 24-hour time period will 
be considered an overdose. Overdoses that meet the regulatory definition of SAE will be reported 
as an SAE (see Appendix 3).
In the event of an overdose, the investigator should:

Contact the medical monitor immediately

Closely monitor the participant for AEs/SAEs and laboratory abnormalities until 
11C-BMS-986196 can no longer be detected systemically. The specific follow up duration will 
be determined after consultation with the medical monitor and will depend on the actual tracer 
dose administered. Because 50% recovery of BTK is projected to occur within 7 days, 
in-person follow-up beyond 7 days in the absence of AEs is not required. 

Document the quantity of the excess dose as well as the duration of the overdose in the CRF
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2).
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9.4.1
Physical Examinations
A complete PE includes examination of head, eyes, ears, nose, and throat (HEENT), heart, lungs, 
abdomen, extremities, skin and in Parts A and C only, a limited neurological exam. In Part B, the 
 serves as neurological examination. A partial PE will be symptom-oriented and 
include areas with previously noted abnormalities and/or newly emergent symptoms.
Complete and/or partial PEs may be performed by a Doctor of Medicine, or someone who is 
authorized to perform the examinations by training and has been delegated this task by the 
investigator. Every effort should be made to ensure the same evaluator will complete the 
examination for each participant at all visits throughout the study. Documentation of the person 
who performed the examination is to be recorded in source notes.
9.4.2
Height and Weight
Height and body weight will be measured per the Schedules of Activities (Section 2). BMI will be 
calculated using the equation: BMI = weight (kg)/(height[m]²).
9.4.3
Vital Signs
After resting quietly in a supine position for at least 5 minutes, vital signs (oral or tympanic body 
temperature, respiration rate, blood pressure [BP], and heart rate [HR]) will be recorded as per 
Schedules of Activities (Section 2). At Visits 1 and 2, the vital signs assessment prior to discharge 
can be performed in sitting or supine position.
For BP, the participant’s arm should be supported at the level of the heart, and BP should be 
recorded to the nearest mmHg. Preferably, the same arm should be used throughout the study. The 
same size BP cuff, which has been properly sized and calibrated, will be used to measure BP each 
time. The use of automated devices for measuring BP, respiration rate, and HR are acceptable. 
However, manual HR (if used) will be measured by palpitation in the brachial/radial artery for at 
least 30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and HR should be obtained prior to the nominal time of the blood collection.
9.4.4
Allen’s Test (Part A and Part B only)
The Allen’s test is a clinical assessment of arterial blood flow supply to the hand. For the test, the 
participant raises the extended arm, ideally from a supine position, such that the hand is above the 
heart level. The participant then clinches a fist for at least 30 seconds, and the assessor places 
manual pressure on the radial and ulnar artery to limit the blood flow for several seconds. The 
participant then opens the fist and the palm of the hand should look pale. The assessor then releases 
the manual pressure from the ulnar artery and watches the palm of the hand, which should return 
to its normal color within approximately 5 to 15 seconds for a normal test result.
9.4.5
Electrocardiograms
Single 12-lead ECGs in the supine position will be performed as per the Schedule of Activities 
(Section 2). Participants will have rested in the supine position for at least 5 minutes prior to each 
ECG. A local ECG read will be performed. Clinically significant abnormal findings will be 
recorded as AEs.
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9.4.6
Clinical Safety Laboratory Assessments

Investigators must document their review of each laboratory safety report.
A local laboratory will perform the analyses and will provide reference ranges for these tests.
Participants in Parts A and C are required to fast for at least 10 hrs prior to specimen collection. 
Results of clinical laboratory tests performed on Day -1 must be available and reviewed for study 
eligibility, if applicable, prior to tracer administration. 
Specimens will be collected at least 1.5 hrs after the first tracer administration and at least 1.5 hours 
after the second tracer administration. 
Table 9.4.6-1:
Clinical Laboratory Assessments
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase
Alanine aminotransferase 
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Amylase
Lipase
Lactate dehydrogenase 
Creatinine
Blood urea nitrogen 
Uric acid
Fasting or non-fasting glucose
Total protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatine kinase
Creatinine clearance (Screening only)
Coagulation (Screening only)
INR
aPTT
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
pH
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Table 9.4.6-1:
Clinical Laboratory Assessments
Microscopic examination of the sediment if blood, protein or leukocyte esterase are positive on the dipstick
Serology 
Serum for hepatitis C antibody, hepatitis B core antibody, hepatitis B surface antigen, HIV-1 and -2 antibody 
(Screening only)
Other Analyses
Test for drugs of abuse (urine; Screening and prior to Day 1 tracer administration; Parts A and C only)
Alcohol test (urine or breath; Screening and prior to Day 1 tracer administration) 
Cotinine test (urine; Screening and prior to Day 1 tracer administration; Parts A and C only)
Urine or serum pregnancy test (Parts A and B only; WOCBP only; Screening and prior to Day 1 tracer 
administration)
FSH test (women < 55 years for confirmation of postmenopausal status; refer to Appendix 4) 
QuantiFERON-TB Gold Plus (Screening; Part C only)
Abbreviations: aPTT, activated partial thromboplastin time; FSH, follicle stimulating hormone; HIV, human 
immunodeficiency virus; INR, international normalized ratio; WOCBP, women of childbearing potential.
9.4.7
Suicidal Risk Monitoring (Part C only)
BMS-986196 is CNSpenetrant. It is unknown whether BMS-986196 affects mood and/or suicidal 
ideation/behavior. In Part C, study participants will be assessed for suicidal ideation/behavior with 
the C-SSRS (baseline version at Screening and since last visit/last assessment version afterwards).
Participants treated with BMS-986196 should be monitored appropriately and observed closely 
for suicidal ideation and behavior or any other unusual changes in behavior. Consideration should 
be given to discontinuing BMS-986196 in participants who experience signs of suicidal ideation 
or behavior.
9.4.8
Other Safety Assessment
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 investigator and/or the qualified 
neurologist as per standard medical/clinical judgment.
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9.6
Immunogenicity Assessments 
Not applicable. 
9.7
Genetics
Not applicable.
9.8
Biomarkers
No blood samples for 
 or downstream target engagement as pharmacodynamics 
(PD) analysis will be collected or analyzed in Parts A and B. Blood collection for measuring blood 
 will occur in Part C, as detailed in the Schedule of Assessments (Table 2-4).
Table 9.8-1:
Biomarker Sampling Schedule for All Participants in Parts A and B 
(IM038010)
Study Day
Time 
(Event)
Hour
Time
(Relative To Dosing)
Hour: Min
SARS-CoV-2 Serum 
Sample (Parts A and B 
only)
Screening
Not applicable
Not applicable
X
Visit 1
Not applicable
Not applicable
Not applicable
Visit 2
Not applicable 
Not applicable
Not applicable
Visit 3
Not applicable
Not applicable
Not applicable
Abbreviations: Min, minutes; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Table 9.8-2:
Target Engagement as Pharmacodynamics Sampling Schedule for 
Part C (IM038010)
Study Day of Sample 
Collection
Event
Time Relative to Last 
BMS-986196 Dose 
(hr:min)
BMS-986196  Whole 
Blood Sample for PD
Visit 1
Predose
-00:30
X
Visit 2
Postdose
24:00
X
Abbreviations: hr, hour; min, minute; PD, pharmacodynamic. , 
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For Parts A and B, serum samples will be collected from all participants and shipped to the Sponsor 
for potential evaluation of 
, if warranted. 
Results will not be used to determine eligibility.
TE as PD whole blood sample collection, labeling, processing, storage, and shipping will be 
provided to the site in the laboratory/procedure manual.
9.9
Additional Research
This protocol will not include sample collection and/or residual sample storage for additional 
research.
Additional research is intended to expand the research and development capability at Bristol Myers 
Squibb and will support as yet undefined research aims that will advance our understanding of 
disease and options for treatment. This may also include genetic/genomic exploration aimed at 
exploring disease pathways, progression and response to treatment etc. 
9.10
Other Assessments
Not applicable.
9.11
Health Economics OR Medical Resource Utilization and Health 
Economics
Health economics/medical resource utilization and health economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Statistical Hypotheses
Not applicable.
10.2
Sample Size Determination 
The sample size in Parts A to C of the study is not based on statistical power considerations or 
formal sample size calculations. In Part A, up to 8 healthy participants (at least 2 females and 
2 males are planned) will be enrolled, in Part B, up to 8 participants with MS will be enrolled, and 
in Part C, up to 12 healthy participants will be enrolled, such that in this study, up to approximately 
28 participants will have evaluable PET scans. Participants with non-evaluable PET scans may be 
replaced, ie, the total number of enrolled participants may exceed 28 if participants have to be 
replaced. 
10.3
Analysis Sets
For the purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who provide written (signed) informed consent.
Safety 
All participants who received at least 1 dose of tracer administration. 
PET
All participants who received at least 1 dose of tracer administration and have 
any available PET scan data.
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Population
Description
Response-Evaluable 
All participants who receive at least 1 dose of tracer administration, and: 
1) 1 evaluable whole-body PET scan in Part A (Response-Evaluable 1)
2) At least 1 evaluable cranial PET scan in Part A or B (Response-Evaluable 2)
3) 2 evaluable cranial PET scans in Parts B and C (Response-Evaluable 3) 
Per Protocol
All participants who receive at least 1 dose of tracer administration, and: 
1) 1 evaluable whole-body PET scan without major important protocol 
deviations in Part A (Per-Protocol 1)
2) At least 1 evaluable cranial PET scan without major important protocol 
deviations in Part A or B (Per-Protocol 2) 
3) 2 evaluable cranial PET scans without major important protocol deviations 
in Parts B and C (Per-Protocol 3) 
Abbreviations: PET, positron emission tomography.
10.4
Statistical Analyses
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the selection of participants to be included in the analyses and procedures for accounting 
for missing, unused, and spurious data.
10.4.1
General Considerations
Details on statistical considerations will be included in the SAP. Statistical analyses in this study 
will be detailed in the SAP.
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10.4.2
Primary Endpoint(s)
Table 10.4.2-1:
Endpoints
Primary Endpoint
Description
Timeframe
Incidence, severity, seriousness, 
type of AEs. (Safety Population)
Incidence of AEs, SAEs, severe, 
type of AEs. AEs listed by 
frequency
Treatment emergent during the 
study
Incidence of clinically significant 
abnormal findings. (Safety 
Population) 
Incidence of clinically significant 
abnormal findings in ECG, 
laboratory values, VS, physical 
examination
Treatment emergent during the 
study
Radiation dosimetry (Part A only). 
(Response-Evaluable 1 Population)
Organ absorbed dose and 
whole-body effective dose
After 11C-BMS-986196 tracer 
administration at Visit 1
Window of acquisition. 
(Response--Evaluable 2 Population) 
Time during which peak PET signal 
is detected 
Part A Visit 2, and Part B Visit 1 
and Visit 2 after 11C-BMS-986196 
tracer administration 
Test-Retest Repeatability (Part B 
only). (Response-Evaluable 3 
Population)
Quantitative analysis of PET signal 
in CNS between 2 evaluable PET 
sessions
Visit 1 and Visit 2 after 
11C-BMS-986196 tracer 
administration 
% Free brain BTK relative to 
baseline (Part C only)
Proportion of free brain BTK at 
Visit 2 relative to Visit 1
Visit 1 and Visit 2
Abbreviations: AE, adverse event; CNS, central nervous system; ECG, electrocardiogram; PET, positron emission 
tomography; SAE, serious adverse event; VS, vital signs.
All recorded AEs will be listed according to system organ class and preferred term and tabulated 
by study part. ECGs as reported on the ECG CRF (including abnormality) will be reported 
separately. Vital signs as reported on the VS CRF will be reported separately. Physical 
examinations as recorded on the PE CRF will be reported separately. Clinical laboratory test results 
as reported on Lab CRF will be reported separately. Vital signs, ECGs, and laboratory test results 
will be summarized.
For test-retest repeatability in Part B, descriptive statistics will be reported by measurement. A 
scatter plot of test versus retest with the line of equality will be created. A plot of differences 
between retest and test versus the mean of the test and retest may also be constructed. The 
estimated limits of agreement will be also presented on this plot.
The proportion of free brain BTK relative to baseline will be summarized for Part C. 
Descriptive statistics and plots may be provided for the other endpoints. Other details may be 
added in the SAP as appropriate.
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10.4.3
Secondary Endpoint(s)
Table 10.4.3-1:
Secondary Endpoints
Secondary Endpoint
Description
Timeframe
11C-BMS-986196 signal 
characterization. 
(Response-Evaluable 1 Population)
SUV, VT, and other relevant 
quantitative PET measures as 
applicable in the brain
Visit 1 and Visit 2 
Abbreviations: PET, positron emission tomography; SUV, standardized uptake value; VT, volume of distribution.
Descriptive statistics will be provided for the secondary endpoint. Plots may be also created.
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10.4.5
Other Safety Analysis
Not applicable.
10.4.6
Other Analyses 
Not applicable.
10.5
Interim Analyses 
Not applicable.
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11
REFERENCES
1
Sun C, Nierman P, Kendall EK, et al. Clinical and biological implications of target occupancy 
in CLL treated with the BTK inhibitor acalabrutinib. Blood 2020;136:93-105.
2
Alsadhan A, Cheung J, Gulrajani M, et al. Pharmacodynamic analysis of BTK inhibition in 
patients with chronic lymphocytic leukemia treated with acalabrutinib. Clin Cancer Res 
2020;26:2800-9.
3
Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an oral BTK inhibitor 
in multiple sclerosis. N Engl J Med 2019:380:2406-17.
4
BMS-986196 Investigator’s Brochure Version 04. Bristol-Myers Squibb Company; 2023. 
Document Control No. 930164366.
5
Genevier HC, Hinshelwood S, Gaspar HB, et al. Expression of Bruton’s tyrosine  kinase 
protein within the B cell lineage. Eur J Immunol 1994;24:3100-5.
6
Shinohara M, Koga T, Okamoto K, et al. Tyrosine kinases Btk and Tec regulate osteoclast 
differentiation by linking RANK and ITAM signals. Cell 2008;132:794–806.
7
Goldmann L, Duan R, Kragh T, et al. Oral Bruton tyrosine kinase inhibitors block activation 
of the platelet Fc receptor CD32a (FcγRIIA): a new option in HIT? Blood Adv 2019;3:4021-
33.
8
Dispenza MC, Pongracic JA, Singh AM, et al. Short-term ibrutinib therapy suppresses skin 
test responses and eliminates IgE-mediated basophil activation in adults with peanut or tree 
nut allergy. J Allergy Clin Immunol 2018;141:1914-16.e7.
9
Singh SP, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and 
malignancies. Mol Cancer 2018;17:57. 
10 Lassmann H. Pathogenic mechanisms associated with different clinical courses of multiple 
sclerosis. Front Immunol 2019;9:3116.
11 OCREVUSTM (ocrelizumab) injection, for intravenous use. Initial U.S. Approval: 2017. 
Genetech, Inc, South San Francisco, CA.
12 Dahal UP, Obach RS, Gilbert AM. Benchmarking in vitro covalent binding burden as a tool to 
assess potential toxicity caused by nonspecific covalent binding of covalent drugs. Chem Res 
Toxicol 2013;26:1739-45.
13 Erickson RI, Schutt LK, Tarrant JM, et al. Bruton’s tyrosine kinase small molecule inhibitors 
induce a distinct  pancreatic toxicity in rats. J Pharmacol Exp Ther 2017;360:226-38.
14 CALQUENCE® (acalabrutinib) capsules, for oral use. Initial U.S. Approval: 2017. 
AstraZeneca Pharmaceuticals LP, Wilmington, DE.
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15 IMBRUVICA® (ibrutinib) capsules, for oral use. Initial U.S. Approval: 2013. Pharmacyclics 
LLC, Sunnyvale, CA.
16 Scheer B, Perel A, Pfeiffer UJ. Clinical review: complications and risk factors of peripheral 
arterial catheters used for haemodynamic monitoring in anaesthesia and intensive care 
medicine. Crit Care. 2002;6:199-204. 
17 FDA. Benefits and risks MRI. Accessed February 17, 2021. Available from URL: 
https://www.fda.gov/radiation-emitting-products/mri-magnetic-resonance-imaging/benefits-
and-risks 
18 Takano A, Varrone A, Gulyás B, et al. Guidelines to PET measurements of the target 
occupancy in the brain for drug development. Eur J Nucl Med Mol Imaging. 2016;43:2255-
2262.
19 Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions 
of the McDonald criteria. Lancet Neurol. 2018;17:162-173. 
20 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41.
 
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
Anti-HBc
hepatitis B core antibody
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminase
AUC
area under the concentration-time curve
AUC(0-24h)
area under the plasma concentration-time curve from time zero to 
24 hours postdose
AxMP
auxiliary medicinal product
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BTK
Bruton’s tyrosine kinase
BTKi
Bruton’s tyrosine kinase inhibitor
CCr
creatinine clearance
CD
cluster of differentiation
CFR
Code of Federal Regulations 
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed concentration
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
Case Report Form, paper or electronic
CRU
clinical research unit
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
computed tomography
CTAg
Clinical Trial Agreement 
DCBB
daily covalent binding burden
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Term
Definition
DILI
drug-induced liver injury
DSM 5
Diagnostic and Statistical Manual of Mental Disorders (5th Edition)
EAE
experimental autoimmune encephalomyelitis
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EDSS
Expanded Disability Status Scale
eGFR
estimated glomerular filtration rate
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
g
gram
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
GSH
glutathione
HBsAg
hepatitis B surface antigen
HCG
human chorionic gonadotropin
HCV Ab
hepatitis C virus antibody
HEENT
head, eyes, ears, nose, and throat
hERG
human ether a go go-related gene 
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
heart rate
hrs
hours
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council on Harmonisation 
ICMJE
International Committee of Medical Journal Editors
ICRP
International Commission on Radiological Protection
IEC
Independent Ethics Committee
IgG
immunoglobulin G
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Term
Definition
IKr
rapid delayed rectifier potassium channel current 
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
INR
international normalized ration
IP
Investigational Product
IRB
Institutional Review Board
IT
information technology
IUS
intrauterine hormone-releasing system
IV
intravenous
kg
kilogram
KLH
keyhole limpet hemocyanin
L
liter
LAM
lactational amenorrhea method
MAD
multiple ascending dose
MBq
megabecquerel
mg
milligram
min
minute
mL
milliliter
MoA
mechanism of action
MRI
magnet resonance imaging
MS
multiple sclerosis
mSv
millisievert
g
microgram
ng
nanogram
Non-IMP
Non-investigational Medicinal Product
NOAEL
no-observed-adverse-effect level
NTCP
sodium taurocholate cotransporting polypeptide
OATPs
organic anion transporting polypeptides
PCR
polymerase chain reaction
PD
pharmacodynamic
PE
physical examination
PET
positron emission tomography
PET-CT
positron emission tomography - computed tomography
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Term
Definition
PET-MRI
positron emission tomography - magnetic resonance imaging
PK
pharmacokinetic
PO
oral
QD
quaque die, once daily
RANK
receptor activator of nuclear factor kappa-Β
RSC
Radiation Safety Committees
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCr
serum creatinine
SUSAR
suspected, unexpected serious adverse reaction
SUV
standardized uptake value
T
time
TB
tuberculosis
TMF
trial master file
UK
United Kingdom
ULN
upper limit of normal
VS
vital signs
VT
volume of distribution 
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The terms “participant” and “subject” refer to a person who has consented to participate in the 
clinical research study. Typically, the term “participant” is used in the protocol and the term
“subject” is used in the Case Report Form (CRF).
REGULATORY AND ETHICAL CONSIDERATIONS
This study will be conducted in accordance with:

Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP)
Guidelines

Applicable laws, regulations, and requirements
The study will be conducted in compliance with the protocol. The protocol,
any 
revisions/amendments,
and the participant informed consent form (ICF) will receive 
approval/favorable 
opinion 
by 
Institutional 
Review 
Board/Independent 
Ethics 
Committee (IRB/IEC), and regulatory authorities according to applicable regulations prior to 
initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation) that is likely to affect, 
to a significant degree, one or more of the following: (1) the rights, physical safety or mental 
integrity of one or more participants; (2) the scientific value of the clinical trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP regulation(s) or 
trial protocol(s).
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). 
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, Investigator’s Brochure, product labeling information, ICF, 
participant recruitment materials (eg, advertisements), and any other written information to be 
provided to participants.
The investigator, Sponsor, or designee should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, administrative letters) annually, or more 
frequently, in accordance with regulatory requirements or institution procedures.
The investigator is responsible for providing oversight of the conduct of the study at the site and 
adherence to requirements of the following where applicable:
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
ICH guidelines, 

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)

European Union Directive 2001/20/EC; or

European Regulation 536/2014 for clinical studies (if applicable), 

European Medical Device Regulation 2017/745 for clinical device research (if applicable),

the IRB/IEC

and all other applicable local regulations.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and, if 
applicable, also by the local Health Authority), except where necessary to eliminate an immediate 
hazard(s) to study participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s), the deviation or change will be submitted as soon 
as possible to:

IRB/IEC

Regulatory authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and, if applicable, also by the local Health Authority, must be sent to Bristol-Myers 
Squibb (BMS).
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the ICF 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 participants 
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 participants prior to enrollment.
FINANCIAL DISCLOSURE
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information, in accordance with regulations, to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. Investigators 
are responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
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The Sponsor or designee will provide the investigator with an appropriate sample ICF, which will 
include all elements required by the ICH GCP, and applicable regulatory requirements. The sample 
ICF will adhere to the ethical principles that have their origin in the Declaration of Helsinki.
The investigator or his/her representative must:

Obtain IRB/IEC written approval/favorable opinion of the written ICF and any other 
information to be provided to the participant prior to the beginning of the study and after any 
revisions are completed for new information.

Provide a copy of the ICF and written information about the study in the language in which 
the participant is proficient prior to clinical study participation. The language must be 
nontechnical and easily understood. 

Explain the nature of the study to the participant or participant’s legally acceptable 
representative and answer all questions regarding the study.

Inform participant that his/her participation is voluntary. Participant or participant’s legally 
acceptable representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.

Allow time necessary for participant or participant’s legally acceptable representative to 
inquire about the details of the study.
Obtain an ICF signed and personally dated by participant or participant’s legally acceptable 
representative and by the person who conducted the informed consent discussion. 

Include a statement in participant’s medical record that written informed consent was obtained 
before participant was enrolled in the study and the date the written consent was obtained. The
authorized person obtaining the informed consent must also sign the ICF.

Re-consent participant to the most current version of the ICF(s) during his/her participation in 
the study, as applicable.
Revise the ICF whenever important new information becomes available that is relevant to the 
participant’s consent. The investigator, or a person designated by the investigator, should fully 
inform the participant or participant’s legally acceptable representative of all pertinent aspects of 
the study and of any new information relevant to the participant’s willingness to continue 
participation in the study. This communication should be documented. 
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participant’s signed 
ICF, and, in the US, the participant’s signed HIPAA Authorization.
The ICF must also include a statement that BMS and local and foreign regulatory authorities have 
direct access to participant records.
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The rights, safety, and well-being of the study participants are the most important considerations 
and should prevail over interests of science and society.
BMS COMMITMENT TO DIVERSITY IN CLINICAL TRIALS
The mission of BMS is to transform patients’ lives through science by discovering, developing, 
and delivering innovative medicines that help them prevail over serious diseases. 
BMS is committed to doing its part to ensure that patients have a fair and just opportunity to 
achieve optimal health outcomes.
BMS is working to improve the recruitment of a diverse participant population with the goal that 
the clinical trial becomes more reflective of the real-world population and the people impacted by 
the diseases studied.
DATA PROTECTION, DATA PRIVACY, AND DATA SECURITY
BMS collects and processes personal data of study participants, patients, health care providers, 
and researchers for biopharmaceutical research and development to advance innovative, high-
quality medicines that address the medical needs of patients. BMS ensures the privacy, protection, 
and confidentiality of such personal data to comply with applicable laws. To achieve these goals, 
BMS has internal policies that indicate measures and controls for processing personal data. BMS 
adheres to these standards to ensure that collection and processing of personal data are limited and 
proportionate to the purpose for which BMS collects such personal data. This purpose is clearly 
and unambiguously notified to the individual at the time of collection of personal data. In the true 
spirit of science, BMS is dedicated to sharing clinical trial information and data with participants, 
medical/research communities, the media, policy makers, and the general public. This is done in a 
manner that safeguards participant privacy and informed consent while respecting the integrity of 
national regulatory systems. Clinical trial data, health-related research, and pharmacovigilance 
activities on key-coded health data transferred by BMS across national borders is done in 
compliance with the relevant data protection laws in the country and GCP requirements.
BMS protects Personal Information with adequate and appropriate security controls as indicated 
under the data protection laws. To align with the recommended security standards, BMS has 
adopted internal security standards and policies to protect personal data at every stage of 
its processing.
To supplement these standards, BMS enters into Clinical Trial Agreements (CTAgs) with 
confidentiality obligations to ensure proper handling and protection of personal data by third 
parties accessing and handling personal data.
BMS takes unauthorized access and disclosure of Personal Information very seriously. BMS has 
adopted the security standards that include National Institute of Standards and Technology 
Cybersecurity Framework for studies in the US. BMS aligns with these standards to continuously 
assess and improve its ability to protect, detect, and respond to cyber attacks and other 
unauthorized attempts to access personal data. These standards also aid in mitigating possible 
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adverse effects. Furthermore, BMS Information Technology has defined 6 principles to protect our 
digital resources and information: 
1)
Responsibilities of information technology (IT) Personnel
2) Securing the BMS Digital Infrastructure
3) Identity and Access Management
4) External Partner Connections
5) Cyber Threat Detection and Response
6) Internal Cyber Incident Investigation
SOURCE DOCUMENTS
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be explained. 

The investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available.

Definitions of what constitutes source data can be found in hospital records, clinic and office 
charts, laboratory notes, memoranda, evaluation checklists and dispensing records.
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are handwritten 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 records/electronic health 
records, adverse event (AE) tracking/reporting, protocol-required assessments, and/or drug 
accountability records.
When paper records from such systems are used in place of an 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. 
STUDY INTERVENTION RECORDS
Records for study intervention (whether supplied by BMS, its vendors, or the site) must 
substantiate study intervention integrity and traceability from receipt, preparation, administration, 
and through destruction or return. Records must be made available for review at the request of 
BMS/designee or a Health Authority.
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If
Then
Supplied by BMS (or its vendors):
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 
participant, including unique participant 
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/biocomparability, 
if applicable 

dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the Delegation 
of Authority Form
Sourced by site and not supplied by BMS 
or its vendors (examples include IP 
sourced 
from 
the 
sites 
stock or 
commercial supply or a specialty 
pharmacy)
The investigator or designee accepts responsibility 
for documenting traceability and study treatment 
integrity in accordance with requirements applicable 
under 
law 
and 
the 
standard 
operating 
procedures/standards of the sourcing pharmacy
BMS or its designee will provide forms to facilitate inventory control if the investigational site 
does not have an established system that meets these requirements.
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 Sponsor or designee electronic data capture (EDC) tool, eCRFs will be prepared 
for all data collection fields except for fields specific to SAEs and pregnancy, which will be 
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reported on the electronic SAE form and Pregnancy Surveillance Form, respectively. If the 
electronic SAE form is not available, a paper SAE form can be used. 
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
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 and SAE/pregnancy CRFs must be promptly reviewed, signed, and dated by 
the investigator or qualified physician who is a sub-investigator and who is delegated this task on 
the Delegation of Authority Form. Sub-investigators in Japan may not be delegated the CRF 
approval task. The investigator must retain a copy of the CRFs, including records of the changes 
and corrections.
Each individual electronically signing eCRFs must meet Sponsor or designee training 
requirements and must only access the BMS EDC tool using the unique user account provided by 
the Sponsor or designee. User accounts are not to be shared or reassigned to other individuals.
MONITORING
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
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 that the 
facilities remain acceptable.
In addition, the study may be evaluated by the Sponsor or designee 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 the Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) 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 or its designee, whichever is longer. 
The investigator (or head of the study site in Japan) must contact BMS prior to destroying any 
records associated with the study.
BMS or its designee will notify the investigator (or head of the study site in Japan) 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, study site, IRB). Notice 
of such transfer will be given in writing to BMS or its designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS or a vendor or sourced by the 
investigator), such as partially used study treatment containers, vials, and syringes, may be 
destroyed on site.
If
Then
Study treatments supplied by BMS (including 
its vendors)
Any unused study interventions supplied by 
BMS can only be destroyed after being 
inspected and reconciled by the responsible 
Study Monitor,
unless study treatments 
containers must be immediately destroyed as 
required for safety, or to meet local regulations 
(eg, cytotoxics or biologics).
Partially used study interventions and/or 
empty containers may be destroyed after 
proper reconciliation and documentation. But 
unused IMP must be reconciled by site 
monitor/Clinical Research Associate prior to 
destruction.
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors; eg, study treatments 
sourced from the site’s stock or commercial 
supply or a specialty pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal of study interventions, 
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. The following minimal standards must be 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 standard operating procedures and a copy provided to BMS upon request.
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
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 (eg, 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 Study 
Monitor to review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met, the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non-study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
STUDY AND SITE START AND CLOSURE
The Sponsor/designee reserves the right to close the study site or to terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
DISSEMINATION OF CLINICAL STUDY DATA
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national, or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
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CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the Clinical Study Report (CSR). 
For each CSR related to this protocol, the following criteria will be used to select the Signatory 
Investigator:

Involvement in trial design
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to the Sponsor or designee. 
Any publications or abstracts arising from this study must adhere to the publication requirements 
set forth in the Clinical Trial Agreement (CTAg) governing [study site or investigator] 
participation in the study. These requirements include, but are not limited to, submitting proposed 
publications to the Sponsor or designee at the earliest practicable time prior to submission or 
presentation and otherwise within the time period set forth in the CTAg.
Scientific publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
Principal Investigator, sub-investigator, or any other member of the study staff without the prior 
written consent of the Sponsor.
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable participants with quality data), analysis, or interpretation of data for the 
work (eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work.
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a clinical investigation participant administered study 
treatment 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 treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, electrocardiograms, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.

Exacerbation of a chronic or intermittent pre-existing condition, including either an increase 
in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration, even though 
it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/serious adverse event (SAE) unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae and should specify “intentional overdose” as the verbatim 
term.
Events NOT Meeting the AE Definition

Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE, even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death.
Is life-threatening (defined as an event in which the participant 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).
NOTE: 
The following hospitalizations are not considered SAEs in Bristol-Myers Squibb (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.

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).

Admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols).
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 participant 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 and 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 9.2.7 for the definition of potential DILI.) 
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Pregnancy and DILI must follow the same transmission timing and processes to BMS as used for 
SAEs. (See Section 9.2.5 for reporting pregnancies.)
EVALUATING AES AND SAES
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration,
will be considered and investigated.

The investigator will also consult the Investigator’s Brochure and/or product information for 
marketed products in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
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Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category utilized for rating the intensity of 
an event, and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.
Follow-up of AEs and SAEs
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.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
REPORTING OF SAES TO SPONSOR OR DESIGNEE

SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form.

The required method for SAE data reporting is through the electronic case report 
form (eCRF).

The paper SAE Report Form is intended only as a back-up option when the electronic 
data capture system is unavailable/not functioning for transmission of the eCRF to BMS 
(or designee).
In this case, the paper form is transmitted via email or confirmed facsimile 
transmission.
When paper forms are used, the original paper forms are to remain on site.

Pregnancies must be recorded on paper Pregnancy Surveillance Forms and transmitted via 
email or confirmed facsimile transmission.
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SAE Email Address: 
SAE Facsimile Number: Will be provided by local site monitor.
SAE Telephone Contact (required for SAE and pregnancy reporting): Will be provided by local 
site monitor.
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Appendix 4 provides general information and definitions related to Woman of Childbearing 
Potential and methods of contraception that can be applied to most clinical trials. For information 
specific to this study regarding acceptable contraception requirements for female and male 
participants, refer to Section 6.1 of the protocol. Only the contraception methods as described in 
Section 6.1 are acceptable for this study.
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state 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 
> 40 mIU/mL to confirm menopause.
Note: 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. Suggested 
guidelines for the duration of the washout periods for HRT types are presented below. 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
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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.
End of Relevant Systemic Exposure
End of relevant systemic exposure is the timepoint where the Investigational Medicinal Product 
(IMP) or any active major metabolites have decreased to a concentration that is no longer 
considered to be relevant for human teratogenicity or fetotoxicity. This should be evaluated in 
context of safety margins from the no-observed-adverse-effect level or the time required for 5 half-
lives of the IMP to pass.
METHODS OF CONTRACEPTION
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of < 1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation. (This method of contraception can only be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol.)b

Oral (birth control pills)

Intravaginal (rings)

Transdermal

Combined (estrogen-and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy.

Progestogen-only hormonal contraception associated with inhibition of ovulation. (This
method of contraception can only be used by WOCBP participants in studies where 
hormonal contraception is permitted by the study protocol.)b

Oral

Injectable

Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy.
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation. (This method of contraception can only be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol.)b

Intrauterine device.

Intrauterine hormone-releasing system (IUS). (This method of contraception can only be 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol.)b,c
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
Bilateral tubal occlusion.

Vasectomized partner
Male participants will be required to always use a latex or other synthetic condom during any 
sexual activity (eg, vaginal, anal, oral) with WOCBP, even if the participants have undergone a 
successful vasectomy or if their partner is already pregnant or breastfeeding.

Sexual abstinence.
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

Continuous abstinence must begin at least 30 days prior to initiation of study therapy.

It is not necessary to use any other method of contraception when complete abstinence is 
elected.

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2.

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participant chooses to forego complete abstinence.

Periodic abstinence (including, but not limited to, calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM) are not acceptable methods of contraception for this study.
NOTES: 
a Typical use failure rates may differ from failure rates when contraceptive methods are used consistently and 
correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative 
methods of contraception should be utilized. For information specific to this study regarding permissibility of 
hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 7.7.1 PROHIBITED AND/OR 
RESTRICTED TREATMENTS of the protocol.
c IUSs are acceptable methods of contraception in the absence of definitive drug interaction studies when hormone 
exposures from intrauterine devices do not alter contraception effectiveness. For information specific to this 
study regarding permissibility of hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 
7.7.1 PROHIBITED AND/OR RESTRICTED TREATMENTS of the protocol.
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Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of > 1% per year when used consistently and correctly.

Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously.

Diaphragm with spermicide.

Cervical cap with spermicide.

Vaginal sponge with spermicide.

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action. (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited.)
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, postovulation methods).

Withdrawal (coitus interruptus).

Spermicide only.

LAM.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of pregnancy information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and Appendix 3.
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APPENDIX 5
COCKCROFT GAULT FORMULA
Males: CCr = (140 - age) x body weight/(72 x SCr)
Females: CCr = (140 - age) x body weight x 0.85/(72 x SCr)
CCr = creatinine clearance [milliliter per minute]
SCr = serum creatinine [in milligram per deciliter]
Body weight in kilograms
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41.
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APPENDIX 6
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 04, 09-May-2022
The primary purpose for this amendment is to: 

Accurately account for the radiation exposure resulting from a cranial computed tomography 
(CT) scan. 

To facilitate operational conduct of the study by: 
o
Allowing for a shorter interval between positron emission tomography (PET) scans.
o
Allowing a third PET scan in Part B in case 1 PET scan procedure is not successful. 
o
Allowing up to 6 cranial CT scans in Part B (1 before and 1 after each PET scan) to account 
for potential movement during the PET procedure.
o
Specifying that fasting requirements are only for Part A participants.
o
Allowing vital sign assessment in sitting position.
Minor changes, corrections, and edits to improve accuracy, clarity, and formatting of the protocol 
have also been included. 
Additional revisions, including to sections of the Protocol Summary, have been made to align the 
protocol with respect to these changes.
This protocol amendment applies to future participants.
Summary of key changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
Table 2-1: Screening 
Procedural Outline for Parts 
A and B (IM038010); 
Table 2-3: Imaging 
Procedural Outline for Part 
B (IM038010); 
Table 3.3.1-1: Risk 
Assessment; 
Section 6.3.1: Meals and 
Dietary Restrictions; 
Section 9.4.6: Clinical 
Safety Laboratory 
Assessments
Specified that fasting is only required for 
Part A participants.
To reduce study burden for 
participants with multiple sclerosis 
(MS) in the study.
Table 2-2: Imaging 
Procedural Outline for Part 
A (IM038010); Table 2-3: 
Imaging Procedural Outline 
for Part B (IM038010);
Section 5.1: Overall Design; 
Figure 5.1-1: Study Design 
Schema;
Table 7.1-1: Study 
Interventions;
Reduced minimum interval between 2 PET 
scans from 3.5 hours to 2 hours.
Facilitate operational conduct and 
allow for shorter visit duration if 
2 PET scans are done on the same 
day.
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Summary of key changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale
Section 9.1.1.1: PET 
Assessments
Table 2-3: Imaging 
Procedural Outline for Part 
B (IM038010) 
Added footnote “e” to 11C-BMS-986196 
tracer administration on Visit 2.
To clarify that third administration
is permissible if a PET scan has to 
be repeated.
Section 3.3 Benefit/Risk 
Assessment;
Section 5.5 Justification for 
Dose; 
Table 5.5-1: Radiation 
Exposure from PET Tracer 
Administration and CT 
Scans;
Section 9.1.1.1: PET 
Assessments

Added text to allow for 2 cranial CT 
scans (1 before and 1 after each cranial 
PET scan) in Parts A and B, and 
specified the maximum number of 
cranial CT scans in Parts A and B. 

Added text to allow for a third PET 
scan and up to 6 cranial CT scans in 
Part B.
Facilitate operational conduct by 
providing the option for an 
additional PET scan in case 1 PET 
scan procedure is not successful, 
and by providing the option for up 
to 6 CT scans (1 before and 1 after 
each PET scan) to account for 
movement of participants with MS 
during the PET procedure.
Section 3.3 Benefit/Risk 
Assessment;
Table 3.3.1-1: Risk 
Assessment;
Section 5.5 Justification for 
Dose; 
Table 5.5-1: Radiation 
Exposure from PET Tracer 
Administration and CT 
Scans

Estimation of radiation exposure from 
cranial CT scan was reduced from 
1.5 mSv to approximately 0.3 mSv. 

In Parts A and B, cumulative exposure 
from PET and CT scans was updated 
to account for added options of a third 
PET scan (Part B only) and additional 
cranial CT scans before and after each 
cranial PET scan.

Equivalent duration of average United 
Kingdom (UK) background radiation 
was changed to account for maximum 
new cumulative exposure total. 

Increased maximum 
 
 from 5.4% to 
8.1%. 

The cranial CT scan sequences 
used at participating sites result 
in radiation exposure of 
approximately 0.3 mSv, not 
1.5 mSv, resulting in lower 
radiation exposure than 
originally estimated and 
facilitating up to 3 PET scans 
and 6 cranial CT scans without 
increasing maximum radiation 
exposure relative to the prior 
versions of the protocol.

The option of a third PET scan 
adds to the maximum radiation 
exposure derived from PET 
tracer.

The cumulative exposure 
values in Parts A and B change 
due to lower exposure derived 
from cranial CT scan and 
option of a third PET scan.

To account for increased 
 
 following a third 
PET scan.  
Section 5.1 Overall Design, 
Figure 5.1-1: Study Design 
Schema

Corrected spelling to specify that 
2 PET-CT or PET-MRI scans must be 
evaluable in up to 8 study participants 
(not that study participants must be 
evaluable).  

To improve accuracy of 
protocol language. 
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Summary of key changes for Protocol Amendment 04
Section Number & Title
Description of Change
Brief Rationale

Added footnote “a” to Figure 5.1-1.

Added text on maximum blood 
volume for participants undergoing 
arterial sampling only, arterial and 
venous sampling, and undergoing 
3 PET scans.

To ensure that Figure 5.1-1 is 
consistent with the study 
design language and that up to 
2 participants may be enrolled 
in Part A, after Part B has been 
initiated. 

To provide more detailed 
information of the different 
scenarios and account for the 
addition of a third PET scan.
Section 9.1.1.1: PET 
Assessments

Updated the maximum number of 
whole-body CT scans to 1. 

Removed duplicate assessment of 
hematology and clinical chemistry for 
participants in Part B if 2 PET scan 
visits are performed on the same day.

To clarify the limits for number 
of whole-body CT scans in Part 
A.

To align with footnote in 
Table 2-3.
Section 9.4.3: Vital Signs
Added sitting position as a new option for 
assessing Visits 1 and 2 vital signs prior to 
discharge.
To facilitate site operations.
Section 10.4.2: Primary 
Endpoint(s)
Changed the window acquisition time 
frame from Part A Visit 1 to Part A Visit 2.
Correction. 
Appendix 2: Study 
Governance Considerations
Added 2 new sections: BMS Commitment 
to Diversity in Clinical Trials and Data 
Protection, Data Privacy, and Data 
Security.
Added to align with BMS 
commitment to diversity in clinical 
trials and to comply with European 
Union Clinical Trials Regulation 
(EU-CTR) requirement.
Throughout the protocol
Minor language and formatting changes.
To improve clarity of the protocol. 
Overall Rationale for Protocol Amendment 03, 21-Feb-2022
The primary purpose for this amendment is to allow venous blood sampling during cranial positron 
emission tomography (PET). This would be necessary if emerging data from this ongoing study 
indicate that a (pseudo) reference region cannot be reliably established, therefore making future 
studies with 11C-BMS-986196 without arterial input function challenging. This change is being 
implemented to facilitate future studies with 11C-BMS-986196 without arterial line.
Additional revisions, including to sections of the Protocol Summary, have been made to align the 
protocol with respect to these changes.
This protocol amendment applies to future participants.
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Summary of Key Changes for Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-2: Imaging 
Procedural Outline for Part 
A (IM038010)

Added pregnancy test for Visit 2

Added venous line placement 
procedure for venous blood sampling

Added footnote “a” regarding visits for 
Part A participants prior to and after 
initiation of Part B

Pregnancy test was added to 
Visit 2 to improve consistency 
with eligibility criteria 

Enable venous blood sampling 
in up to 2 participants of Part A

Clarified visit sequence of 
newly added participants
Table 2-3: Imaging 
Procedural Outline for Part 
B (IM038010)
Added venous line placement procedure for 
venous blood sampling
Enable venous blood in up to 
6 participants of Part B
Section 5: Study Design

Increased total evaluable participants 
to up to 16

Deleted the following text: “Part A 
must be completed before initiation of 
Part B”

Increased total Part A participants to 
up to 8

Added text to Part A treatment period 
on when 2 additional participants can 
be enrolled due to emerging data from 
Part B

Updated amount of blood to be drawn 
from Part A and Part B 

Updated the maximum amount of 
blood to be drawn in 24 hours to 
420 mL

Protocol amendment increases 
maximum total number of 
participants and maximal 
number of Part A participants 
by 2

Clarified that addition of 
2 additional Part A participants 
is based on emerging data from 
Part B

Updated maximal blood 
volume collected, accounting 
for additional venous blood 
samples
Table 7.1-1: Study 
Interventions
Added “up to” 2 doses
Address number of doses 
administered in Part A participants 
that have been added as part of the 
amendment 
Section 7.2: Method of 
Study Intervention 
Assignment
Updated the total number of enrolled 
participants to exceed 16 if participants 
have to be replaced
Protocol amendment increases 
maximum total number of 
participants and maximal number of 
Part A participants by 2 
Section 9.1: Efficacy 
Assessments

Added text about venous lines for PET 
assessments

Clarified that 2 additional participants 
enrolled to Part A will undergo the 
cranial PET scan with arterial and 
venous blood samples drawn during 
the procedure

Added text on when up to 
6 participants in Part B may undergo 
venous and arterial blood sampling 
Clarify procedure for collecting 
venous blood samples in Parts A 
and B 
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Summary of Key Changes for Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
Section 10.2: Sample Size 
Determination

Increased total Part A participants to 
up to 8

Increased evaluable participants to up 
to 16

Updated the total number of enrolled 
participants to exceed 16 if participants 
have to be replaced
Protocol amendment increases 
maximum total number of 
participants and maximal number of 
Part A participants by 2
Overall Rationale for Protocol Amendment 02, 02-Nov-2021
This protocol amendment is being produced 
 for the 
following reasons:
5) Revisions to AE-based stopping rules

Updated the procedures for study restart after stopping rules have been met.
Revisions apply to future participants enrolled in the study, and where applicable, to all 
participants currently enrolled.
Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Section 8.4 AE-defined 
Stopping Rules
Updated the procedure for 
study restart after stopping 
rules are met.
Revision was made 
 
Overall Rationale for Revised Protocol 01, 22-Oct-2021
This protocol amendment is being produced 
 for the 
following reasons:
6) Revisions to Exclusion Criteria

Removal of required consultation with the BMS clinical trial physician regarding the eligibility 
of a participant with any sequelae from a prior SARS-CoV-2 infection.

Removal of participants with malaria falciparum infection.

Removal of any exception granted by the Sponsor medical monitor regarding the use of any 
prescription drugs within 4 weeks or 5 times the elimination half-life (if known), whichever is 
longer before tracer administration. 

Removal of any exception granted by the Sponsor medical monitor regarding the use of any 
investigational drugs or placebo within 4 weeks or 5 times the elimination half-life (if known), 
whichever is longer before tracer administration. 
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
Removal of any exception granted by the Sponsor medical monitor with regards to the 
participant’s participation in another clinical trial concurrent with this study. Addition of the 
investigator assessment on whether or not to enroll the participant meeting this criterion.
7) Revisions to (S)AE-based stopping rules

Specifying stricter criteria for triggering (S)AE-based stopping rules and specifying the 
procedures for study restart after stopping have been met.
Revisions apply to future participants enrolled in the study, and where applicable, to all 
participants currently enrolled.
Summary of Key Changes for Protocol Amendment 01
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Updated Key Exclusion 
Criteria 
Updated to include changes 
to exclusion criteria 1l and 1p 
in Section 6.2.
Section 3.3 Benefit/Risk 
Assessment, Risks Associated 
with Use of an Arterial 
Catheter
Section 9.1.1.1 PET 
Assessments
Changed “experienced 
physician” to “experienced 
staff”
Incorporated Administrative 
Letter 01 that clarified that 
arterial line placement will be 
performed by experienced 
staff. This clarification 
ensures that arterial line 
placement is performed 
according to the standard 
practice at the participating 
sites.
Summary and Section 6.2: 
Exclusion Criterion: 1l
Exclusion criterion 1l was 
modified to remove the 
consultation with the BMS 
clinical trial physician and 
add examples of sequelae.
Exclusion criterion criteria 
was updated
 
 
Summary and Section 6.2: 
Exclusion Criterion: 1p
Exclusion criterion 1p was 
modified to remove the 
exclusion of falciparum.
Exclusion criterion was 
updated 
 
Section 6.2: Exclusion 
Criterion: 3b
Section 7.7.1: Prohibited 
and/or Restricted Treatments
Exclusion criterion 3b and 
Section 7.7.1 were modified 
to remove the exception of 
any drugs cleared by the 
Sponsor medical monitor.
Exclusion criterion was 
updated 
 
. Section 7.7.1 was 
updated to be consistent with 
exclusion criterion.
Section 6.2: Exclusion 
Criterion: 3c
Exclusion criterion 3c was 
modified to remove the 
exception of any drugs 
Exclusion criterion was 
updated 
 
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Summary of Key Changes for Protocol Amendment 01
Section Number & Title
Description of Change
Brief Rationale
cleared by the Sponsor 
medical monitor.
Section 6.2: Exclusion 
Criterion: 6c
Section 7.7.2: Other 
Restrictions and Precautions
Exclusion criterion 6c and 
Section 7.7.2 were revised to 
remove the exception of any 
drugs cleared by the Sponsor 
medical monitor and add the 
investigator assessment for 
safety. Examples for non-
interventional and lifestyle 
and dietary intervention 
studies were also added to the 
exclusion criterion. 
Exclusion criterion was 
updated 
 
 Section 7.7.2 was 
updated to be consistent with 
exclusion criterion.
Section 8.4 AE-defined 
Stopping Rules
Revised (S)AE-based 
stopping rules (section title 
was also updated) and 
specified the procedure for 
study restart after stopping 
rules are met. A minor update 
was made to Section 8.1 to 
reflect the changes to Section 
8.4.
Revision was made 
 
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SAP_001.pdf: 
Official Title of Study: 
A Phase 1, Open-label, Multi-part Study to Evaluate the Safety, Tolerability, Kinetics, Biodistribution, 
and CNS Signal of the Positron Emission Tomography Ligand 11C-BMS-986196 in Healthy 
Participants After Intravenous Administration and to Evaluate the Safety, Tolerability, Kinetics, and CNS 
Signal Repeatability of 11C-BMS-986196 After Repeat Intravenous Administration in Participants With 
Multiple Sclerosis 
NCT Number: NCT05064436 
Document Date (Date in which document was last revised): 12 April 2024 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE 1, OPEN-LABEL, MULTI-PART STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, KINETICS, AND BIODISTRIBUTION, AND CNS SIGNAL OF THE 
PET LIGAND 11C-BMS-986196 IN HEALTHY PARTICIPANTS AFTER 
INTRAVENOUS ADMINISTRATION AND TO EVALUATE THE SAFETY, 
TOLERABILITY, KINETICS, AND CNS SIGNAL REPEATABILITY AFTER REPEAT 
IV ADMINISTRATION IN PARTICIPANTS WITH MULTIPLE SCLEROSIS
PROTOCOL(S) IM038010
VERSION # FINAL 1.0
DATE: 12-APR-2024
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................4
LIST OF FIGURES ....................................................................................................................5
1
BACKGROUND AND RATIONALE......................................................................6
2
STUDY DESCRIPTION ..........................................................................................7
2.1
Study Design ............................................................................................................7
2.2
Treatment Assignment............................................................................................10
2.3
Blinding and Unblinding.........................................................................................10
2.4
Protocol Amendments.............................................................................................10
3
OBJECTIVES ........................................................................................................10
3.1
Primary...................................................................................................................10
3.2
Secondary...............................................................................................................11
11
4
ENDPOINTS..........................................................................................................11
5
SAMPLE SIZE AND POWER...............................................................................12
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................13
6.1
Study Periods..........................................................................................................13
6.2
Treatment Regimens...............................................................................................13
6.3
Populations for Analyses ........................................................................................13
7
STATISTICAL ANALYSES..................................................................................14
7.1
General Methods ....................................................................................................14
7.2
Study Conduct........................................................................................................14
7.3
Study Population ....................................................................................................14
7.3.1
Participant Disposition...........................................................................................14
7.3.2
Demographic Characteristics .................................................................................14
7.3.3
Medical History and Specific Disease History ........................................................14
7.3.4
Prior and Concomitant Medications and Procedures..............................................14
7.4
Extent of Exposure .................................................................................................14
7.5
Imaging ..................................................................................................................15
7.5.1
Primary Imaging Endpoints....................................................................................16
7.5.2
Secondary Imaging Endpoint..................................................................................17
17
7.6
Safety.....................................................................................................................17
7.6.1
Deaths ....................................................................................................................17
7.6.2
Adverse Events .......................................................................................................17
7.6.3
Serious Adverse Events...........................................................................................18
7.6.4
Clinical Laboratory Evaluations.............................................................................18
7.6.5
ECG .......................................................................................................................18
7.6.6
Vital Signs and Physical Measurements..................................................................18
7.6.7
Physical Examination Findings...............................................................................18
7.6.8
Allen’s Test.............................................................................................................18
18
8
CONVENTIONS....................................................................................................19
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8.1
Decimal Places .......................................................................................................19
8.2
Imputation of Missing Dates for Adverse Events ....................................................19
8.2.1
Incomplete Start Date.............................................................................................19
8.2.2
Incomplete Stop Date..............................................................................................19
9
CONTENT OF REPORTS .....................................................................................20
10
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................20
11
DOCUMENT HISTORY........................................................................................20
APPENDIX 1
ABBREVIATIONS................................................................................21
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LIST OF TABLES
Table 4-1:
Objectives and Endpoints .......................................................................11
Table 6.3-1:
Analysis Populations ..............................................................................13
Table 7.5-1:
Description of Imaging Endpoints ..........................................................16
Table 11-1:
Document History ..................................................................................20
Table 11-2:
List of Abbreviations..............................................................................21
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LIST OF FIGURES
Figure 2.1-1:
Study Design Schema...............................................................................9
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1
BACKGROUND AND RATIONALE
The purpose of this Statistical Analysis Plan (SAP) is to outline the planned final analysis to be 
completed to support generation of the Clinical Study Report (CSR) for study IM038010 titled “A 
Phase 1, Open-label, Multi-part
Study to Evaluate the Safety, Tolerability, Kinetics,
Biodistribution and CNS Signal of the Positron Emission Tomography Ligand 11C-BMS-986196 
in Healthy Participants after Intravenous Administration and to Evaluate the Safety, Tolerability, 
Kinetics, and CNS Signal Repeatability of 11C-BMS-986196 after Repeat Intravenous 
Administration in Participants with Multiple Sclerosis”.
 analyses not necessarily 
identified in this SAP may be performed to support the clinical development program. Any 
performed post-hoc or unplanned analyses not identified in this SAP will be clearly identified as 
such in the CSR. The SAP was prepared in compliance with ICH E9.
Research Hypothesis:
11C-BMS-986196 covalently binds and inhibits Bruton’s tyrosine kinase (BTK), a kinase 
expressed in B-cells, monocytes, macrophages, microglia, dendritic cells, natural killer cells, 
granulocytes, mast cells, basophils, eosinophils, osteoclasts, and platelets. BTK plays a role in 
intracellular signaling cascades downstream of the B-cell receptor, activating immunoglobulin G 
immune complex receptors (FCγRIIa and FCγRIIIa), the high affinity immunoglobulin E receptor 
(FcεRI), and the receptor activator of nuclear factor kappa-Β (RANK).
This is the first study testing 11C-BMS-986196 as a Positron Emission Tomography (PET) ligand 
in humans. This study is supported by preclinical Good Laboratory Practices (GLP) toxicity and 
safety studies, including in rats and cynomolgus monkeys, in the context of an Investigational New 
Drug (IND) submission. 
There is no formal primary research hypothesis for this study to be statistically tested. The purpose 
of this study is to assess 11C-BMS-986196, a novel PET tracer for BTK in healthy participants and 
in participants with multiple sclerosis (MS) to facilitate its use for:

Assessment of central nervous system (CNS)
 in future clinical 
studies in patients with MS

Dose selection of compounds that target the BTK receptor in the CNS, including dose selection 
for unlabeled BMS-986196

Assessing the presence of BTK-expressing cells in participants with inflammatory CNS 
diseases, including MS
Overall, the data from this study will contribute to general research and the development of a novel 
means to visualize CNS inflammation, and are expected to facilitate development of therapies for 
progressive MS.
Schedule of Analyses:
A final statistical analysis will be conducted after study closure and database lock. No interim 
analysis is planned for this study.
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2
STUDY DESCRIPTION
2.1
Study Design
This is a Phase 1, open-label study in healthy participants and participants with MS to evaluate a 
novel, positron-emitting ligand 11C-BMS-986196, for measurement of unbound BTK. The study 
will include up to 28 evaluable participants (Part A: up to 8 healthy participants; Part B: up to 
8 participants with MS; Part C: up to 12 healthy participants). The study consists of 3 periods: 
screening, treatment, and safety follow up. See Figure 2.1-1.
All participants will undergo PET scanning with 11C-BMS-986196. An initial dose of 11C-BMS-
986196 will be administered at doses up to 20 μg with the radioactivity of the dose at 
approximately 370 MBq (10 mCi). In Part B and Part C, the radioactive dose and participant 
preparation may be revised based on results of radiation dosimetry obtained in Part A, but
administered mass will not exceed 20 μg. 
Part A (Whole-Body Radiation Dosimetry and Cranial PET Imaging): Up to 6 evaluable 
healthy adult participants (at least 2 male and 2 female participants are planned) will complete 
whole-body positron emission tomography – computed tomography (PET-CT) imaging after a 
bolus intravenous (IV) administration of 11C-BMS-986196 under fasting conditions, to confirm 
tracer safety, assess image acquisition window, determine radiation dosimetry of the administered 
radiotracer, and assess optimal imaging time. The PET scan will last approximately 2 hours. At 
least 2 hours and at most 6 days after the first tracer administration, participants will receive a 
second tracer administration and undergo cranial PET imaging using either PET-CT or positron 
emission tomography – magnetic resonance imaging (PET-MRI), depending on the availability of 
equipment. If the interval between the first and second PET scan is 4 days or more, the study site 
staff must contact the participant remotely (eg, by phone) on Day 4 (ie, 3 days after the first PET 
scan) and record adverse events (AEs) and any concomitant medications. Following an observation 
period of approximately 1 hour after completion of all PET scanning procedures, participants will 
be discharged from the PET center and enter the safety follow-up period. Up to 6 healthy 
participants will complete Part A before initiation of Part B.
If emerging data from Part B indicate that venous blood sampling is likely to be required in future 
studies using 11C-BMS-986196 without arterial blood sampling (eg, because a [pseudo]-reference 
region cannot be reliably established), 2 additional participants can be enrolled in Part A at the 
discretion of the Sponsor. These additional 2 participants will only undergo cranial PET imaging 
using either PET-CT or PET-MRI, depending on the availability of equipment (ie, not whole-body 
PET-CT).
Part B (Characterization of 11C-BMS-986196 binding in the human brain): Up to 8 
participants with MS will complete 2 cranial PET-CT or PET-MRI scans (depending on equipment 
availability) after a bolus IV administration of 11C-BMS-986196, separated by at least 2 hours and 
at most 6 days to determine the optimal quantification parameters, including within-participant 
variability under test and retest conditions. Following an observation period of approximately 1 
hour after completion of PET scanning procedures, participants will be discharged from the PET 
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center and enter the safety follow-up period. If the interval between the first and second PET scan 
is 4 days or more, the study site staff must contact the participant remotely (eg, by phone) on Day 
4 (ie, 3 days after the first PET scan) and record AEs and any concomitant medications. 
Participants who had a MS relapse within 30 days prior to Day 1 must start Scan 2 on Day 1 or
Day 2. Up to 8 participants with MS will complete Part B. 
Part C (Quantification of free BTK availability in the humain brain): Up to 12 evaluable 
healthy adult participants will complete 2 evaluable cranial PET-CT or PET-MRI scans (dependent 
on equipment availability). The first cranial PET scan will occur on Day 1 after a bolus IV 
administration of 11C-BMS-986196. After completion of the first evaluable PET scan (on the same 
day or the day following the PET scan), participants will receive orally adimistered unlabeled 
BMS-986196 on-site or at home once daily (QD) for preferably 1 day: approximately 24 hours 
after the (last) dose of BMS-986196, participants will undergo the second cranial PET scan after 
a bolus IV administration of 11C-BMS-986196. If the second PET scan cannot be performed in 
this time frame, it is permissible to administer a single dose of unlabeled BMS-986196 up to 7 
days after the Day 1 PET (eg, in case of scheduling conflicts). In addition, in case of synthesis 
failure of PET tracer it is permissible to administered multiple doses of unlabeled BMS-986196 in 
order to have BMS-986196 administered 24 hours prior to the second PET scan, if Sponsor agrees. 
No more than 7 doses can be administered. Up to 3 dose levels of (unlabeled) BMS-986196 will 
be tested (15 mg, 30 mg, and 60 mg QD) and approximately 4 participants per dose level will be 
tested. Initially, participants will be assigned to the 30 mg dose level. After an interim review of 
PET results from 2 to 4 evaluable participants, the next dose level (15 mg or 60 mg) will be 
determined. At least 2 evaluable participants should have completed PET imaging at the second 
dose level before participants are assigned to the last dose level.
Safety Follow-up Period: For Part A and Part B, participants will be contacted remotely by phone 
(or web-call; email or text contact without verbal contact is not sufficient) 3 days (± 1 day) after 
completion of all PET scanning procedures and will be asked about AEs and concomitant 
medications. An in-person visit is optional. For Part C, participants will attend one in-person 
follow-up visit (Visit 3) 7 days after completion of all PET scanning procedures on Visit 2. During 
Visit 3, participants will undergo clinical assessments, have blood collected for laboratory tests, 
and will be asked about AEs and concomitant medications. For Visit 4, participants will be 
contacted remotely by phone (or web-call; email or text contact without verbal contact is not 
sufficient) 28 days (+ 3 days) after completion of Visit 2 and will be asked about AEs and 
concomitant medications. At the discretion of the investigator, Visit 4 can be conducted in-person. 
Upon completion of Visit 4, participants will have completed the study. 
The study design schematic is presented in Figure 2.1-1.
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Figure 2.1-1:
Study Design Schema
Part A - Safety, Tolerability, and Dosimetry in Healthy Participantsa
Part B - Repeatability of 11C-BMS-986196 PET in Participants with MS
Part C - Quantification of Free BTK Availability in Healthy Participants
Abbreviations: BTK, Bruton’s tyrosine kinase; IV, intravenous; hr, hour; MS, multiple sclerosis; PET, positron 
emission tomography; QD, once daily.
a Prior to initiation of Part B, all Part A participants will undergo Visits 1 and 2. After initiation of Part B, up to 
2 participants may be added to Part A and will not undergo Visit 1, only Visit 2. For these participants only, Visit 
2 will be regarded as Day 1.
b Visit 2 tracer administration must be done at least 2 hours and at most 6 days after Visit 1 tracer administration (ie, 
Day 2 to Day 7).
c Participants who had a MS relapse within 30 days prior to Day 1 must start Scan 2 on Day 1 or Day 2.
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d After completion of the first evaluable PET scan (on the same day or the day following the PET scan), participants 
will receive orally administered unlabeled BMS-986196 QD for preferably 1 day; and approximately 24 hours after 
the (last) dose of BMS-986196, participants will undergo the second cranial PET scan. If the second PET scan 
cannot be performed in this time frame, it is permissible to administer a single dose of unlabeled BMS-986196 up 
to 7 days after the Day 1 PET (eg, in case of scheduling conflicts) or to dose unlabeled BMS-986196 once per day 
for up to 7 days (eg, in case of synthesis failure of the PET tracer) if the Sponsor agrees.
Physical examinations, vital sign measurements, 12-lead ECGs, and clinical laboratory evaluations 
will be performed at selected times throughout the study. Participants will be closely monitored 
for AEs throughout the study. 
2.2
Treatment Assignment
This is a non-randomized, open-label study. Treatment will be assigned to participants in the order 
of enrolment.
2.3
Blinding and Unblinding
This is a non-randomized, open-label study. Blinding procedures are not applicable.
2.4
Protocol Amendments
Protocol Amendment 1, dated 22-Oct-2021, 
 included revisions to the exclusion criteria and to the (S)AE-based stopping rules. These 
revisions did not affect the statistical analysis outlined in the protocol.
Protocol Amendment 2, dated 02-Nov-2021, 
 
 included revisions to the (S)AE-based stopping rules. These revisions did not affect 
the statistical analysis outlined in the protocol.
Protocol Amendment 3, dated 21-Feb-2022, included revisions to allow venous blood sampling 
during cranial PET. These revisions did not affect the statistical analysis outlined in the protocol.
Protocol Amendment 4, dated 09-May-2022, included revisions to accurately account for the 
radiation exposure resulting from cranial CT scan, to allow a shorter interval between PET scans, 
to allow a third PET scan in Part B in case of unsuccessful scans, to allow up to 6 cranial CT scans 
in Part B (1 before and 1 after each PET scan), to specify that fasting requirements are only 
applicable to Part A participants, and to allow vital signs assessment in sitting position. These 
revisions did not affect the statistical analysis outlined in the protocol.
Protocol Amendment 5, dated 30-Jun-2023, included revisions to add a novel Part C to the 
protocol, to quantify free BTK in the brain before and approximately 24 hours after oral 
administration of unlabeled BMS-986196 at doses of 15 mg, 30 mg, and 60 mg.
3
OBJECTIVES
3.1
Primary
The primary objectives of this study are: 

To assess safety, tolerability, kinetics, and CNS signal repeatability of the novel tracer 
11C-BMS-986196 in healthy participants and in participants with MS.
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
To assess the safety of BMS-986196.

To quantify the proportion of free BTK in the brain after administration of unlabeled BMS-
986196.
3.2
Secondary
The secondary objective of this study is to assess 11C-BMS-986196 signal characterization.
4
ENDPOINTS
The study endpoints are summarized in Table 4-1.
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess safety, tolerability, kinetics, 
and CNS signal repeatability of the 
novel tracer 11C-BMS-986196 in 
healthy participants and in participants 
with MS

Incidence, severity, seriousness, and type of 
AEs; clinically significant abnormalities in 
ECG, VS, laboratory values, physical 
examination, and C-SSRS

Radiation dosimetry calculated from PET-CT 
images in healthy participants

Image acquisition window after administration 
of 11C-BMS-986196 

Test-retest repeatability based on quantitative 
analysis of CNS PET-MRI images (eg, SUV
and/or VT) in participants with MS

% Free brain BTK relative to baseline
Secondary
To assess 11C-BMS-986196 signal 
characterization

Calculated SUV and VT in the brain
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Abbreviations: AE, adverse event; BTK, Bruton’s tyrosine kinase; CNS, central nervous system; C-SSRS, Columbia-
Suicide Severity
Rating Scale; ECG, electrocardiogram; 
 
 
 MS, multiple sclerosis; PET, positron emission tomography; PET-CT, positron emission 
tomography - computed tomography; PET-MRI, positron emission tomography - magnetic resonance imaging; 
 
 SUV, standardized uptake value; VS, vital signs; VT, volume 
of distribution.
5
SAMPLE SIZE AND POWER
The sample size in Parts A to C of the study are not based on statistical power considerations or 
formal sample size calculations. In Part A, up to 8 healthy participants (at least 2 females and 
2 males are planned) will be enrolled and in Part B, up to 8 participants with MS will be enrolled,
and in Part C, up to 12 healthy participants will be enrolled, such that in this study, up to 
approximately 28 participants will have evaluable PET scans. Participants with non-evaluable PET 
scans may be replaced, ie, the total number of enrolled participants may exceed 28 if participants 
have to be replaced.
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6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
Important note: As it was decided to terminate this study earlier and not to follow with the dosing 
of Part C anymore, the following sections will refer to Parts A and B only. A synoptic CSR will 
be written for this study.
6.1
Study Periods
Study Day 1 will be defined as the day of first administration of tracer 11C-BMS-986196. The day 
before the first administration will be defined as Study Day -1, there is no Study Day 0. 
For statistical analysis, the following analysis periods will be defined:

Pre-treatment period: starts at signing of informed consent (ICF) and lasts up to first dosing 
date/time on Study Day 1 .

On treatment period: starts at first dosing date/time on Study Day 1 and lasts in each study 
part.
6.2
Treatment Regimens
Parts A and B of this study are designed as non-randomized, single-arm studies; therefore,
participants in each study part will be analyzed as treated for all imaging and safety analyses.
6.3
Populations for Analyses
For analysis, analysis populations as defined in Table 6.3-1 will be used.
Table 6.3-1:
Analysis Populations
Population
Description
Enrolled
All participants who provide written (signed) informed consent.
Safety
All participants who received at least 1 dose of tracer administration.
PET
All participants who received at least 1 dose of tracer administration and have any 
available PET scan data.
Response-Evaluable 
All participants who receive at least 1 dose of tracer administration, and: 
1) 1 evaluable whole body PET scan without major important protocol deviations in Part 
A (Response-Evaluable 1)
2) At least 1 evaluable cranial PET scan in Part A or B (Response-Evaluable 2)
3) 2 evaluable cranial PET scans in Part B (Response-Evaluable 3)
Per Protocol
All participants who receive at least 1 dose of tracer administration, and: 
1) 1 evaluable whole body PET scan without major important protocol deviations in Part A
(Per-Protocol 1)
2) At least 1 evaluable cranial PET scan without major important protocol deviations in 
Part A or B (Per-Protocol 2)
3) 2 evaluable cranial PET scans without major important protocol deviations in Part B
(Per-Protocol 3) 
Abbreviations: PET, positron emission tomography.
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7
STATISTICAL ANALYSES
SAS® version 9.4 or higher will be used for statistical analyses, tabulations, and graphical 
presentations.
7.1
General Methods
Unless otherwise noted, descriptive summaries will be presented for continuous variables using 
number of participants (N), mean, standard deviation (SD), median, minimum, and maximum. 
Frequency summaries for categorical variables will utilize counts and percentages. Percentages 
will be rounded to one digit after the decimal and, therefore, may not always sum up to exactly
100%. 
Baseline is defined as the last non-missing result prior to first dosing of study treatment (Day 1).
Note: For assessments with multiple measurements on Day 1, the value with relative time recorded 
as “pre-dose”, “pre-infusion” or similar, as appropriate per parameter, will be considered as 
baseline.
If not otherwise stated and as appropriate per analysis population, summary statistics will be 
calculated for participants in Part A, participants in Part B, and overall (Parts A and B combined)
as appropriate. This will also serve the purpose of directly comparing results from healthy 
participants and participants with MS.
7.2
Study Conduct
Not appropriate. 
7.3
Study Population
7.3.1
Participant Disposition
Participant disposition of the enrolled participants and Safety population (enrolled, entered, 
completed, discontinued, along with primary reasons for discontinuation, as apropriate) will be 
summarized separately for the pre-treatment and treatment and study, as appropriate.
7.3.2
Demographic Characteristics
The demographic characteristics will be summarized for the Safety population.
7.3.3
Medical History and Specific Disease History
Not applicable.
7.3.4
Prior and Concomitant Medications and Procedures
Not applicable.
7.4
Extent of Exposure
The time between the first and the second administration of the PET tracer will be derived from 
the administration dates and times recorded in the CRF and presented in hours. 
Exposure in terms of administered dose will be recorded as drug mass as well as radioactive dose. 
The planned radioactive dose will be recorded in the CRF as well. Summary statistics will be 
presented for the administered dose per visit for drug mass and radioactive dose, for the cumulative 
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administered dose for drug mass and radioactive dose, for the cumulative planned radioactive dose,
and for the relative radioactive dose intensity. Relative radioactive dose intensity will be derived 
as:
Relative radioactive dose intensity (%) = Cumulative administered radioactive dose / Cumulative 
planned radioactive dose *100%. 
Treatment exposure will be summarized for the Safety population as follows:

Number (%) of participants receiving PET tracer 11C-BMS-986196 (1 dose, 2 doses, 3 doses, 
>3 doses)

Time (hours) between last administration of 11C-BMS-986196 at Visit 1 and first
administration of 11C-BMS-986196 at Visit 2

Total administered mass (μg) of 11C-BMS-986196 per visit

Cumulative administered mass (μg) of 11C-BMS-986196

Total administered radioactive dose (MBq) of 11C-BMS-986196 per visit

Cumulative administered radioactive dose (MBq) of 11C-BMS-986196

Cumulative planned radioactive dose (MBq) of 11C-BMS-986196

Relative radioactive dose intensity (%) of 11C-BMS-986196
7.5
Imaging
Imaging endpoints will be analyzed using descriptive statistics and tables will not include the total 
column. Two-sided 95% confidence intervals may be presented for some analyses as defined in 
the following and will be considered descriptive measures of association only. No formal testing 
for statistical significance will be conducted in this analysis.
Sensitivity analyses of primary and secondary imaging endpoint may be carried out, if deemed 
necessary, based on the corresponding per-protocol populations as defined in Section 6.3.
In addition to the statistical analysis covered in the SAP, an imaging report will be provided by the 
imaging vendor at time of final analysis. The imaging report may be reported as an appendix to 
the synoptic CSR. The imaging report will provide further analyses and results to guide 
interpretation of the imaging data. In particular, primary imaging endpoints relating to the analysis 
of radiation dosimetry data and recommendation of the optimal image acquisition window after 
administration of 11C-BMS-986196 in Part A will only be provided in the imaging report and are 
therefore not included in the SAP.
Results for relevant quantitative PET parameters will be presented separately for regions of interest 
(ROI) as appropriate in this study. The list below includes expected ROIs but may not be 
exhaustive. ROIs to be evaluated in this study will be further specified in the vendor imaging report
and the transferred quantitative data.

Cortical grey matter, Normal appearing white matter, Whole brain (Parts A and B)

T2 lesions, T2 lesion-free areas (Part B only)
A short description of imaging-related endpoints in this study is provided in Table 7.5-1.
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Table 7.5-1:
Description of Imaging Endpoints
Parameter
Definition
Radiation dosimetry
Measurement and assessment of radiation exposure and absorption of 
ionizing radiation in body tissue.
Image acquisition window after 
tracer administration
Period of time required to collect the imaging data during a scan.
Standardized uptake value (SUV)
Semi-quantitative measurement of tracer uptake in body tissue defined as 
ratio of radioactivity per unit volume of a region of interest to the 
radioactivity per unit volume of the whole body.
Volume of distribution (VT)
Ratio of the radioligand concentration in a region of interest to the 
radioligand concentration in plasma at equilibrium.
7.5.1
Primary Imaging Endpoints
Radiation dosimetry calculated from PET-CT images in healthy participants: As noted in Section 
7.5 above, analysis of radiation dosimetry will be provided in the imaging report and is not 
included in the SAP. 
Image acquisition window after administration of 11C-BMS-986196: As noted in Section 7.5
above, the determination of the image acquisition window after administration of the PET tracer
will be provided in the imaging report and is not included in the SAP.
Test-retest repeatability based on standardized uptake value (SUV) of CNS PET images in 
participants with MS: The test-retest repeatability will be based on a quantitative analysis of cranial 
PET images and will be evaluated for the Response-Evaluable 3 population (Part B only).
Calculated SUV (g/mL) in the brain will be summarized using descriptive statistics and will be 
presented by visit and for each appropriate ROI.
For each participant in the Response-Evaluable 3 population, the difference between test and retest 
values will be derived as well as the test-retest repeatability (%), which is defined based upon the 
absolute value of the difference between test and retest values normalized by their mean:
Test-retest difference = ܴܶെܶ,
Test-retest repeatability (%) = 100% െ2 ൈቚ
ோ்ି்
ோ்ା்ቚൈ100%,
with T being the calculated value for the parameter measured at Visit 1 (test) and RT being the 
calculated value for the same parameter measured at Visit 2 (retest). Summary statistics of the test-
retest difference and test-retest repeatability will be presented for each appropriate ROI.
In addition, the 95% limits of agreement for the difference will be derived for each appropriate 
ROI as the corresponding mean difference ±1.96 times the standard deviation of the difference.
As sensitivity analysis, tabulation of test-retest analysis of calculated SUV may be repeated, if 
deemed appropriate, for the Per-Protocol 3 population (Part B only).
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Test-retest repeatability based on volume of distribution (VT) of CNS PET images in participants 
with MS: The test-retest repeatability of calculated VT (mL/cm3) in the brain will be evaluated in 
the same manner as described for calculated SUV above.
7.5.2
Secondary Imaging Endpoint
To characterize the 11C-BMS-986196 tracer signal, summary statistics will be provided for
calculated SUV and VT in the brain and presented by visit and each appropriate ROI for the 
Response-Evaluable 2 population (Parts A and B). As sensitivity analysis for the secondary 
imaging endpoint, the analysis may be repeated, if deemed appropriate, for the Per-Protocol 2 
population (Parts A and B).
7.6
Safety
For the calculation of the changes from baseline, baseline will be defined as the last non-missing 
observation including unscheduled measurements recorded before the first dosing of study 
treatment.
Data collected from sampling at unscheduled visits or time-points at post-dose will be excluded 
from summary tables by visit or time-point.
7.6.1
Deaths
All reported deaths after enrolment (i.e., participant has signed the informed consent) will be listed 
for the Enrolled population.
7.6.2
Adverse Events
All AEs will be coded and grouped into Preferred Terms (PT) by System Organ Class (SOC), 
using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent adverse events (TEAEs) will be defined as any AEs that start on or after 
administration of study treatment and until 10 days after last dose of study treatment or date of last 
study visit, whichever is later.
Only TEAEs will be tabulated. Events will be assigned to the study treatment administered to the 
participant. For tabulating incidence of TEAEs, the proportion of participants having an TEAE
will be calculated as the number of participants experiencing the event, divided by the total number 
of participants in the Safety population. TEAEs will be summarized by SOC, PT, treatment, and 
overall.
AE counting rule:
Where a participant has the same adverse event, based on preferred terminology, reported multiple 
times in a single analysis period, the participant will only be counted once at the preferred 
terminology level in adverse event frequency tables.
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Where a participant has multiple adverse events within the same system organ class in a single 
analysis period, the participant will only be counted once at the system organ class level in adverse 
event frequency tables.
When a participant 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:

Relationship to study medication

Severity/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:

Severity/Intensity of event

Onset date and time
Listings of all recorded AEs will be provided for the Enrolled population.
7.6.3
Serious Adverse Events
All reported serious adverse events (SAEs) if any will be summarized by SOC, PT, treatment, and 
overall.
7.6.4
Clinical Laboratory Evaluations
A listing of pregnancy test results will be created.
7.6.5
ECG
Summary statistics will be presented for each ECG parameter (heart rate, PR interval, QRS
duration, QT interval, QTcF interval) and the corresponding changes from baseline by visit and 
time-point, for each study part. 
7.6.6
Vital Signs and Physical Measurements
Not applicable.
7.6.7
Physical Examination Findings
Frequency and percentage of participants with an abnormal physical examination will be provided 
by visit.
7.6.8
Allen’s Test
Not applicable.
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8
CONVENTIONS
8.1
Decimal Places
Unless otherwise specified, minimum and maximum will be reported to the precision as the data 
collected, and with one more decimal place for the mean, median, and standard deviation. Data 
recorded or derived with more than 2 digits after the decimal will be displayed with minimum and 
maximum rounded to 2 decimal places and mean, median, and standard deviation rounded to 3 
decimal places in summary tables, and with all decimal places in listings (or as space allows).
8.2
Imputation of Missing Dates for Adverse Events 
8.2.1
Incomplete Start Date
Missing day and month:

If the year is the same as the year of the first dosing date, then the day and month of the first 
dosing date will be assigned to the missing fields.

If the year is prior to the year of first dosing date, then December 31 will be assigned to the 
missing fields.

If the year is after the year of first dosing, then January 1 will be assigned to the missing fields.
Missing day only:

If the month and year are the same as the year and month of first dosing date, then the first 
dosing date will be assigned to the missing day.

If either the year of the partial date is before the year of the first dosing date or the years of the 
partial date and the first dosing date are the same but the month of partial date is before the 
month of the first dosing date, then the last day of the month will be assigned to the missing 
day.

If either the year of the partial date is after the year of the first dosing date or the years of the 
partial date and the first dose date are the same but the month of partial date is after the month 
of the first dosing date, then the first day of the month will be assigned to the missing day.

If the stop date is not missing, and the imputed start date is after the stop date, the start date 
will be imputed by the stop date. 
Missing day, month, and year:

No imputation is needed, the corresponding AE will be included as TEAE. 
8.2.2
Incomplete Stop Date
If the imputed stop date is before the start date, then the imputed stop date will be equal to the start 
date.
Missing day and month:

If the year of the incomplete stop date is the same as the year of the last dosing date, then the 
day and month of the last dosing date will be assigned to the missing fields. 
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
If the year of the incomplete stop date is prior to the year of the last dosing date or prior to the 
year of the first dosing date, then December 31 will be assigned to the missing fields. 

If the year of the incomplete stop date is prior to the year of the last dosing date but is the 
same as the year of the first dosing date, then the first dosing date will be assigned to the 
missing date. 

If the year of the incomplete stop date is after the year of the last dosing date, then January 1 
will be assigned to the missing fields.
Missing day only:

If the month and year of the incomplete stop date are the same as the month and year of the 
last dosing date, then the day of the last dosing date will be assigned to the missing day. 

If either the year of the partial date is not equal to the year of the last dosing date or the years 
of the partial date and the last dosing date are the same but the month of partial date is not 
equal to the month of the last dosing date, then the last day of the month will be assigned to 
the missing day.
9
CONTENT OF REPORTS
Statistical components for the clinical study report will be based on the content of this statistical 
analysis plan (SAP). Details of the tables, listings, and figures, as appropriate, to be prepared for 
the final synoptic CSR will be included in a study-specific Data Presentation Plan (DPP).
10
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL
The statistical analysis of the secondary imaging endpoint will be carried out for the Response-
Evaluable 2 population. The protocol erroneously refers to the Response-Evaluable 1 population 
here, however, this subset would apply to endpoints based on whole body scan data, not cranial
scan data.
11
DOCUMENT HISTORY
Table 11-1:
Document History
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Number
Author(s)
Description
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APPENDIX 1
ABBREVIATIONS
Table 11-2:
List of Abbreviations
Abbreviation
Description
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
BMS
Bristol Myers Squibb
BTK
Bruton’s Tyrosine Kinase
CNS
Central Nervous System
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CT
Computed Tomography
%CV
Coefficient of Variation
DPP
Data Presentation Plan
ECG
Electrocardiogram
EDC
Electronic Data Capture
GdE
Gadolinium Enhancing
GLP
Good Laboratory Practices
ICH
International Conference on Harmonization
IND
Investigational New Drug
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MS
Multiple Sclerosis
NCI-CTC
National Cancer Institute - Common Terminology Criteria
PDAP
Protocol Deviation Assessment Plan
PET
Positron Emission Tomography
PT
Preferred Term
ROI
Region of Interest
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
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Table 11-2:
List of Abbreviations
Abbreviation
Description
SE
Standard Error
SI
International System of Units
SOC
System Organ Class
SUV
Standardized Uptake Value
TEAE
Treatment-Emergent Adverse Event
VS
Vital Signs
VT
Volume of Distribution
WHO-DD
World Health Organization’s Drug Dictionary
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