Open Label, Adaptive Design, Ascending, Multiple-Dose Study to Evaluate Safety and Efficacy of BMS-986004 in Adult Subjects With Primary Immune Thrombocytopenia (ITP)
Phase: PHASE1
Conditions: Immune Thrombocytopenic Purpura
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
IM140103
IND Number:
118,393
Ex-US
Non-IND
EUDRACT Number
2014-001429-33
Date:
20-Jun-2014
Revised Date:
08-Aug-2016
CLINICAL PROTOCOL IM140103
Open Label, Adaptive Design, Ascending, Multiple-Dose Study to Evaluate Safety and Efficacy 
of BMS-986004 in Adult Subjects with Primary Immune Thrombocytopenia (ITP)
Revised Protocol Number: 03
Incorporates Amendment 06
Study Director/ Medical Monitor
Marek Honczarenko, M.D., Ph.D.
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. All other rights reserved. References to BMS in this 
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2
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Revised Protocol No.: 03
Date: 08-Aug-2016
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol03
08-Aug-2016
Incorporates all changes from Amendment 06
Global 
Amendment 06
08-Aug-2016
The purpose of this amendment is to add Long Term Extension (LTE) 
period to the study 
Revised 
Protocol 02
02-Apr-2015
Incorporates all changes from Amendment 4
Amendment 04
02-Apr-2015
The purpose of this amendment is to add two follow-up visits, add Data 
Monitoring Committee, further clarify the Exploratory Biomarker 
Analyses section and update blood volume and duration of the study. 
Revised 
Protocol 01
31-Jul-2014
Incorporates all changes from Amendment 2
Amendment 02
31-Jul-2014
The purpose of this amendment is to provide clarification and 
consistency on various sections in the protocol:  for consistency, upper 
limit of age has been updated in some sections of the protocol to > 18 
years old, early decision for dose escalation section has been updated and 
correction has been made to method of assigning subject identification 
section. In addition, some typographical edits, format updates and 
clarifications are made throughout the protocol.
Original 
Protocol
20-Jun-2014
Not applicable
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SYNOPSIS
Clinical Protocol IM140103
Protocol Title: Open Label, Adaptive Design, Ascending, Multiple-Dose Study to Evaluate Safety and Efficacy of 
BMS-986004 in Adult Subjects with Primary Immune Thrombocytopenia (ITP)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):  Total of 40 subjects will be enrolled for the study, treated in dose panels of 10 subjects each. Four (4) 
dose panels are planned to be enrolled sequentially in an ascending manner, with dose intensity selected to provide 
increased levels of immunosuppression at steady state. Dose levels that are planned to be evaluated in this trial are 
expected to elicit a range of clinical response. Based on current preclinical projections, the doses range from 75 mg 
to 1500 mg every two weeks. 
BMS-986004 will be administered once every 2 weeks as an IV infusion for a total of 7 doses. Subjects will receive 
investigational product on Day 1/Week 0, Week 2, Week 4, Week 6, Week 8, Week 10 and Week 12, for a total of 7 
doses. 
During the long term extension (LTE) period, BMS-986004 will be administered once every 2 weeks as an IV 
infusion for 24 weeks and during 2 Taper visits.
Study Phase: Phase 1b/2
Research Hypothesis: Because current study is an open label trial without placebo control, there is no formal 
research hypothesis to be statistically validated. The purpose of this study is to test if BMS-986004 will be effective 
in normalizing platelet counts in subjects with ITP, as well as to assess the safety, PK and immunogenicity of 
multiple doses of BMS-986004 in ITP subjects.
Primary Objectives:

To assess the overall safety and tolerability of multiple doses of BMS-986004, when administered in subjects 
with chronic ITP.
Secondary objectives: 

To evaluate efficacy of BMS-986004 in the treatment of thrombocytopenia in subjects with chronic ITP, as 
measured by platelet response/complete response (R/CR) and other clinical parameters. 

To establish BMS-986004 dose response, as measured by platelet count and other clinical parameters.

To measure the target engagement of BMS-986004 following multiple IV doses

To assess the effect of BMS-986004 on markers associated with the risk of thromboembolism (TE) in the 
multiple dose setting

To assess pharmacokinetics and immunogenicity of multiple doses of BMS-986004 in subjects with chronic 
ITP
 
 
 
 
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Long Term Extension Period Objective:
To assess the long term clinical safety, tolerability and efficacy of BMS-986004. 
Study Design:  This is a Phase 1b/2, multicenter, open-label study to evaluate the safety, efficacy, dose response, 
and pharmacology (PK, target engagement and PD) of BMS-986004 in subjects with ITP. 
The study will comprise a short-term period and a long-term extension (LTE) period. 
The short-term period, is divided into three phases: Response Phase (6 weeks), Remission Phase (6 weeks) and 
Follow Up phase (8 weeks).
Screening evaluations to determine subject eligibility will be performed 21 days prior to study drug administration. 
The screening period may exceed 21 days but not more than 42 days total only after a discussion with and approval 
by the Study Director. If an extension in screening time is granted, the patient must still follow the platelet count 
rules for enrollment. The baseline platelet count determining enrollment eligibility will be based on the mean of two 
determinations taken within a week before the first dose. To be eligible for enrollment, platelet count needs to be 
less than 30,000/ mm3 and show stable or declining trend. If the mean platelet count is between 30,000 - 35,000/ 
mm3 the subject may be considered for enrollment on a case by case basis after discussion with and approval by the 
Study Director.
Following screening, a total of 40 evaluable subjects are planned for the study. Subjects are considered evaluable if 
they receive the first 4 doses of study drug and complete the required safety and efficacy evaluations at Day 50. 
Non-evaluable subjects will be replaced to maintain a count of 10 subjects in each dose panels, except subjects will 
not be replaced if they are discontinued from the study secondary to an adverse event unless the adverse event can 
be determined to be unrelated to treatment.
Subjects are treated in dose panels of 10 subjects each. Four (4) dose panels are planned to be enrolled sequentially 
in an ascending manner, with dose intensity selected to provide increased levels of immunosuppression at steady 
state. Dose levels (range from 75 mg to 1500 mg administered every two weeks) that are planned to be evaluated in 
this trial are expected to elicit a range of clinical response. 
BMS-986004 will be administered once every 2 weeks as an IV infusion for a total of 7 doses. Four (4) doses will be 
administered during the Response Phase over a 6 week treatment period. The remaining 3 doses will be 
administered during the Remission Phase of the study over a 6 week treatment period. Subjects will receive 
investigational product on Day 1/Week 0, Week 2, Week 4, Week 6, Week 8, Week 10 and Week 12, for a total of 7 
doses. 
Each dose cohort will enroll 10 new subjects, starting with the respective dose level at Day1/Week 0, regardless of 
the number of subjects joining a dose cohort because of intra-subject dose escalation. 
A new cohort may be opened to treat subjects at a dose lower than 75 mg if at least 6 subjects treated at the 75 mg 
cohort achieve platelet Response (R) (platelet count ≥ 30,000/mm3 and at least 2-fold increase from the baseline
count and absence of bleeding), at the end of response phase (Week 6). The new cohort would follow the same 
schedule as the other cohorts including intra-subject dose escalation.
The Long-term extension (LTE) period is optional and will include eligible subjects (defined as subjects from 
either cohort 3 or cohort 4 who complete 12 weeks (85-days) of treatment and who achieve a response as defined by 
at least a doubling of platelets from Short Term Day 1 baseline and a platelet count of ≥ 35,000/mm3. If a subject 
has platelet counts close to a doubling of platelets and/or between 30,000-35,000 platelets/mm3, the subject may be 
considered for the long term extension on a case by case basis, which will involve a review of data from the short 
term period and which will require approval by the Study Director.
Intra-subject dose escalation
Intra-subject dose escalation could occur after the subject has completed the Response Phase of the study. Subject 
will receive the next higher dose of BMS-986004 if clinically significant response has not been achieved based on 
measurement of platelet count on the last two consecutive counts performed at Day 43 and Day 50, and a favorable 
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safety profile is observed. Clinically significant response is defined as achieving platelet count ≥ 50,000/mm3 with 
an increase of at least 20,000/mm3 from baseline and absence of bleeding. Subject will then be dosed at the higher 
dose level for the remainder of the study (Remission Phase).
Dose frequency adjustment for responders exceeding 450,000/mm3 (for non-splenectomized subjects) and 
600,000/mm3(for splenectomized subjects) platelet count
For both the short-term period and the long-term extension, in the event that platelet count exceeds 450,000/mm3 for 
non-splenectomized subjects and 600,000/mm3 for subjects who underwent splenectomy, in the absence of recent 
(administered within two weeks) rescue medication, as indicated by the two consecutive platelet count 
measurements, dosing of the BMS-986004 should be stopped. Subject will remain in the study and platelet counts 
will be then assessed based on the normal study visit schedule. Dosing of BMS-986004 could be reinitiated only 
after discussion between Study Director and Investigator if clinically appropriate and dictated by the medical 
judgment and subject’s safety.
Dose escalation for dose panel and stopping rules
Decisions regarding dose escalation will be made based on the review of all cumulative safety information which 
includes, in general, the safety data through study Day 15 from the 10 subjects in the preceding lower dose cohort. If 
neither of the below stopping rules is present in dose panel, then dose escalation may proceed within the next higher 
dose level. However, escalation to the next higher cohort may occur when none of the stopping rules have been met 
and no less than 5 subjects in a cohort have been followed for at least 2 weeks under certain conditions as illustrated 
in the section of early decision of dose escalation for dose panel.
The stopping rules listed below will be used to determine whether it is safe to escalate to the next higher cohort. 
Dose escalation to the next planned dose will not proceed if any of the following criteria are met (Adverse event 
grading as defined by the Common Terminology Criteria for Adverse Events [CTCAE, Version 4.0]):

Five or more subjects in a cohort have platelet counts >450,000/mm3 for non-splenectomized subjects and 
>600,000/mm3 for subjects who underwent splenectomy, and platelet count raise is not attributable to a rescue 
or concomitant therapy.

Two or more subjects have serious adverse events in the same organ system (Grade 3 and above), that are 
determined to be related to study medication

It is determined that the limit of safety and/or tolerability has been reached. This decision will be made 
following discussions between the Study Team and the Investigator
If any of the above criteria are met within a dose level, the progression to a higher dose level will be put on hold and 
all safety data available across the study will be evaluated to estimate the risk of proceeding to the higher dose level. 
The review will include all of the subject(s) that experienced SAEs listed above. In addition, data set may include 
subjects from a dose panel, the entire dose panel, or if appropriate, all randomized subjects treated to date. 
In addition, decision may be made following discussions between the Study Team and the Investigator to halt dose 
escalation for reasons not defined above, including but not limited to, observing a single serious adverse event in 
individual subjects, observing trends in a given dose panel and across dose panels, and/or it is determined that the 
limit of safety and/or tolerability has been reached. 
If dose escalation is stopped due to any of these findings, additional cohorts may receive the same or lower doses of 
the investigational compound.
At the time of dose escalation, dose levels of new cohorts may be adjusted to lower doses if the accumulated safety 
data so dictates.
Adaptive dose selection may be performed to adjust some pre-selected doses, e.g., the third or/and fourth cohort 
doses, using accumulated efficacy and dose or exposure data. Models based on response rate, such as but not limited 
to (Bayesian) logistic regression, (Bayesian) EMax model, may be utilized to predict a dose satisfying certain 
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efficacy criteria, which might be different from the standard. If there are enough responding subjects with multiple 
platelet measurements, changes of platelet count may be directly modeled by dose and study day to facilitate dose 
prediction. The selected dose for a cohort should not exceed the originally planned dose for that cohort, i.e., selected 
dose for cohort C should not be larger than 675mg and it should be at most 1500mg for cohort D.
Figure 3.1.3-1:
Study Design Schematic: Short Term Period
*Will not apply to subjects entering LTE
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Figure 3.1.3-2:
Study Design Schematic: Short Term Period
Figure 3.1.3-3:
Study Design Schematic: Long term extension period
Early Decision of Dose escalation for dose panel
When a cohort is filled and a new subject is available to be treated, an early decision can be made on whether to 
open the next higher cohort if not all the subjects have completed the evaluation period. The early decision rule is 
based on controlling the probability of making a wrong early decision, called decision risk, to be at most 15%. 
Detailed information on deriving the decision risk is included in Appendix 1. 
The early decision rule is based on the largest number of subjects who developed AE of interest which is drug-
related SAE within the same organ system at grade 3 or higher. The early decision does not directly take into 
consideration other criteria as covered by the stopping rule. As such, its decision can be modified upon agreement 
from both investigators and sponsor. In case subjects are allocated to the higher cohort and at least one stopping rule 
as stated above is triggered toward the lower dose cohort when more events are observed at the lower cohort, 
decision will be made upon agreement from both investigators and sponsor after considering all safety data.
Three count numbers are used by the decision rule and are defined as follows.

Titration-Dose Evaluable Subjects (nH): the number of subjects who are titrated and complete the evaluation 
period (2 weeks) starting from the first titration dose (on day 43).

Start-Dose Evaluable Subjects (nL): the number of subjects who develop drug related SAE at grade 3 or higher 
or complete the evaluation period (2 weeks) from the first dose (on day 1) but haven’t completed the 2 weeks 
evaluation period following the first titration dose (on day 43) if being titrated to a higher dose.
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
Subjects with AE of Interest (k): the largest number of subjects who developed drug related SAE within the 
same organ system at grade 3 or higher, which could happen any time after the first dose of BMS-986004 till 
the decision making day. The value of k is allowed to be either 0 or 1. Note that it doesn’t distinguish at which 
stage of treatment, prior to or post titration, that such AE happened.
Minimum Requirement for Cohort Escalation
A set of minimum safety requirement, as listed below, must be met in order to make an early decision.

There must be at least 5 (nL+nH>=5) safety evaluable subjects (with safety data through study Day 15)

A higher dose than the new cohort’s start dose must be shown tolerated in the IM140-002 study.
Early Decision Rule:
If there is not AE of interest observed, the early decision rule is the same as the minimum requirements.
If there is one AE of interest observed, the early decision rule is shown in Table 3.1.4-1, where W represent wait, 
i.e., not enough evidence to enable dose panel escalation, and E represents escalate.
If there are least two subjects with AE of interest, stopping rule is triggered, and subject cannot be treated at the next 
higher cohort.
Study Population:  
Male and Female subjects ≥18 years old with persistent or chronic ITP according to American Society of 
Hematology (ASH), with or without prior splenectomy guidelines will be eligible to participate in the study. 
Women of childbearing potential (WOCBP) must not be nursing or pregnant and must be using an acceptable 
method of contraception for at least 4 weeks before dosing. WOCBP must have a negative pregnancy test within 24 
hours prior to dosing with study medication
Study Drug includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for BMS-986004
Medication 
Potency 
IP/Non-IP 
Lyophilized Cake of BMS-986004 
for injection,190 mg/vial
50 mg/mL
IP
Study Assessments:  

Safety Outcome Measures:  Safety assessments will be based on medical review of adverse event reports and 
the results of vital sign measurements, ECGs, physical examinations, and clinical laboratory tests. The 
incidence of observed adverse events will be tabulated and reviewed for potential significance and clinical 
importance.

Efficacy Assessments: Response (R) - platelet count ≥ 30,000/mm3 and at least 2-fold increase from the 
baseline count and absence of bleeding, or Complete response (CR) - platelet count ≥ 100,000/mm3 and absence 
of bleeding, or Overall response rate (ORR) defined as the proportion of subjects who achieved a CR or R.

Pharmacokinetic Measures: Pharmacokinetic parameters (Cmax, Ctrough), will be derived from serum 
concentration versus time

Biomarker Measures:  CD40L receptor occupancy and free soluble CD40L will be measured to determine target 
engagement. Total soluble CD40L will be measured as a potential PD biomarker. Platelet-associated anti-
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platelet antibody titers will be measured to explore possible effects on the primary pathogenic disease 
mechanism in ITP. Whole genome RNA profiling in the peripheral blood will be undertaken to explore CD40 
pathway activation and to enumerate plasmablasts by gene expression. Peripheral blood mononuclear cells 
(PBMCs) will be purified from whole blood and analyzed by flow cytometry to determine if baseline leukocyte 
phenotypes inform on patient response to therapy and/or if leukocyte phenotypes are affected by drug therapy. 
Plasma molecules that may be associated with the disease or drug target pathway, including cytokines and 
chemokines, will be measured. The primary safety biomarkers, d-Dimer and Thrombin anti-Thrombin (TAT), 
will be monitored to evaluate risk of thromboembolism. Exploratory safety biomarkers to monitor possible 
effects on protective immunity will include immune cell enumeration by T, B, NK TruCount and phenotyping 
by flow cytometry. 
Statistical Considerations:
Sample Size:
The number of subjects is not based on statistical power considerations. If 4 responders are observed out of 10 
subjects at a dose level, a 90% confidence interval for the response rate is (0.15, 0.70).
Endpoints:
Primary endpoints of safety will be measured by AE, SAE, ECG, and laboratory abnormalities including safety 
biomarkers of d-Dimer and TAT. 
Secondary endpoint of efficacy is measured by response rate. Secondary endpoints of PK include Cmax, CLT, 
AUC(TAU), Ctrough, AI_AUC, and AI_Cmax.
Exploratory endpoints include time to response, duration of response, and time to peak response.
Endpoints for the Long Term Extension Period
Primary endpoints of safety for the long-term extension period will be measured by AE, SAE, ECG, and laboratory 
abnormalities including safety biomarkers of d-Dimer and TAT.
The endpoint of efficacy is measured by response rate.
Analyses:
Demographics and Baseline Characteristics
Frequency distributions of gender and race will be tabulated. Summary statistics for age, body weight, height, and 
Body Mass Index (BMI) will be tabulated. Prior therapies will be listed and summarized for each dose.
Safety Analyses
All recorded adverse events will be listed and tabulated by system organ class, preferred term and treatment. Vital 
signs and clinical laboratory test results will be listed and summarized by treatment. Any significant physical 
examination findings, and clinical laboratory results will be listed. ECG readings will be evaluated by the 
investigator and abnormalities, if present, will be listed.
Efficacy Analyses
Platelet count and change from baseline will be listed for all treated subjects. Response status will be reported 
together with time to respond, time to peak response, and duration of response. Response rate will be provided by 
cohort and treatment phase (response phase or remission phase).
Bleeding score will be listed for each subject. Bleeding events and the number of subjects experiencing any bleeding 
episode will be summarized by panel.
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Pharmacokinetic Analyses
PK parameters will be summarized by treatment. Geometric means and coefficients of variation will be presented 
for Cmax (after dose 1 and dose 6), AUC(TAU), CLT,  and Ctrough. Additionally, scatter plots of Cmax versus 
dose will be provided to assess the dependency on dose. A statistical analysis using a power model will be applied to 
assess dose proportionality.
Immunogenicity Analyses
Data from the assessment of immunogenicity markers (anti-BMS-986004 antibodies) will be listed by subjects. In 
addition, immunogenicity data will be listed separately for all the subjects who have at least one positive assay. 
Number and frequency of positive subjects will be summarized by dose. Definition of different positivity will be 
available in the study’s Statistical Analysis Plan (SAP).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Analyses
Modeling analysis of PK of BMS-986004 will be conducted using a population approach as appropriate and 
reported separately from the clinical study report.
Long Term Extension Analyses
Similar and appropriate analyses (demographics and baseline characteristics, efficacy analyses, safety analyses, etc) 
will be conducted for the LTE analysis population when applicable. The analyses for the LTE analysis population 
are descriptive in nature.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
 
 
 
 
 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
 
1.3.4 Long Term Extension Period Objective ................................................... 
 
 
 
 
 
 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
1.5.1 Potential risks associated with BMS-986004 .......................................... 
1.5.2 Potential Thromboembolic Effect ............................................................ 
1.5.3 Potential Immunosuppressive effect ........................................................ 
1.5.4 Risk of Infusion Reactions ........................................................................ 
1.5.5 Other ........................................................................................................ 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Intra-subject dose escalation ................................................................... 
3.1.2 Dose frequency adjustment for responders exceeding 450,000/mm3(for 
non-splenectomized subjects) and 600,000/mm3(for splenectomized 
subjects) platelet count ............................................................................... 
3.1.3 Dose escalation for dose panel and stopping rules ................................. 
3.1.4 Early decision of dose escalation for dose panel ..................................... 
3.1.5 Long Term Extension ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
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3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.3.4 Criteria for Long Term extension ............................................................ 
3.4 
 
 
 
 
 
 
 
 
 
 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Follow up ............................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.3.2 Laboratory Test Assessments ................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.2 Secondary Efficacy Assessments .............................................................. 
5.4.3 Long Term Extension Period Efficacy Assessments ................................ 
5.4.3.1 Primary Efficacy Assessment .......................................................... 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetics: Collection and Processing ........................................ 
5.5.2 Pharmacokinetic Sample Analyses .......................................................... 
5.5.3 Labeling and Shipping of Biological Samples ......................................... 
 
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5.8 Outcomes Research Assessments ..................................................................... 
5.9 Other Assessments ............................................................................................ 
5.9.1 Immunogenicity Assessments ................................................................... 
5.9.1.1 Immunogenicity Sample Collection and Analysis ........................... 
5.10 Results of Central Assessments ...................................................................... 
5.11 Sampling for Medical Research ...................................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.3.4 Endpoint for the Long Term Extension Period ........................................ 
8.3.4.1 Primary Endpoints for LTE ............................................................ 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Immunogenicity Analyses ......................................................................... 
 
. 
8.4.8 Long Term Extension Analyses ................................................................ 
8.4.9 Exploratory Analyses for the Long Term Extension ................................ 
8.4.10 Outcomes Research Analyses ................................................................ 
8.4.11 Other Analyses ....................................................................................... 
8.4.11.1 Immunogenicity Analysis .............................................................. 
8.4.11.2 Population PK Analysis ................................................................ 
8.5 Interim Analyses ............................................................................................... 
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9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 ADAPTIVE EARLY DECISON FOR DOSE PANEL ESCALATION
................................................................................................................................. 
APPENDIX 2 ADAPTIVE DOSE SELECTION......................................................... 
 
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1.2
Research Hypothesis 
Because current study is an open label trial without placebo control, there is no formal research 
hypothesis to be statistically validated. The purpose of this study is to test if BMS-986004 will
be effective in normalizing platelet counts in subjects with ITP, as well as to assess the safety, 
PK and immunogenicity of multiple doses of BMS-986004 in ITP subjects. 
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1.3
Objectives(s)
1.3.1
Primary Objectives

To assess the overall safety and tolerability of multiple doses of BMS-986004, when 
administered in subjects with chronic ITP.
1.3.2
Secondary Objectives

To evaluate efficacy of BMS-986004 in the treatment of thrombocytopenia in subjects with 
chronic ITP, as measured by platelet response/complete response (R/CR) and other clinical 
parameters. 

To establish BMS-986004 dose response, as measured by platelet count and other clinical 
parameters.

To measure the target engagement of BMS-986004 following multiple IV doses

To assess the effect of BMS-986004 on markers associated with the risk of 
thromboembolism (TE) in the multiple dose setting

To assess pharmacokinetics and immunogenicity of multiple doses of BMS-986004 in 
subjects with chronic ITP.
 
 
 
 
 
1.3.4
Long Term Extension Period Objective

To assess the long term clinical safety, tolerability and efficacy of BMS-986004. 
 
 
 
 
 
 
 
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1.5
Overall Risk/Benefit Assessment
BMS-986004 is currently being evaluated in humans in a FIH SAD study which is being 
performed in healthy subjects to investigate the safety, tolerability, PK and PD of BMS-986004. 
To-date, BMS-986004 has not been studied in the ITP patient population and hence no efficacy 
or benefit data is established for this population. However, no clinically significant risks have 
been identified in the FIH study to-date and the safety margins in non-clinical studies are 
favorable which justifies careful evaluation of BMS-986004 in the ITP patient population.
BMS-986004 could potentially provide clinical benefit by normalizing platelet counts in patients 
with ITP.   This study will be initiating at a dose that has demonstrated relatively low 
immunosuppressive effect and has demonstrated no clinically significant risks in the FIH study.
Dose panels will be enrolled sequentially in an ascending manner upon careful review of all 
cumulative safety information. Cumulative safety data will include all additional data that is 
available in the FIH study as well as data collected during the ITP study. To manage the safety 
risks, careful clinical and laboratory monitoring and criteria relative to dose escalation and 
stopping rules have been established for this protocol and include thresholds for serious 
infections, liver function tests, platelet counts above established thresholds, and other adverse 
events. 
It is expected that ITP subjects will derive clinical benefit from BMS-986004 and help guide 
dose selection and design of future studies in the clinical development of BMS-986004. Primary 
efficacy assessments will include the proportion of patients achieving platelet count at least 
≥30,000/mm3 and at least 2-fold increase from the baseline count and absence of bleeding.
The subjects planned to be enrolled in this study have limited therapeutic options since they have 
failed conventional therapies including immunosuppresive therapies, splenectomy and TPO 
mimetics. It is anticipated that efficacious doses of BMS-986004 will provide long lasting 
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therapeutic benefit for ITP patients. Ultimately, targeting CD40L may provide opportunity to 
inhibit autoimmune processes leading to thrombocytopenia and induce durable disease 
remission. It may thus offer novel therapeutic modality, currently not available to patients.
Given the lack of therapeutic options for ITP subjects who have failed all conventional therapies, 
BMS-986004 with its distinct mechanism of action and known safety profile appears to have a 
favorable Risk/Benefit profile.
Detailed information regarding the preclinical toxicology findings based on nonclinical studies 
in monkeys with BMS-986004 can be found in Section 1.5.2 and the Investigator Brochure.
1.5.1
Potential risks associated with BMS-986004
BMS-986004 is a dimeric anti-human CD40L VH dAb formatted with the Fc-tail from abatacept 
(modified IgG1) that is entirely inert in Fc effector function, especially in context of FcγRIIa. All 
data from nonclinical and NHP studies demonstrate that BMS-986004 exhibited no activity in 
various platelet activation assays, as well as in direct biacore binding analysis with FcγRIIa. 
Based on previous clinical experience with antibodies targeting costimulatory molecules and in 
particular with anti-CD40L antibodies, potential risks include: (1) increased probability of TE; 
(2) an increase in susceptibility to infection and (3) immunogenic potential including infusion 
reactions and formation of ADA. In addition to conventional safety assessments, general risk 
mitigation plan includes the following:

To initiate dosing at 75 mg dose that has demonstrated favorable safety profile in healthy 
subjects in clinical evaluation. This dose is expected to elicit a sub-optimal response while 
ensuring very good safety profile.

To utilize safety criteria for intra-subject dose escalation and safety criteria for dose-panel 
escalation and stopping rules.
1.5.2
Potential Thromboembolic Effect
To continue to mitigate the potential risk of thromboembolism, the following safety measures are 
included in ITP study:

Close monitoring of any potential TE activities after BMS-986004 administration. In addition 
to observing clinical manifestations of both venous and arterial TE, the primary safety 
biomarkers, d-Dimer and Thrombin anti-Thrombin (TAT), will be monitored to evaluate risk 
of thromboembolism. 

TE related exclusion criteria have been added to the protocol; patients with history 
thromboembolic disease (including TIA, stroke, pulmonary embolism, deep vein thrombosis 
and thrombotic complications) or significant cardiovascular disease (including congestive 
heart failure, arrhythmias and other conditions known to increase risk of TE) are excluded.
1.5.3
Potential Immunosuppressive effect
As with any novel immunomodulating agent, there is a possibility of reducing normal immune 
function as a consequence of targeted CD40L blockade and therefore the following safety 
measures are included in the ITP study:
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
Exclusion criteria relative to positive tests for hepatitis B and C, TB and HIV have been 
included in the protocol.

Concurrent or recent use of systemic immune-modulating agents is prohibited or restricted to 
reduce potential risks associated with combinations of immune suppressors.

Patients will be very closely followed and evaluated for any signs or symptoms of infection 
and complete blood count (CBC) differential counts, lymphocyte immunophenotyping, and
measurement of serum Ig-levels (IgG, IgA and IgM) and CRP will be monitored frequently.
1.5.4
Risk of Infusion Reactions
As with any biological product, infusion reactions are a risk, even following a single dose. To 
reduce the risk of infusion reactions, patients will be closely monitored by trained personnel 
experienced with treatment of anaphylaxis and lesser infusion reactions. In addition, IV 
administration of study drug will not exceed infusion rate of 12.5 mg/min (Table 4-1). 
Furthermore, patients with history of any significant drug allergy or serious adverse reaction or 
hypersensitivity to any IV administered biologic will be excluded from the study.
1.5.5
Other
Risks from the PK, PD, and clinical safety phlebotomy procedures are standard and include 
discomfort at the injection site, bleeding, bruising, and rarely blood clot formation, infection, and 
fainting. Furthermore, rescue medications are permitted in the study for severe bleeding or wet 
purpura or if the investigator thinks the patients is at immediate risk. These medications are to 
be given with the intended purpose of raising platelet counts.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
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2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form(s) which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form(s) and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. The 
language must be non-technical and easily understood. 

Allow time necessary for subject or subject's legally acceptable representative to inquire
about the details of the study.

Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form(s) and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.

If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.

Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
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subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form(s) must also include a statement that BMS and regulatory authorities have 
direct access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
Subjects in this trial will be invited to participate in a voluntary collection for future Medical 
Research. This collection is encouraged but not mandatory, and subjects who decline to 
participate will still be allowed to proceed with the rest of the study providing all other 
conditions are met.
This collection for future Medical Research is intended to expand the translational R&D 
capability at Bristol-Myers Squibb, and will support as yet undefined research aims that will 
advance our understanding of disease and options for treatment. It may also be used to support 
health authority requests for analysis, and advancement of pharmacodiagnostic development to 
better target drugs to the right patients.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase 1b/2, multicenter, open-label study to evaluate the safety, efficacy, dose response, 
and pharmacology (PK, target engagement and PD) of BMS-986004 in subjects with ITP. 
The study will comprise a short-term period and a long term extension (LTE) period. 
The short-term period, is divided into three phases: Response Phase (6 weeks), Remission Phase 
(6 weeks) and Follow Up phase (8 weeks).
Screening evaluations to determine subject eligibility will be performed 21 days prior to study 
drug administration. The screening period may exceed 21 days but not more than 42 days total, 
and only after a discussion with and approval by the Study Director. If an extension in screening 
time is granted, the patient must still follow the platelet count rules for enrollment. The baseline 
platelet count determining enrollment eligibility will be based on the mean of two determinations 
taken within a week of the first dose. To be eligible for enrollment, platelet count needs to be less 
than 30,000/ mm3 and show stable or declining trend. If the mean platelet count is between 
30,000 - 35,000/ mm3 the subject may be considered for enrollment on a case by case basis after 
discussion with and approval by the Study Director.
Following screening, a total of 40 evaluable subjects are planned for the study. Subjects are 
considered evaluable if they receive the first 4 doses of study drug and complete the required 
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safety and efficacy evaluations at Day 50. Non-evaluable subjects will be replaced to maintain a 
count of 10 subjects in each dose panels, except subjects will not be replaced if they are 
discontinued from the study secondary to an adverse event unless the adverse event can be 
determined to be unrelated to treatment.
Subjects are treated in dose panels of 10 subjects each. Four (4) dose panels are planned to be 
enrolled sequentially in an ascending manner, with dose intensity selected to provide increased 
levels of immunosuppression at steady state. Dose levels (range from 75 mg to 1500 mg 
administered every two weeks) that are planned to be evaluated in this trial are expected to elicit 
a range of clinical response. 
BMS-986004 will be administered once every 2 weeks as an IV infusion for a total of 7 doses.
Four (4) doses will be administered during the Response Phase over a 6 week treatment period. 
The remaining 3 doses will be administered during the Remission Phase of the study over a
6 week treatment period. Subjects will receive investigational product on Day 1/Week 0, Week 
2, Week 4, Week 6, Week 8, Week 10 and Week 12, for a total of 7 doses. 
Each dose cohort will enroll 10 new subjects, starting with the respective dose level at 
Day1/Week 0, regardless of the number of subjects joining a dose cohort because of intra-subject 
dose escalation. 
A new cohort may be opened to treat subjects at a dose lower than 75 mg if at least 6 subjects 
treated at the 75 mg cohort achieve platelet Response (R) (platelet count ≥ 30,000/mm3 and at 
least 2-fold increase from the baseline count and absence of bleeding), at the end of response 
phase (Week 6). The new cohort would follow the same schedule as the other cohorts including 
intra-subject dose escalation.
The long term extension (LTE) period is optional and will include eligible subjects from either 
cohort 3 or cohort 4 who complete 12 weeks (85-days) of treatment and who achieve a response
as defined by at least a doubling of platelets from Short Term Day 1 baseline and a platelet count 
of ≥ 35,000/mm3, and absence of bleeding and any significant AEs as assessed on D71 or if more 
recent platelet count is available, based on the most recent platelet count or on the average of the 
two consecutive most recent platelet counts, whichever is higher. If a subject has platelet counts 
close to a doubling of platelets and/or between 30,000-35,000 platelets/mm3 and absence of 
bleeding and any significant AEs as assessed on D71, the subject may be considered for the long 
term extension on a case by case basis, which will involve a review of data from the short term 
period and which will require approval by the Study Director.
3.1.1
Intra-subject dose escalation
Intra-subject dose escalation could occur after the subject has completed the Response Phase of 
the study. The intra-subject dose escalation decision will be based on review of the safety 
information and platelet count after 4 weeks of treatment. The decision to escalate dose for the 
subject will be made after evaluating platelet count at Day 50, 7 days after the 4th dose of 
BMS-986004 has been administered. Subject will receive the next higher dose of BMS-986004 if 
clinically significant response has not been achieved based on measurement of platelet count on 
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the last two consecutive counts performed at Day 43 and Day 50, and a favorable safety profile is 
observed (see Table 3.1.1-1). Clinically significant response is defined as achieving platelet 
count ≥ 50,000/mm3 with an increase of at least 20,000/mm3 from baseline and absence of 
bleeding. Subject will then be dosed at the higher dose level for the remainder of the study 
(Remission Phase), receiving investigational product at that dose on Week 8, Week 10 and Week 
12. Active treatment period with BMS-986004, regardless of the dose, may not exceed 12 weeks 
for any individual subject. 
Table 3.1.1-1:
Dose Adjustment after Response Phase
Platelet Count at Day 43 and Day 50 (7 days after the 
4th dose) 
(X /mm3)
Action
50,000
Dose increase, as indicated by the next dose panel
≥50,000 with an increase of at least 20,000 from baseline
Dose remains constant on bi-weekly schedule
3.1.2
Dose frequency adjustment for responders exceeding 450,000/mm3(for 
non-splenectomized subjects) and 600,000/mm3(for splenectomized 
subjects) platelet count
For both the Short Term Study and the Long Term Extension plan, in the event that platelet
count exceeds 450,000/mm3 for non-splenectomized subjects and 600,000/mm3 for subjects who 
underwent splenectomy, in the absence of recent (administered within two weeks) rescue 
medication, as indicated by the two consecutive platelet count measurements, dosing of the 
BMS-986004 should be stopped. Subject will remain in the study and platelet counts will be then 
assessed based on the normal study visit schedule. Dosing of BMS-986004 could be reinitiated 
only after discussion between Study Director and Investigator if clinically appropriate and 
dictated by the medical judgment and subject’s safety.
3.1.3
Dose escalation for dose panel and stopping rules
Decisions regarding dose escalation will be made based on the review of all cumulative safety 
information which includes, in general, the safety data through study Day 15 from the 
10 subjects in the preceding lower dose cohort. If neither of the below stopping rules is present in 
dose panel, then dose escalation may proceed within the next higher dose level. However, 
escalation to the next higher cohort may occur when none of the stopping rules have been met 
and no less than 5 subjects in a cohort have been followed for at least 2 weeks under certain
conditions as illustrated in section 3.1.4.
The stopping rules listed below will be used to determine whether it is safe to escalate to the next 
higher cohort. Dose escalation to the next planned dose will not proceed if any of the following 
criteria are met (Adverse event grading as defined by the Common Terminology Criteria for 
Adverse Events [CTCAE, Version 4.0]):
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
Five or more subjects in a cohort have platelet counts >450,000/mm3 for non-splenectomized 
subjects and >600,000/mm3 for subjects who underwent splenectomy, and platelet count 
raise is not attributable to a rescue or concomitant therapy.

Two or more subjects have serious adverse events in the same organ system (Grade 3 and 
above), that are determined to be related to study medication,

It is determined that the limit of safety and/or tolerability has been reached. This decision 
will be made following discussions between the Study Team and the Investigator,
If any of the above criteria are met within a dose level, the progression to a higher dose level will 
be put on hold and all safety data available across the study will be evaluated to estimate the risk 
of proceeding to the higher dose level. The review will include all of the subject(s) that 
experienced SAEs listed above. In addition, data set may include subjects from a dose panel, the 
entire dose panel, or if appropriate, all randomized subjects treated to date. 
In addition, decision may be made following discussions between the Study Team and the 
Investigator to halt dose escalation for reasons not defined above, including but not limited to, 
observing a single serious adverse event in individual subjects, observing trends in a given dose 
panel and across dose panels, and/or it is determined that the limit of safety and/or tolerability 
has been reached. 
If dose escalation is stopped due to any of these findings, additional cohorts may receive the 
same or lower doses of the investigational compound.
At the time of dose escalation, dose levels of new cohorts may be adjusted to lower doses if the 
accumulated safety data so dictates.
Adaptive dose selection may be performed to adjust some pre-selected doses, e.g., the third 
or/and fourth cohort doses, using accumulated efficacy and dose or exposure data. Models based 
on response rate, such as but not limited to (Bayesian) logistic regression, (Bayesian) EMax, may 
be utilized to predict a dose satisfying certain efficacy criteria, which might be different from the 
standard. If there are enough responding subjects with multiple platelet measurements, changes 
of platelet count may be directly modeled by dose and study day to facilitate dose prediction.
The selected dose for a cohort should not exceed the originally planned dose for that cohort, i.e., 
selected dose for cohort C should not be larger than 675mg and it should be at most 1500 mg for 
cohort D.
The study design schematic is presented in Figure 3.1.3-1.
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Figure 3.1.3-1:
Study Design Schematic: Short-term period
*Will not apply to subjects entering LTE
Figure 3.1.3-2:
Study Design Schematic: Short-term period
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Figure 3.1.3-3:
Study Design Schematic: Long term extension period
3.1.4
Early decision of dose escalation for dose panel
When a cohort is filled and a new subject is available to be treated, an early decision can be 
made on whether to open the next higher cohort if not all the subjects have completed the 
evaluation period. The early decision rule is based on controlling the probability of making a 
wrong early decision, called decision risk, to be at most 15%. Detailed information on deriving 
the decision risk is included in Appendix 1.
The early decision rule is based on the largest number of subjects who developed AE of interest 
which is drug-related SAE within the same organ system at grade 3 or higher. The early decision 
does not directly take into consideration other criteria as covered by the stopping rule. As such, 
its decision can be modified upon agreement from both investigators and sponsor. In case 
subjects are allocated to the higher cohort and at least one stopping rule as stated above is 
triggered toward the lower dose cohort when more events are observed at the lower cohort, 
decision will be made upon agreement from both investigators and sponsor after considering all 
safety data. 
Three count numbers are used by the decision rule and are defined as follows.

Titration-Dose Evaluable Subjects (nH): the number of subjects who are titrated and 
complete the evaluation period (2 weeks) starting from the first titration dose (on day 43).

Start-Dose Evaluable Subjects (nL): the number of subjects who develop drug related SAE at 
grade 3 or higher or complete the evaluation period (2 weeks) from the first dose (on day 1) 
but haven’t completed the 2 weeks evaluation period following the first titration dose (on day 
43) if being titrated to a higher dose.

Subjects with AE of Interest (k): the largest number of subjects who developed drug-related 
SAE within the same organ system at grade 3 or higher, which could happen any time after 
the first dose of BMS-986004 till the decision making day. The value of k is allowed to be 
either 0 or 1. Note that it doesn’t distinguish at which stage of treatment, prior to or post 
titration, that such AE happened.
Minimum Requirement for Cohort Escalation
A set of minimum safety requirement, as listed below, must be met in order to make an early 
decision.
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
There must be at least 5 (nL+nH>=5) safety evaluable subjects (with safety data through 
study Day 15)

A higher dose than the new cohort’s start dose must be shown tolerated in the IM140-002 
study.
Early Decision Rule:
If there is not AE of interest observed, the early decision rule is the same the minimum 
requirements.
If there is one AE of interest observed, the early decision rule is shown below in Table 3.1.4-1, 
where W represent wait, i.e., not enough evidence to enable dose panel escalation, and E 
represents escalate.
If there are least two subjects with AE of interest, stopping rule is triggered, and subject cannot 
be treated at the next higher cohort.
Table 3.1.4-1:
Decision Rule for Early Panel Escalation When There Is One Subject 
with AE of Interest (k=1)
Titration-Dose Evaluable 
Subjects (nH)a
Start-Dose Evaluable Subjects (nL)b
1
2
3
4
5
6
7
8
9
0
Wc
W
W
W
W
W
W
W
Ed
1
W
W
W
W
W
W
E
E
2
W
W
W
W
W
E
E
3
W
W
W
W
E
E
4
W
W
W
E
E
5
W
W
E
E
6
W
E
E
7
E
E
8
E
a the number of subjects who are titrated and complete the evaluation period (2 weeks) starting from the titration’s 
first dose.
b the number of subjects who develop AE of interest or complete the evaluation period (2 weeks) from the first 
dose but could not be classified into the “Titration-Dose Evaluable Subjects” group.
c W: Wait
d E: Escalate
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), and clinical 
laboratory evaluations will be performed at selected times throughout the dosing interval. 
Subjects will be closely monitored for adverse events throughout the study. Blood samples will 
be collected for up to 336 hours after study drug administration for pharmacokinetic (PK) 
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analysis. Approximately 910 mL of blood will be drawn from each subject during the short-term 
period (~162 days including Screening and follow up period). Less than 500mL of blood will be 
drawn during the LTE period.
The approximate duration of the short-term period is 23 weeks (approximately 162 Days).  This 
includes a 21 day screening period, a 12 week treatment period and a 2 month follow up period.
An extended screening period (up to 42 days) is possible but only with the approval of the Study 
Director, and all other eligibility rules and screening rules must still be met. If subject is eligible 
and opts to continue into LTE, the 2 month follow-up period will not be performed after the 
short-term period is completed and the subject will enter the LTE directly. If the subject opts not 
to enter the LTE, then a 2 month follow-up visit will be completed. 
The approximate duration of the long term extension is approximately 55 weeks. This includes 
24 weeks of every other week dosing of 1500 mg, two-taper visits (7 weeks total), and a 24 week 
follow-up period (no treatment).
3.1.5
Long Term Extension
The long term extension (LTE) period is optional and will include eligible subjects who have 
completed Day 85 (12-weeks of treatment) and who have consented to participate. Eligible 
subjects [platelet count ≥ 35,000/mm3 with at least a doubling of platelets from short-term 
baseline, or patients approved by the Study Director on a case by case basis who are close to a 
two-fold increase from short term baseline and/or have 30,000-35,000 /mm3 platelets and 
absence of bleeding and any significant AEs as assessed on D71 or if more recent platelet count 
is available, based on the most recent platelet count or on the average of the two consecutive 
most recent platelet counts, whichever is higher], will receive a 1500 mg dose every other week 
for 24 weeks. Subjects who complete 24 weeks LTE will receive a taper regimen consisting of 
1500mg dose on Day 190 and a final dose on Day 218 before entering the 24 week follow-up 
period (no treatment). 
A separate informed consent must be signed by the patients to enter the LTE period.
3.2
Post Study Access to Therapy
At the end of the 12 week treatment study period, all eligible subjects in Cohort 3 and 4 will have 
the option to continue into the LTE period. The investigator should ensure that the subject 
receives appropriate standard of care to treat the condition under study.
3.3
Study Population
For entry into the short-term period of the study, the following criteria MUST be met prior to 
dosing on Day 1 of the Short Term Period. No exceptions will be granted. 
For entry into the long term extension, subjects must remain on study medication, complete the 
short-term period (up to 12 weeks of treatment), qualify per guidance for an increase in platelet 
count and safety, and sign a new informed consent. 
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3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) The signed written informed consent form must be obtained from the subject in 
accordance with requirement of the study center’s IRB, prior to initiation of any protocol 
required procedures.
2. Target Population
a) Adults (≥18 years old), diagnosed with persistent or chronic ITP according to American 
Society of Hematology (ASH)/British Committee for Standards in Haematology (BCSH) 
guidelines, with or without prior splenectomy. 
b) Subjects previously received one or more prior ITP therapies and must have had initially 
responded to at least one prior ITP therapy. Previous treatments for ITP include but are 
not limited to TPO mimetics/agonists, corticosteroids, immunoglobulins, azathioprine, 
danazol, cyclophosphamide and/or rituximab.
c) Subjects have had relapsed ITP i.e. failed to achieve a sustained (for more than 3 month) 
platelet count ≥ 50,000/mm3 to at least one prior ITP therapy.
d) The platelet count (calculated from the mean of the 2 counts taken within a week of the 
first dose, during the screening and pre-treatment periods) must be less than 30,000/mm3 
with no count greater than 35,000/mm3. If the mean of the counts is between 30,000-
35,000/mm3, the subject may still be eligible but enrollment will be on a case by case 
basis and require approval by the Study Director.
e) Subject Re-enrollment:  This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / 
has not been treated). If re-enrolled, the subject must be re-consented.
f)
A complete blood count must be within the reference range (including white blood count 
[WBC] differential not indicative of a disorder other than ITP), with the following 
exceptions: 
i)
subjects with hemoglobin levels between 9 g/dL for females and 10 g/dL for males 
and the lower limit of normal (LLN) are eligible for inclusion, if anemia was clearly 
attributable to ITP (excessive blood loss); 
ii) absolute neutrophil count (ANC) greater than or equal to 1500/L (elevated 
WBC/ANC due to corticosteroid treatment is acceptable)
g) Prothrombin Time/International Normalized Ratio (PT/INR) and activated partial 
thromboplastin time (aPTT) must have been within 80% to 120% of the normal range 
with no known hypercoagulable state.
h) The following clinical chemistries MUST NOT exceed 2 times the normal reference 
range: ALT, AST, alkaline phosphatase, and bilirubin >1.5 times upper limit normal 
(ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct 
bilirubin is <35%)
i)
Albumin must be within 80 to 120% of normal range
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3. Age and Reproductive Status
a) Males and Females, ≥18 years old.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug (84 days) plus 5 half-lives of study drug (20 days) plus 30 
days (duration of ovulatory cycle) for a total of 134 days post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (84 days) plus 5 
half-lives of the study drug (20 days) plus 90 days (duration of sperm turnover) for a total 
of 194 days post-treatment completion.
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements.  However they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of one method of highly effective contraception as 
listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

Male condoms with spermicide

Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirenaby WOCBP 
subject or male subject’s WOCBP partner. Female partners of male subjects participating in 
the study may use hormone based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug 

IUDs, such as ParaGard

Tubal ligation

Vasectomy

Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence
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3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Secondary immune thrombocytopenia e.g. due to SLE, CLL, CVID, APS
b) Drug induced thrombocytopenia
c) History of MDS (Myelodysplastic Syndrome).
d) Subject exhibit an identifiable alternative cause of their thrombocytopenia, such as 
splenomegaly, family thrombocytopenia, bacteraemia, sepsis or active infection requiring 
or not therapy.
2. Medical History and Concurrent Diseases
a) Any severe medical condition (cardiac, hepatic or renal disorder) other than chronic ITP. 
(Note: "Severe" is defined as Grade 3 and above as a rule according to guidelines 
described by the Common Terminology Criteria for Adverse Events, Version 4.03)
b) History of thromboembolic disease within the last 24 month (e.g., transient ischemic 
attack [TIA], stroke [CVA], pulmonary embolism [PE]), history of deep vein thrombosis 
(DVT).
c) Subjects with a history of significant cardiovascular disease (e.g., congestive heart failure 
[CHF] New York Heart Association Grade III/IV, arrhythmia known to increase the risk 
of thromboembolic events [e.g., atrial fibrillation], subjects with a QT interval corrected 
for heart rate of > 450 msec, angina, coronary artery stent placement, angioplasty, 
coronary artery bypass grafting)
d) Inability to be venipunctured and/or tolerate venous access.
e) Any other sound medical, psychiatric and/or social reason as determined by the
investigator.
f)
Subject treated with drugs that affect platelet function, (e.g. aspirin and/or NSAIDs) or 
anti-coagulants for more than 3 consecutive days within 2 weeks of the study start.
3. Physical and Laboratory Test Findings
a) An abnormal (positive) direct Coombs' test in patients who have not received IVIg or IV 
anti-D immunoglobulin within 30 days.
b) Positive blood screen for Hepatitis C antibody
c) Positive blood screen for HIV-1, -2 antibodies or p24 antigen (HIV viral RNA test may 
be conducted if the investigator deems necessary).
d) Positive test for active Hepatitis B infection as indicated by screening using Hepatitis B 
surface antigen (HBsAg), Hepatitis B surface antibody (anti-HBs) and Hepatitis B core 
antibody (anti-HBc) (See Appendix 3).
e) Positive quantiFERON® TB test. 
f)
Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, ECG or clinical laboratory determinations beyond what 
is consistent with the target population.
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4. Allergies and Adverse Drug Reaction
a) History of serious adverse reaction or hypersensitivity to IV administered biological 
therapeutic.
b) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).
5. Other Exclusion Criteria
a) Prior exposure to BMS-986004
b) Prisoners or subjects who are involuntarily incarcerated
c) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
d) Inability to comply with restrictions and prohibited activities/treatments as listed in 
Section 3.4.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 in the absence of other biological or physiological causes. In addition, 
Females under the age of 55 years must have a documented serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause.
Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used: The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. If the serum FSH level is >40 mlU/ml at any time 
during the washout period, the woman can considered postmenopausal

1 week minimum for vaginal hormonal products, (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.3.4
Criteria for Long Term extension
Subjects who enter the short-term period according to the eligibility criteria outlined in Sections 
3.3.1 and 3.3.2, and who complete 12 weeks on study medication and at Short Term Day 71 or if 
more recent platelet count is available, based on the most recent platelet count or on the average 
of the two most recent platelet counts, whichever is higher have ≥ 35,000 platelets/mm3 and at 
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least a doubling of platelets compared to Short Term Day 1 baseline, are eligible for participation 
in the LTE period. If a subject has completed 12 weeks on study medication and on Day 71 or if 
more recent platelet count is available, based on the most recent platelet count or on the average 
of the two consecutive most recent platelet counts, whichever is higher platelet counts are close 
to a doubling of platelets and/or between 30,000-35,000 platelets/mm3 and there is an absence of 
bleeding and any significant AEs, the subject may be considered for the long term extension on a 
case by case basis, which will involve a review of data from the short term period and which will 
require approval by the Study Director.
A separate informed consent must be signed to enter the LTE period.
 
 
 
 
 
 
 
 
 
 
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sponsor, subjects will continue with regularly scheduled visits
3.5
Discontinuation of Subjects following any Treatment with Study Drug
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment and/or participation in the study

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Unblinding a subject for any reason (emergency or non-emergency)

An opportunistic or systemic fungal, viral or bacterial infection of a serious nature, that in the 
opinion of the investigator or medical monitor, contraindicates further dosing of 
investigational product after resolution.

Malignancy, except basal cell carcinoma.

Severe hypersensitivity reaction (anaphylaxis) to the study drug, Grade 3 or higher
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
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warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue investigational product should comply with protocol specified 
follow-up procedures as outlined in Section 5. The only exception to this requirement is when a 
subject withdraws consent for all study procedures including post-treatment study follow-up or 
loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness).
Subjects refusing to return to the site or to continue participation in the study should be 
documented as “withdrawal of consent” rather than “lost to follow-up.” Investigators should 
document attempts to re-establish contact with missing subjects throughout the study period. If 
contact with a missing subject is re-established, the subject should not be considered 
lost-to-follow-up and any evaluations should resume according to the protocol.
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Follow up
In this study, increase in platelet count is a key endpoint of the study. Post treatment study 
follow-up is of critical importance and is essential to preserving subject safety and the integrity 
of the study. Subjects who discontinue study treatment must continue to be followed for 
collection of outcome and/or survival follow-up data as required and in line with Section 5 until 
death or the conclusion of the study.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
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All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a Sponsor-
retained third-party representative to assist site staff with obtaining subject’s contact information 
or other public vital status data necessary to complete the follow-up portion of the study. The site 
staff and representative will consult publicly available sources, such as public health registries 
and databases, in order to obtain updated contact information. If after all attempts, the subject 
remains lost to follow-up, then the last known alive date as determined by the investigator should 
be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. 

Study required premedication, and

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications)

Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
BMS-986004 will be administered as a solution intravenously. Table 4-1 below indicates the 
total dose and number of vials per dose for each.
Table 4-1:
Treatment Administration
Treatment
Total Daily 
Dose
Volume of 
Reconstituted 
50 mg/mL 
BMS-986004
Number of 
BMS-986004 
Vials
Prime 
Filter
Infusion 
Volume
(mL)
Infusion 
Time 
(min)
Rate 
(mg/min)
1
75 mg IV
3 mL
1
YES
50
120
0.625
2
225 mg IV
4.5 mL
2
NO
100
120
1.875
3
675 mg IV
13.5 mL
4
NO
100
120
5.625
4
1500 mg IV
30 mL
8
NO
100
120
12.500
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The study drug should be dispensed by the pharmacist or qualified designee and administered as 
an infusion using an infusion pump. Do not ever administer study drug by intravenous push 
(IVP) or bolus injection. A physician must be present at the infusion site during all 
administrations of study drug.
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be monitored 
before infusion (at anytime the day of dosing, prior to infusion), approximately every 15 minutes 
during infusion, at the end of the infusion (within 10 minutes after the infusion has stopped), and 
approximately every 30 minutes after completion of the infusion until stable, as judged by the 
investigator. If an anaphylactoid-like infusion reaction or anaphylactic reaction occurs, vital 
signs will be taken more frequently, as warranted by the severity of the reaction. Blood pressure 
and heart rate will also be taken prior to discharge from the site on visits in which study drug is 
administered.
Subjects should not be premedicated unless they have had a prior infusion reaction, since the 
primary objective of this study is to evaluate the expected frequency of safety events and 
tolerability of the study drug. However, after a reaction determined to be an infusion reaction has 
been documented, the investigator may elect to administer prophylactically an anti-histamine or 
Tylenol for the comfort and safety of the subject prior to subsequent infusions.
Product description and storage information is described in Table 4-3.
Table 4-2:
Treatment Administration During Long Term Extension
Total Daily 
Dose
Volume of 
Reconstituted 
50 mg/mL 
BMS-986004
Number of 
BMS-986004 
Vials
Prime 
Filter
Infusion 
Volume 
(mL)
Infusion 
Time (min)
Rate (mg/min)
1500 mg IV
30 mL
8
NO
100
120
12.500
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product is: BMS-986004 Injection. BMS-986004 is a clear to 
slightly opalescent, colorless to pale yellow solution; may contain particulate matter upon visual 
inspection. The drug product is a preservative free, ready to use solution contained in a 10 cc vial 
with 20 mm opening, Type I flint glass, 1-panel, open label. 
Each vial of drug product contains the labeled amount of BMS-986004, 190 mg/vial (50 mg/mL) 
in 10 mM Sodium Phosphate, pH 6.5, 25 mM Arginine HCl, 250 mM Sucrose. A 13% overfill is 
included in each vial to account for vial, needle syringe (VNS) holdup. This drug product can be 
used for intravenous administration only
4.2
Non-investigational Product
Not Applicable. 
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Preparation for Intravenous Use
Dilution of BMS-986004 Injection for IV use must be performed using sterile disposable 
syringes. Prior to IV administration, BMS-986004 Injection is diluted with 0.9% Sodium 
Chloride Injection (NS) to prepare dosing solutions with BMS-986004 concentrations ranging 
from 1.5 to 15 mg/mL. The product is to be infused over 2 hours for each panel, using a 
volumetric pump at the protocol specific dose(s) and rate(s) through the IV infusion set as 
indicated in Table 4-1. Care must be taken to ensure the sterility of the prepared solution, as the 
drug product does not contain anti-microbial preservatives or bacteriostatic agents. 
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BMS-986004 Injection should be stored refrigerated at 2° - 8°C (36° - 46°) with protection from 
light. After withdrawal into an appropriate sized syringe and dilution with NS (in the 
concentration range of 1.5 to 15 mg/mL), the product must be administered intravenously within 
two hours. The diluted BMS-986004 solutions  may be stored in PVC, IV bags for up to 24 hours 
at refrigerated and protected from light, (2° - 8°C) or up to 4 hours (which includes the infusion 
time of two hours) at room temperature (15° - 25°C) and ambient lighting conditions. Regardless 
of the storage condition, the BMS-986004 infusion must be completed within 24 hours after 
transfer of the reconstituted BMS-986004 solution to an infusion container and dilution in 
normal saline. 
Recommended safety measures for preparation and handling include protective clothing, gloves, 
and safety cabinets. Partially used or empty vials of BMS-986004 Injection should be discarded 
as per the site procedures
4.4
Method of Assigning Subject Identification
During the Screening visit, the investigative site will call into the enrollment option of the 
Interactive Voice Response System (IVRS) designated by BMS for assignment of a 5-digit 
subject number that will be unique across all sites. Enrolled subjects, including those not dosed, 
will be assigned sequential subject numbers starting with 00001, eg, 00001, 00002, 00003.... 
00010. The patient identification number (PID) will ultimately be comprised of the site number 
and subject number. For example, the first subject screened (ie, enrolled) at site number 1, will 
have a PID of 0001 00001. 
Enrolled subjects meeting all eligibility criteria will be assigned to a dose cohort. Specific
instructions regarding enrollment and dose cohort assignment will be provided to the
investigational sites in their training materials.
Specific instructions for using IVRS will be provided to the investigational sites in a separate
document.
Subjects will not be replaced if they are discontinued from the study secondary to an adverse 
event unless the adverse event can be determined to be unrelated to treatment. The replacement 
subject will receive the same treatment as the subject being replaced.
4.5
Selection and Timing of Dose for Each Subject
Dose escalation and modifications will be guided by the approach described in Section 3.1.
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor compliance.
After administration of BMS-986004, an examination of the injection site is required.
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4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible BMS Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
Arrangements for the return of study drug will be made by the responsible Study Monitor.
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Study assessments and procedures are presented in Table 5.1-1, Table 5.1-2 and Table 5.1-3
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Table 5.1-1:
Screening Procedural Outline (IM140103)
Procedure
Screening
Visit
Day -8
Visit
Day -1
Visit
Notes
Eligibility Assessments
Informed Consent
X
A subject is considered enrolled only when a protocol specific informed consent 
is signed.
Inclusion/Exclusion Criteria
X
X
X
Medical History
X
X
X
Include any toxicities or allergy related to previous treatments.
Safety Assessments
Physical Examination (PE)
X
X
If the screening PE is performed within 24 hours prior to dosing on Day 1 then a 
single exam may count as both the screening and predose evaluation.
Physical Measurements
X
X
Includes height, weight, and BMI.
Vital Signs
X
X
X
Includes body temperature, respiratory rate, seated blood pressure and heart 
rate. Blood pressure and heart rate should be measured after the subject has been 
seated quietly for at least 5 minutes.
Electrocardiogram (ECGs)
X
ECGs should be recorded after the subject has been supine for at least 5 
minutes. 
Laboratory Tests
X
X
X
Includes blood and urine samples. Platelet count included in this test. Eligibility 
requires an average of the screening, D-1 and Predose platelet counts to be in 
accordance with inclusion criteria 2d. (Hematology, Serum Chemistry, 
Urinalysis)
Serology
X
To include Hepatitis C antibody, Hepatitis B surface antigen (Ag), Hepatitis B 
anti-surface Ag antibody, Hepatitis B anti-core Ag antibody, HIV-1, HIV-2 
antibody. Results must be available prior to Day 1 dosing. 
Urine Drug Screen
X
7-panel UDS 
Direct Coomb’s 
X
Pregnancy Test/FSH
X
X
X
For women only (urine or serum)
QuantiFERON Test
X
Unless documented negative test was performed within 6 months of screening
ITP-BAT
X
X
X
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Table 5.1-1:
Screening Procedural Outline (IM140103)
Procedure
Screening
Visit
Day -8
Visit
Day -1
Visit
Notes
Prothrombin Time (PT)
X
Screen for hypercoagulable state; also known as International Normalized Ratio 
(INR)
Activated Partial Thromboplastin 
Time (aPTT)
X
Screen for hypercoagulable state;  must be within 80% to 120% of the normal 
range
Exploratory PD Biomarker 
Assessment
Whole Blood Gene Expression
X
Whole blood sample will be collected to provide a double baseline for enrolled 
patients and control ITP B cell repertoire data from patients who do not enroll 
(screening sample only)
Plasma Soluble Free CD40L Level
X
See Section 5.6
Plasma Soluble Total CD40L Level
X
See Section 5.6
Platelet-Associated Anti-platelet 
Antibodies (WB)
X
See Section 5.6
Platelet Ag-specific B cells by 
ELISPOT assay (WB)
X
See Section 5.6
B cell Repertoire Analysis (WB)
X
X
See Section 5.6
Immune Cell Counts (T, B, and NK) 
and Phenotypes (WB)
X
See Section 5.6
Adverse Event Reporting
Monitor for Serious Adverse Events
X
X
X
All SAEs must be collected that occur during the screening period and within 3 
months of discontinuation of dosing.
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Table 5.1-2:
On Treatment Procedural Outline (IM140103)
Procedure
D 
1
D 
2
D 
4
D 
8
D
15
D
29
D
43
D
50
D
57
D
71
D
72, 
75, 
and 
78
D
85 
/ 
ET
FU1
(D99)a
FU2
(D113)a
FU3 
(D127)a
FU4 
(D141)a
Notes
Safety 
Assessments
Physical 
Examination (PE)
X
X
Physical 
Measurements 
X
X
X
X
X
X
X
X
X
X
Weight only
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See note in screening 
procedures.
Electrocardiogram 
(ECGs)
X
X
X
See note in screening 
procedures. 
Laboratory Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See note in screening procedures 
and Section 5.3.2. Pre-dose on 
Day 1. Platelet count included in 
this test as an efficacy parameter. 
(Hematology, Serum Chemistry, 
and Urinalysis)
Pregnancy Test
X
X
X
X
X
X
X
For women only (urine or serum)
ITP-BAT (SMOG 
Score)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subjects will be graded 
according to the ITP-BAT -
Bleeding Assessment Tool 
Adverse Event 
Reporting
Monitor for Non-
Serious Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitor for 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See note in screening 
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Table 5.1-2:
On Treatment Procedural Outline (IM140103)
Procedure
D 
1
D 
2
D 
4
D 
8
D
15
D
29
D
43
D
50
D
57
D
71
D
72, 
75, 
and 
78
D
85 
/ 
ET
FU1
(D99)a
FU2
(D113)a
FU3 
(D127)a
FU4 
(D141)a
Notes
Serious Adverse 
Events
procedures.
Pharmacokinetic 
(PK) Assessments
Serial Blood PK 
Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 5.5.
Immunogenicity 
Sampling
X
X
X
X
X
X
X
X
X
X
X
See Section 5.5
Exploratory PD 
Biomarker 
Assessments
CD40L Receptor 
Occupancy (WB)
X
X
X
X
X
X
X
X
X
X
See Section 5.6. On Dosing days 
Receptor Occupancy samples 
must be collected prior to dosing.
Whole Blood 
Gene Expression
X
X
X
X*
X
X
See Section 5.6.  (* day 78 only)
Plasma Soluble 
Free CD40L 
Level
X
X
X
X
X
X
X
X
X
See Section 5.6.
Plasma Soluble 
Total CD40L 
Level
X
X
X
X
X
X
X
X
X
See Section 5.6.
Platelet-
Associated Anti-
platelet 
Antibodies (WB)
X
X*
X
See Section 5.6.  (* day 72 only)
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Table 5.1-2:
On Treatment Procedural Outline (IM140103)
Procedure
D 
1
D 
2
D 
4
D 
8
D
15
D
29
D
43
D
50
D
57
D
71
D
72, 
75, 
and 
78
D
85 
/ 
ET
FU1
(D99)a
FU2
(D113)a
FU3 
(D127)a
FU4 
(D141)a
Notes
Platelet Ag-
specific B cells by 
ELISPOT assay 
(WB)
X
X*
X
See Section 5.6  (* day 72 only)
B cell Repertoire 
Analysis (WB)
X
See Section 5.6
Whole blood for 
PBMC isolation
X
X
X
X
See Section 5.7
Plasma for 
cytokine and 
chemokines
X
X
X
X
See Section 5.6
Primary Safety 
(TE) Biomarker 
Assessments
Plasma d-Dimer
X
X
X
X
X
X
X
X
X
X
X*
X
X
X
X
X
See Section 5.6.  (* day 78 only)
Plasma Thrombin 
Anti-thrombin 
(TAT)
X
X
X
X
X
X
X
X
X
X
X*
X
X
X
X
X
See Section 5.6.  (* day 78 only)
Serum Troponin I
X
X
X
X
X
X
X
X
X
X
X*
X
X
X
X
X
See Section 5.6.  (* day 78 only)
Exploratory 
Safety Biomarker 
Assessments
C-reactive Protein 
(CRP)
X
X
X
X
X
X
X
X
X
X*
X
X
X
X
X
See Section 5.6.  (* day 78 only)
Immunoglobulin 
(IgM, IgG, IgA) 
X
X
X
X
X
X
X
X
X
X*
X
X
X
X
X
See Section 5.6.  (* day 78 only)
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Table 5.1-2:
On Treatment Procedural Outline (IM140103)
Procedure
D 
1
D 
2
D 
4
D 
8
D
15
D
29
D
43
D
50
D
57
D
71
D
72, 
75, 
and 
78
D
85 
/ 
ET
FU1
(D99)a
FU2
(D113)a
FU3 
(D127)a
FU4 
(D141)a
Notes
Immune Cell 
Counts (T, B, and 
NK) and 
Phenotypes (WB)
X
X
X*
X
X
X
See Section 5.6.  (* day 78 only)
Clinical Drug 
Supplies
Study Drug 
Administration 
X
X
X
X
X
X
X
Report to study 
site
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a Only if subject is not entering the LTE after completing 12-weeks of study medication
Abbreviations: D = Day, FU=follow-up, ET=early term visit
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Table 5.1-3:
Long term Extension Procedural Outline (IM140103)
Procedure / Visit Day
(3 days is allowed for all visits, 
including LTE Day 1)
LTE 
D1a
Every-other 
week Visits 
(Q2W)
LTE
D15, 29, 43,
57, 71, 85, 
99, 113, 127, 
141, 155, 169
(±3 days)
Taper Period 
Visit 1 
LTE D190
(±3 days)
Taper Period 
Visit 2 
LTE 218
(±3 days)
Monthly 
Follow-up 
Period
LTE D248, 
278, 308, 338, 
368, 398
(±3 days)
Notes
Confirm subject has completed 12 
weeks of treatment and has signed 
informed consent to participate in the 
LTE
X
Safety Assessments
Physical Examination (PE)
X
X
X
X
X
Physical Measurements 
X
X*
X
X (On D248
and 398 only)
Weight only. *LTE D85 
only
Vital Signs
X
X
X
X
X
Includes body temperature, 
respiratory rate, seated 
blood pressure and heart 
rate. Blood pressure and 
heart rate should be 
measured after the subject 
has been seated quietly for 
at least 5 minutes.
Electrocardiogram (ECGs)
X
X*
X
ECGs should be recorded 
after the subject has been 
supine for at least 5 minutes.
*On Day 71 only.
Laboratory Tests
X
X
X
X
X
Includes blood and urine 
samples. Platelet count 
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Table 5.1-3:
Long term Extension Procedural Outline (IM140103)
Procedure / Visit Day
(3 days is allowed for all visits, 
including LTE Day 1)
LTE 
D1a
Every-other 
week Visits 
(Q2W)
LTE
D15, 29, 43,
57, 71, 85, 
99, 113, 127, 
141, 155, 169
(±3 days)
Taper Period 
Visit 1 
LTE D190
(±3 days)
Taper Period 
Visit 2 
LTE 218
(±3 days)
Monthly 
Follow-up 
Period
LTE D248, 
278, 308, 338, 
368, 398
(±3 days)
Notes
included in this test. 
(Hematology, Serum 
Chemistry, Urinalysis)
Pregnancy Test
X
X*
X
X
X
For women only (urine or 
serum) must be negative to 
continue dosing. *On LTE 
D29, D57, D85, D113, 
D141, D169 only
Adverse Event Reporting
Monitor for Non-Serious Adverse 
Events
X
X
X
X
X
Monitor for Serious Adverse Events
X
X
X
X
X*
*All SAEs must be
collected within 3 
months of 
discontinuation of 
dosing
PK & Immunogenicity Assessments
PK Sampling
X
X
X
X
X* 
*On LTE D248, D278,
D308 only
Immunogenicity Sampling
X
X
X
X
X*
*On LTE D248, D278,
D308 only
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Table 5.1-3:
Long term Extension Procedural Outline (IM140103)
Procedure / Visit Day
(3 days is allowed for all visits, 
including LTE Day 1)
LTE 
D1a
Every-other 
week Visits 
(Q2W)
LTE
D15, 29, 43,
57, 71, 85, 
99, 113, 127, 
141, 155, 169
(±3 days)
Taper Period 
Visit 1 
LTE D190
(±3 days)
Taper Period 
Visit 2 
LTE 218
(±3 days)
Monthly 
Follow-up 
Period
LTE D248, 
278, 308, 338, 
368, 398
(±3 days)
Notes
Biomarker Assessments
Plasma Soluble Free CD40L Level
X
X
X
Plasma Soluble Total CD40L Level
X
X
X
Plasma Collection
X
X
X
Clinical Drug Supplies
Contact IVRS
X
X
X
X
Study drug administration (1500 mg)
X
X
X
X
Report to Study Site
X
X
X
X
X
(+/- 3 days visit window for 
all visits)
a Study procedures performed on Day 85 of the short term period will be used as the starting point for LTE Day 1 procedures. They do not need to be performed 
twice. Patient in LTE, the Day 85 of the short term period and Day 1 of the LTE study dose are the same.
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In the event of multiple procedures are required at a single timepoint, the following is a list of 
procedures from highest priority to low:
1) Pharmacokinetic Sampling
2) Safety (ECG)
3) Safety (clinical labs)
5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value).
Any new result will override the previous result (i.e., the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
5.2
Study Materials
The site will provide all required materials for the tests performed locally (ie, relevant clinical 
laboratory tests and urine drug screens). The site will have available a well-calibrated scale for 
recording body weight, a 12-lead ECG machine, and a calibrated sphygmomanometer and 
thermometer for vital signs assessments. A current and fully stocked advanced cardiac life 
support (ACLS) cart will be immediately available on the premises. The site will have a 
refrigerated centrifuge, a monitored and alarmed refrigerator, and freezer (-20°C or below), as 
well as containers and dry ice for shipment and storage of blood samples. The site will provide 
all materials required for accurate source documentation of study activities and for housing the 
subjects during the study. BMS will provide a BMS approved protocol and any amendments or 
administrative letters (if required), The Bleeding Assessment Tool (ITP-BAT), BMS-986004
Investigator Brochure, Pregnancy surveillance forms, NCI CTCAE version 4.0 and a Pharmacy 
Manual. Case report forms (electronic or hard copy) will be provided by BMS. The Central 
Laboratory will provide a lab manual, labels and tubes for the collection and handling of blood 
(including PKs, biomarker and immunogenicity) specimens.
5.3
Safety Assessments
Safety assessments will be based on medical review of adverse event reports and the results of 
vital sign measurements, ECGs, physical examinations, clinical laboratory tests and clinical 
tolerability of the drug. 
The safety of BMS-986004 will be assessed primarily by summarizing treatment emergent 
AEs/SAEs and by evaluating laboratory and biomarker safety assessment, including hematology, 
clinical chemistry and coagulation.
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The occurrence of treatment-emergent AEs and SAEs will be summarized from the first 
administration of study drug through Study Day 85. Treatment-emergent AEs and SAEs that 
occur after the first administration of study drug will be summarized by system organ class and 
preferred terms, by severity, and by relationship to study drug and reviewed for potential 
significance and clinical importance. Treatment-emergent AEs and SAEs will be summarized for 
each of the BMS-986004 dose cohorts, and for all BMS-986004 doses combined.
5.3.1
Imaging Assessment for the Study
Not applicable.
5.3.2
Laboratory Test Assessments
A central/local laboratory will perform the analyses and will provide reference ranges for these 
tests.
Results of clinical laboratory tests performed on Day -1 must be available prior to dosing.
The following clinical laboratory tests will be performed:
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Hematology (Local Lab)
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
RBC
Reticulocyte percent
Prothrombin Time (PT) / International Normalized Ratio (INR) (Screening only)
Activated Partial Thromboplastin Time (aPTT) (Screening only)
Peripheral Blood Biomarkers
CD40L Receptor occupancy (by flow cytometry)
Platelet-associated anti-platelet antibody titers
Platelet Ag-specific B cells by ELISPOT
Immune cell counts (T, B and NK cells) and phenotypes (by flow cytometry)
Gene expression
PBMC 
Plasma biomarkers
D-dimer
Thrombin anti-Thrombin (TAT)
Free and Total soluble CD40L
Cytokines and Chemokines
Serum biomarkers
Troponin I
Immunoglobulin panel (IgG, IgA, IgM)
CRP
Serum Chemistry (Local Lab)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin
Alkaline phosphatase (AP)
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN)
Uric acid
Glucose
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatine kinase
Creatine Clearance (CLcr)- screening only
Urinalysis (Local Lab)
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Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive 
on the dipstick
Serology (Local Lab)
Serum for hepatitis C antibody, hepatitis B surface antigen (Ag), hepatitis B anti-surface Ag 
antibody, hepatitis B anti-core Ag antibody, HIV-1, -2 antibody (screening only).
Other Analyses (Local Lab)
Pregnancy test (WOCBP only)
Direct Coombs (Screening Only)
Urine for Drug of Abuse (UDS, Screening only)
QuantiFERON TB test (screening only)
Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
on the laboratory pages of the CRF or by another mechanism as agreed upon between the 
investigator and BMS (eg, provided electronically). If the units of a test result differ from those 
printed on the CRF, the recorded laboratory values must specify the correct units. Any abnormal 
laboratory test result considered clinically significant by the investigator must be recorded on the 
appropriate AE page of the CRF (see Section 6.3 Laboratory Test Result Abnormalities).
5.4
Efficacy Assessments
5.4.1
Primary Efficacy Assessment
Proportion of subjects achieving: 

Response (R) - platelet count ≥ 30,000/mm3 and at least 2-fold increase from the baseline 
count and absence of bleeding, or

Complete response (CR) - platelet count ≥ 100,000/mm3 and absence of bleeding, or 
Overall response rate (ORR) defined as the proportion of subjects who achieved a CR or R.
5.4.2
Secondary Efficacy Assessments

Proportion of subjects achieving platelet count ≥ 50,000/mm3 with an increase of at least 
20,000/mm3 from Short Term Day 1 and absence of bleeding

Percent of visits with platelet count above 30,000/mm3 (50,000/mm3 or 100,000/mm3). If 
subject entered study with baseline between 30,000-35,000/mm3 at Short Term Day 1, 
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determine percent of visits with platelet count above subject’s Short Term Day 1 platelet 
count.

Mean platelet count at each visit 

Mean change from baseline in platelet counts at each visit 

Mean fold change from baseline in platelet counts at each visit

Time to response: time from starting treatment to achievement of CR or R.

No response (NR): platelet count < 30,000/mm3 or less than 2-fold increase of baseline 
platelet count or bleeding.

Percentage of participants experiencing any bleeding episode and the total number of 
bleeding events.

Subject's Bleeding Score (measured by the ITP-BAT Bleeding Assessment Test)

Corticosteroid-dependence - the need for ongoing or repeated doses administration of 
corticosteroids for at least 2 months to maintain a platelet count at or above 30,000/mm3
and/or to avoid bleeding.

The duration of response is measured from the achievement of a first measured CR or R until 
the loss of CR or R.

Ability to maintain Response or Complete Response after stopping treatment.
5.4.3
Long Term Extension Period Efficacy Assessments
5.4.3.1
Primary Efficacy Assessment

Response (R) - platelet count ≥ 35,000/mm3 and at least 2-fold increase from the Short-Term 
baseline (Day 1) count and absence of bleeding, or

Complete response (CR) - platelet count ≥ 100,000/mm3 and absence of bleeding, or 
Overall response rate (ORR) defined as the proportion of subjects who achieved a CR or R by 
visit.
5.5
Pharmacokinetic Assessments
Pharmacokinetics of BMS-986004 will be derived from serum concentration versus time data. 
The pharmacokinetic parameters to be assessed include:
Cmax
Maximum observed serum concentration
AUC(TAU)
Area under the concentration-time curve in one dosing interval
Ctrough
Trough observed serum concentration
CLT
Total body clearance
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady-state to Cmax after 
the first dose
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Individual subject pharmacokinetic parameter values will be derived by non compartmental 
methods by a validated pharmacokinetic analysis program. Actual times will be used for the 
analysis.
5.5.1
Pharmacokinetics:  Collection and Processing
Table 5.5.1-1 lists the sampling schedule to be followed for the assessment of pharmacokinetics. 
Further details of blood collection and processing will be provided to the site in the procedure 
manual.
Table 5.5.1-1:
Pharmacokinetic Sampling Schedule for BMS-986004
Study Day/Month
of Sample 
Collection
Event
Time 
(Relative To BMS-
986004 Dose)
Hour: Min
BMS-986004
Blood Sample
BMS-986004
Immunogenicity 
Sample
Collections During Short-Term Period
1
Predose
00:00
X
X
1
EOIa
02:00
X
2
24:00
X
4
72:00
X
8
168:00
X
15
Predose
00:00
X
X
29
Predose
00:00
X
X
43
Predose
00:00
X
X
50
168:00
X
57
Predose
00:00
X
X
57
EOIa
02:00
X
71
Predose
00:00
X
X
71
  EOIa
02:00
X
72
24:00
X
75
96:00
X
78
168:00
X
85
Predose
00:00
X
X
FU 1 (Day  99)
336:00
X
X
FU 2 (Day 113) 
672:00
X
X
FU 3 (Day 127)
1008:00
X
X
FU 4 (Day 141)
1344:00
X
X
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Table 5.5.1-1:
Pharmacokinetic Sampling Schedule for BMS-986004
Study Day/Month
of Sample 
Collection
Event
Time 
(Relative To BMS-
986004 Dose)
Hour: Min
BMS-986004
Blood Sample
BMS-986004
Immunogenicity 
Sample
Collections During Long Term Extension
LTE Day 15
Predose
00:00
X
X
LTE Day 29
Predose
00:00
X
X
LTE Day 43
Predose
00:00
X
X
LTE Day 57
Predose
00:00
X
X
LTE Day 71
Predose
00:00
X
X
LTE Day 85
Predose
00:00
X
X
LTE Day 99
Predose
00:00
X
X
LTE Day 113
Predose
00:00
X
X
LTE Day 127
Predose
00:00
X
X
LTE Day 141
Predose
00:00
X
X
LTE Day 155
Predose
00:00
X
X
LTE Day 169
Predose
00:00
X
X
Taper V1 LTE 190
Predose
00:00
X
X
Taper V2 LTE 218
Predose
00:00
X
X
LTE FU D248
X
X
LTE FU D278
X
X
LTE FU D308
X
X
Other Samples
AEb
AE
X
X
a EOI=End of Infusion, This sample should be taken immediately prior to stopping the infusion (preferably within 
2 minutes prior to the end of infusion). If the end of infusion is delayed to beyond the nominal infusion duration, 
the collection of this sample should also be delayed accordingly. The PK serum sample of EOI must be taken on 
the contralateral arm.
b For subjects who are prematurely discontinued due to AEs, the listed samples should be taken
It is expected that every effort be made to collect PK samples at the times indicated in the 
protocol. The following windows serve as a guideline for PK and Biomarker sample collections:

+/- 2 minutes for samples within the first 2 hours after dose 

+/- 1 day for the 24 hour post dose time point (Day 2, Day 72)

+/- 2 days for sparse sampling for Day 4, Day 8,  Day 75 and Day 78 visit

+/- 3 days for all Long Term Extension samplings
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For the long term extension, immunogenicity and PK serum samples and plasma samples will be 
obtained at every visit during treatment and at the end of the first, second and third months of 
follow up.
5.5.2
Pharmacokinetic Sample Analyses
The serum samples will be analyzed for BMS-986004 by a validated ligand binding assay. In 
addition, serum samples will be archived for potential exposure-biomarker or other exploratory 
analysis, if the need arises and to the extent possible. Exploratory biomarker analysis may 
include assessment of markers associated with inflammatory or autoimmune disease, molecules 
associated with ITP or disease mechanism of action and signaling pathways, with the drug target, 
CD40L, or drug target mechanism of action and signaling pathways, and/or with patient response 
to drug treatment.
5.5.3
Labeling and Shipping of Biological Samples
Detailed instructions for the pharmacokinetic blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the procedure manual.
5.6
Biomarker Assessments
Blood and will be drawn at the times indicated in Table 5.7.1-1 and Table 5.7.1-2 for the 
measurement of target engagement, PD and disease-related biomarkers. Further details of blood 
collection and processing will be provided to the site in the procedure manual.
5.6.1
Primary Safety (TE) Biomarker Assessments
Previous molecules in clinical development targeting CD40L have demonstrated the potential to 
induce thromboembolism (TE). All data from nonclinical, NHP and single ascending dose 
clinical study of BMS-986004 are consistent with the conclusion that BMS-986004 does not
possess platelet activating or other activity associated with the induction of TE. To further 
mitigate the risk of TE in subjects dosed with BMS-986004, a set of primary, accepted markers 
of platelet activation and TE potential will be monitored at frequent intervals and analyzed in 
real-time. Plasma and serum will be collected to monitor the risk and minimize impact of a 
potential TE event. Prothrombin time (PT) and activated Partial thromboplastin time (aPTT) will 
be assessed at screening as measures of a hypercoagulable state. D-dimer and thrombin anti-
thrombin (TAT) in plasma will be quantified as measures of TE risk. Serum troponin I will be 
monitored as an indicator of potentially TE-related subclinical myocardial infarction. Data from 
these primary safety biomarker measurements will be collected and carefully evaluated in the 
context of a thorough review of all available clinical data and used to formulate go/no-go 
decisions prior to dose escalation.
 
 
 
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5.8
Outcomes Research Assessments
Not applicable.
5.9
Other Assessments 
5.9.1
Immunogenicity Assessments
The immunogenic potential of the study medication will be assessed based on levels of anti-
BMS-986004 antibodies.
5.9.1.1
Immunogenicity Sample Collection and Analysis
Serum samples will be collected as described in Table 5.5.1-1. Samples will be assayed for the 
presence of anti-BMS-986004 antibodies by a validated electrochemiluminescence (ECL) 
immunoassay method.
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5.10
Results of Central Assessments
Not applicable.
5.11
Sampling for Medical Research
Where individual subjects have provided separate consent for Medical Research collection, 
residual samples of serum, plasma, RNA and PBMCs will be retained by the BMS Biobank for 
medical research purposes. No additional sampling is required for residual collections. Medical
research collections and retention should be presented to all subjects, except where prohibited by 
local laws or regulations. However, enrollment into the main study is not contingent upon 
consent to participate in future medical research sample banking. 
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)

results in persistent or significant disability/incapacity
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
is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See 
Section 6.1.1 for reporting pregnancies).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

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)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting.
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 3 months of discontinuation of dosing. If applicable, SAEs must be collected that 
relate to any later protocol-specified procedure (eg, a follow-up skin biopsy). 
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The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). The preferred method for SAE data 
reporting collection is through the eCRF.  The paper SAE/pregnancy surveillance forms are only 
intended as a back-up option when the eCRF system is not functioning.  In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
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Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of study exposure, including during at 
least 5 half lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours and in accordance with SAE reporting procedures 
described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
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6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND 
3. 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. 
The key responsibilities for investigators during p-DILI assessment include: (i) Early detection, 
medical evaluation (including the exclusion of other potential causes) and rapid laboratory 
confirmation of liver-related abnormalities, and (ii) Sponsor notification of p- DILI cases via 
SAE forms. Following the gathering and assessment of relevant clinical information the sponsor 
is responsible for: (iii) Timely evaluation and triaging of p-DILI cases, (iv) Expedited reporting 
of p-DILI cases and (v) Expanded review of p-DILI cases including a detailed assessment of all 
available clinical information, investigations and biochemical data.
Investigators are expected to monitor ongoing routine and ad hoc hepatic laboratory test results 
to rapidly determine whether a subject meets p-DILI criteria. They are expected to promptly 
notify BMS of all p-DILI cases. p-DILI cases may be identified by abnormal liver biochemistry 
values, whether or not they are accompanied by liver-related signs and/or symptoms. In both 
cases, expedited confirmation with repeat laboratory testing should occur within 3 business days 
using a Hepatic Laboratory Panel (ALT, AST, TB, AP). Any subject with an abnormal Hepatic 
Laboratory Panel that meets p-DILI criteria is a candidate for study drug discontinuation. Any 
confirmed p-DILI events must be reported (along with a description of the clinical findings) to 
BMS as an SAE within 24hrs of confirmation. 
An extensive clinical history, examination and appropriate investigations should be obtained to 
exclude cholestatic and other apparent causes that may explain the observed abnormalities in 
liver function and/or hepatic signs and symptoms. Other apparent causes include, 
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non-exhaustively and by way of example only: infectious diseases (such as active hepatitis -A, 
-B and -C), congenital diseases (such as Gilbert’s syndrome), neoplastic diseases (such as 
hepatocellular carcinoma), automimmune diseases (such as primary biliary cirrhosis) and the use 
of concomitant hepatotoxic medications (such as antibiotics, the oral contraceptive pill and 
herbal medicines). All investigations to exclude potential causes of liver function abnormalities 
or hepatic signs and/or symptoms should be guided by relevant factors such as the subject’s age, 
gender, clinical history, and signs and symptoms. If necessary, after discussion with Sponsor’s 
safety team, Investigator may perform additional diagnostic tests/procedures to further diagnose 
pDILI (e.g. ultrasound, MRI/MRS, liver biopsy).
6.7
Other Safety Considerations
Any 
significant 
worsening
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
A Data Monitoring Committee (DMC) will perform safety and efficacy assessments at regularly 
scheduled times as well as on an ad hoc basis if needed. The DMC will review relevant safety 
data from preceding Cohorts before the study progresses to the next Cohort. In addition, formal 
DMC monitoring meetings will occur when a maximum of 20 subjects have had at least 6 weeks 
of exposure during the Response Period or 6 months after the first subject is randomized to the 
study (whichever comes first).
Thereafter, DMC monitoring will be performed at approximately 4 month intervals or after each 
additional 10 subjects have had at least 11 weeks of exposure (whichever comes first) until all 
subjects are enrolled into the study. At that time, the DMC will meet every 6 months. With the 
agreement of DMC and BMS this schedule may be modified depending on the rate of subject 
accrual.
The DMC will review safety data including serious adverse events and events of special interest, 
focusing on early signal detection. The DMC will also evaluate the rates of clinical response 
compared to the background rates expected in this study population based on a review of the 
relevant literature. Further details on the content and methods of data reports to the DMC will be 
outlined in the charter of that committee along with the processes and procedures the committee 
will follow. These reviews will be conducted by an internal data monitoring committee made up 
of representatives of the sponsor who are not involved in the day-to-day conduct of the study. 
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The number of subjects is not based on statistical power considerations. If 4 responders are 
observed out of 10 subjects at a dose level, a 90% confidence interval for the response rate is 
(0.15, 0.70).
8.2
Populations for Analyses

All Enrolled Subjects: All subjects who sign an informed consent form.

All Treated Subjects: All subjects who receive at least one dose of study medication, either 
BMS-986004 or placebo.

Pharmacokinetic Subjects: All subjects who receive at least one dose of BMS-986004 and 
have available serum concentration data.
Biomarker Subjects: All treated subjects for whom pharmacodynamic measurements are 
available at both Short Term Day 1 baseline and at least one other time after treatment
LTE:

LTE Analysis Population: All subjects who have received at least one dose of LTE 
medication of 1500 mg.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary objective to establish safety will be measured by the primary endpoints of AEs, 
SAEs, ECG, and laboratory abnormalities including safety biomarkers of d-Dimer and TAT. 
These endpoints will be based on medical reviews of AE reports and the results of vital sign 
measurements, physical examinations, clinical laboratory tests, and ECG parameters including 
heart rate, PR interval, QRS interval, and QTcF interval (QT interval corrected for heart rate).
8.3.2
Secondary Endpoint(s)
The first secondary objective of efficacy will be measured by the following secondary endpoints:

Response Rate (RR): Response rate is defined as the proportion of subjects who are 
responders.
The second secondary objective of assessing pharmacokinetics of BMS-986004 after one and 
multiple doses will be measured by the following secondary endpoints:

Cmax: Maximum observed serum concentration

AUC(TAU): Area under the concentration-time curve in one dosing interval

Ctrough: Trough observed serum concentration

CLT: Total body clearance

AI_AUC: AUC Accumulation Index; ratio of AUC(TAU) at steady state to AUC(TAU) after 
the first dose
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
AI_Cmax: Cmax Accumulation Index; ratio of Cmax at steady-state to Cmax after the first 
dose
 
 
 
 
 
 
8.3.4
Endpoint for the Long Term Extension Period
During the Long Term Extension period, the following endpoints will be assessed cumulatively 
(safety) and over time (efficacy).
8.3.4.1
Primary Endpoints for LTE
The primary objective to establish safety will be measured by the primary endpoints of AEs, 
SAEs, ECG, and laboratory abnormalities including safety biomarkers of d-Dimer and TAT. 
These endpoints will be based on medical reviews of AE reports and the results of vital sign 
measurements, physical examinations, clinical laboratory tests, and ECG parameters including 
heart rate, PR interval, QRS interval, and QTcF interval (QT interval corrected for heart rate).
Response Rate (RR): Response rate at each visit of the LTE is defined as the proportion of LTE 
subjects who are responders on that visit day of the LTE (i.e., achieved or maintained CR or R). 
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Frequency distributions of gender and race will be tabulated. Summary statistics for age, body 
weight, height, and Body Mass Index (BMI) will be tabulated. Prior therapies will be listed and
summarized for each dose.
8.4.2
Efficacy Analyses
Platelet count and change from baseline and fold change from baseline will be listed for all
treated subjects and summarized by panel and visit. Response status will be reported together 
with time to respond, time to peak response, and duration of response. Response rate will be 
provided by panel and treatment phase (response phase or remission phase). Different efficacy 
criteria will be used to evaluate each subject’s responding status.
Bleeding score will be listed for each subject. Bleeding events and the number of subjects 
experiencing any bleeding episode will be summarized by panel.
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8.4.3
Safety Analyses
All recorded adverse events will be listed and tabulated by system organ class, preferred term 
and treatment. Vital signs and clinical laboratory test results will be listed and summarized by 
treatment. Any significant physical examination findings, and clinical laboratory results will be 
listed. ECG readings will be evaluated by the investigator and abnormalities, if present, will be 
listed.
8.4.4
Pharmacokinetic Analyses
PK parameters will be summarized by treatment. Geometric means and coefficients of variation 
will be presented for Cmax (after dose 1 and dose 6), CLT, AUC(TAU), and Ctrough. 
Additionally, scatter plots of Cmax versus dose will be provided to assess the dependency on 
dose. A statistical analysis using a power model will be applied to assess dose proportionality.
8.4.5
Immunogenicity Analyses
Data from the assessment of immunogenicity markers (anti-BMS-986004 antibodies) will be 
listed by subjects. In addition, immunogenicity data will be listed separately for all the subjects 
who have at least one positive assay. Number and frequency of positive subjects will be 
summarized by dose. Definition of different positivity will be available in the study’s Statistical 
Analysis Plan (SAP).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.4.8
Long Term Extension Analyses 
Similar and appropriate analyses (demographics and baseline characteristics, efficacy analyses, 
safety analyses, etc) will be conducted for the LTE analysis population when applicable. The 
analyses for the LTE analysis population are descriptive in nature.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4.10
Outcomes Research Analyses
Not applicable.
8.4.11
Other Analyses 
8.4.11.1
Immunogenicity Analysis
Serum samples will be assayed for the presence of anti-BMS-986004 antibodies. The incidence 
of a positive response will be summarized by treatment group. Similar work will be performed 
for the Long Term Extension.
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8.4.11.2
Population PK Analysis
Modeling analysis of PK and/or exposure-response analysis of BMS-986004 will be conducted 
using a population approach as appropriate and reported separately from the clinical study report.
8.5
Interim Analyses
Data emerging from each panel of this exploratory study may be used for timely decisions about 
adjustments to procedures in subsequent panels, including but not limited to, dose of next higher 
panel, an intermediate dose, and early termination of the study. No formal inferences requiring 
any adjustment to statistical significance level will be performed. 
Models, including but not limited to Bayesian logistic regression, Bayesian EMax, and linear or 
nonlinear regression models, will be examined and built to predict a dose to achieve certain 
efficacy outcomes such as desired response rate or platelet count. Exposure data or PK 
parameters may be included in the model. Efficacy data obtained during the remission phase 
after a subject has been intra-subject dose escalated to a titration dose may be used to provide 
robust and reliable prediction. Timing of dose prediction could be as early as efficacy results 
becoming available for an enough number of subjects treated in the second cohort. Refer to 
Appendix 2 for more discussions and some simulation results. 
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
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currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
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 BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
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BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product.
Records or logs must comply with applicable regulations and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
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The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form The investigator must retain 
a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. For this protocol, the 
Signatory Investigator will be selected as appropriate based on subject recruitment and 
enrollment into the study.
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete 
Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have 
pregnancy tests.  Acceptable alternate methods of highly 
effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete 
abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle 
of the patient. This does not mean periodic abstinence (e.g., 
calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of 
contraception. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
Medical Research
Those scientific activities which cannot be reasonably 
anticipated at the time of trial design, for which we would 
like to collect and/or retain samples from study participants.  
Examples of Medical Research include, but are not limited 
to, new assay development and validation, companion 
diagnostic development, new hypotheses in the interaction of 
drug and the human body, and exploration of emerging 
science in the understanding of disease.
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11
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ACLS
advanced cardiac life support
AI
accumulation index
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
%BE
percent biliary excretion
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BRt
Total amount recovered in bile
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Term
Definition
%BRt
Total percent of administered dose recovered in bile
BUN
blood urea nitrogen
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLD
Dialysate clearance of drug from plasma/serum
CLNR
nonrenal clearance
CLR
renal clearance
CLT
total body clearance
CLT/F (or CLT)
apparent total body clearance
CLT/F/fu 
or 
CLT/fu
Apparent clearance of free drug or clearance of free if (if IV)
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctrough
Trough observed plasma concentration
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Term
Definition
CV
coefficient of variation
CYP
cytochrome p-450
D/C
discontinue
dL
deciliter
DRt
Total amount recovered in dialysate
%DRt
Total percent of administered dose recovered in dialysate
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
EA
extent of absorption
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
eg
exempli gratia (for example)
ESR
Expedited Safety Report
F
bioavailability
Fb
fraction of bound drug
FDA
Food and Drug Administration
FI
fluctuation Index ([Cmax-Ctau)/Cavg])
FRt
total amount recovered in feces
%FRt
total percent of administered dose recovered in feces
FSH
follicle stimulating hormone
%FE
percent fecal excretion
fu
fraction of unbound drug
g
gram
GC
gas chromatography
GCP
Good Clinical Practice
G criteria
adjusted R2 value of terminal elimination phase
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
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Term
Definition
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3
-
bicarbonate
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
kg
kilogram
z
terminal disposition rate constant
L
liter
LC
liquid chromatography
LDH
lactate dehydrogenase
ln
natural logarithm
Lz_Start
The time point starting the log-linear elimination phase defining ther 
terminal half life
Lz_End
The time point ending the log-linear elimination phase defining the 
terminal half life
Lz_N
Number of time points in the log-linear elimination phase defining the 
terminal half life
mg
milligram
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Term
Definition
Mg++
magnesium
MIC
minimum inhibitory concentration
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR
medical research
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for 
molecular weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for 
molecular weight
MR_AUC(TAU)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for 
molecular weight
MR_Cmax
Ratio of metabolite Cmax to parent Cmax, corrected for molecular 
weight
MR_Ctau
Ratio of metabolite Ctau to parent Ctau, corrected for molecular weight
MRT
mean residence time
MS
mass spectrometry
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
pAUCe
Extrapolated partial AUC from last quantifiable concentration to infinity
Pb
percent of bound drug
PD
pharmacodynamics
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PT
prothrombin time
PTT
partial thromboplastin time
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Term
Definition
Pu
percent of unbound drug
QC
quality control
QD, qd
quaque die, once daily
R2
coefficient of determination
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
sp.
species
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF
Half life
T-HALFeff_AUC
Effective elimination half life that explains the degree of AUC 
accumulation observed
T-HALFeff_Cmax
Effective elimination half life that explains the degree of Cmax 
accumulation observed)
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
UR
urinary recovery
%UR
percent urinary recovery
URt
total amount recovered in urine
%URt
total percent of administered dose recovered in urine
UV
ultraviolet
Vss/F (or Vss)
apparent volume of distribution at steady state
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
W
washout
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Term
Definition
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity
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APPENDIX 1
ADAPTIVE EARLY DECISON FOR DOSE PANEL ESCALATION
Introduction
A model-based cohort escalation rule is established to help decide on opening the next cohort for 
newly enrolled subjects when current cohort is filled but not all of its subjects are monitored for 
2 whole weeks regarding drug toxicity and tolerability. The decision rule would allow treating 
subject, once available, at the next cohort without waiting for the completion of every subject’s 
AE evaluation period at the current cohort and at the same time keeping decision risk acceptably 
low.
Please note that AE would be closely monitored throughout the trial for each subject, and the 2 
weeks’ AE evaluation period mentioned here is for the purpose of cohort escalation only. During 
the evaluation period, the numbers of subjects who developed drug-related SAE within the same 
organ system at grade 3 or higher, called AE of interest are counted and the largest number will 
be used.
Decision Risk
The decision risk is mathematically defined as the probability of observing enough number of 
event(s) in the still non-evaluable subjects given data collected from evaluable subjects such that 
cohort escalation is not allowed. Evaluable subjects are those who are observed an AE of interest 
or complete the AE evaluation period. To enroll subject into the next cohort, the non-adaptive 
cohort escalation rule requires, among others, no more than one subject being reported drug-
related serious adverse event or serious infection and infestation within the evaluation period. 
Therefore, if one subject is observed with an AE of interest, the decision risk would be the 
probability of observing at least one more AE of interest in the non-evaluable subjects; if no AE 
of interest is reported, the decision risk is thus the probability of observing at least two AEs of 
interest from the non-evaluable subjects.
Decision Data
To take advantage of the titration design, in which subjects could possibly take a higher dose that 
is to be used initially in the next cohort, the adaptive decision rule makes use of the following 
three statistics: 

Titration-Dose Evaluable Subjects (nH): the number of subjects who are titrated and 
complete the evaluation period (2 weeks) starting from the titration’s first dose (on day 43).

Start-Dose Evaluable Subjects (nL): the number of subjects who develop drug related SAE at 
grade 3 or higher or complete the evaluation period (2 weeks) from the first dose (on day 1) 
but haven’t completed the 2 weeks evaluation period following the first titration dose (on day 
43) if being titrated to a higher dose.

Count of AE of Interest (k): number of subjects with AE of interests, which could happen 
any time after the first dose of BMS-986004 till the decision making day. Apparently, k=0 or 
1. Please note that it doesn’t distinguish at which stage, prior to or post titration, that such AE 
happened.
With sample size of 10 for each cohort, the number if non-evaluable subjects is 10-nH-nL.
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Decision Risk Estimation
Calculation of decision risk is based on the method of Bayesian constrained rate estimate with 
ascending beta prior. It assumes that the rate of AE of interest increases with doses, however, no 
specific mathematical form is given governing the relationship between dose and rate. In this 
way, robustness is achieved by avoiding possible model misspecification. It also assumes that 
rate depends on the maximum dose subject takes, i.e., titrated subjects are equally likely in 
developing AE of interest as subjects who take the titrated dose right in the beginning. The prior 
information is solicited from a phase III study of Abatacept IM101174, in which 12 out 721 
subjects (1.7%) were reported to experience drug related SAEs within short term period (half 
year treatment). The prior used is Beta(0.01, 0.49), which indicates 2% rate and is equivalent of 
contributing 0.5 subject at each dose.
Decision risk for k=1 is listed below (values are provided only for when the number evaluable 
subjects, nH+nL, is at least 5, and at most 9). Bayesian MCMC simulation is performed to 
compute the posterior predictive probability under R version 3.1.0 with a random seed of 
20140625.
Titration-Dose 
Evaluable 
Subjects (nH)
Start-Dose Evaluable Subjects (nL)
1
2
3
4
5
6
7
8
9
0
43.2
34.1
25.4
16.6
8.3
1
38.6
30.0
22.7
14.6
7.2
2
36.0
29.1
21.1
13.9
6.8
3
34.9
27.4
20.0
13.1
6.5
4
33.9
25.9
19.3
12.9
6.2
5
25.7
19.3
12.5
6.0
6
18.4
11.9
5.9
7
11.8
5.7
8
5.7
When k=0, decision risk is close to zero, therefore not provided.
Minimum safety requirement:
Other conditions, as listed below, have to meet to open a new cohort
There must be at least 5 evaluable subjects
The start dose of the new cohort or a higher dose must be shown tolerated in the IM140-002 
study if such dose was or will be tested.
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Decision Rule
Decision rule is derived by comparing decision risk to a pre-selected threshold value when the 
current cohort is filled and a newly enrolled subject is available to be allocated to the next cohort. 
If decision risk is less than the threshold value, the subject will be treated at the next cohort 
(denoted as E in the following table), otherwise, the subject need to wait for more evidence 
coming up (denoted as W). 
An example of decision rule for k=1 is shown below with decision risk being 15%.
Titration-Dose 
Evaluable 
Subjects (nH)
Start-Dose Evaluable Subjects (nL)
1
2
3
4
5
6
7
8
9
0
W
W
W
W
W
W
W
W
E
1
W
W
W
W
W
W
E
E
2
W
W
W
W
W
E
E
3
W
W
W
W
E
E
4
W
W
W
E
E
5
W
W
E
E
6
W
E
E
7
E
E
8
E
Decision rule for k=0 is same as the Minimum safety requirement for any reasonable small 
threshold value.
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APPENDIX 2
ADAPTIVE DOSE SELECTION
Introduction
Bayesian logistic regression model is used to predict an adaptive dose for a given response rate. 
Simulations of both logistic regression and Bayesian logistic regression are provided to show 
their performance in predicting dose for pre-selected response rate. New method of analyzing 
data obtained from the study with titration design is also included. More detailed discussion will 
be available in the study’s statistical analysis plan (SAP).  
Adaptive dose selection is not limited to the Bayesian logistic regression model described in this 
appendix. Alternative modeling includes, for example, nonlinear or linear mixed effect 
regression of longitudinal platelet count. Specifically, when PK exposure data are available, 
model based on PK exposure may be a better choice than that on dose only since there are only a 
few distinct values of doses. 
Adaptive dose selection can be performed as early as when the third cohort is about to enroll 
subjects. However, it is advised that the predicted dose would be more reliable when more data 
are available, e.g., when the fourth cohort is about to enroll. For safety reasons, the selected dose 
to be administered at a higher cohort cannot be larger than what is planned for that cohort.
Bayesian Logistic Model Description
The model is described below:
where, at each dose level i, di is dose in mg, pi is the expected response rate, ni is the number of 
subjects treated at dose di, and yi is the number of responders. Model parameters β are assumed a 
normal distribution with mean μ and variance ψ. Explaining variable, dose, is in log scale, and is 
subtracted by an offset of log(75), where 75 is the minimum dose administered at cohort 1. By 
subtracting such an offset value, intercept parameter μ alone can be interpreted as the log odd 
value of the expected response rate for cohort 1, and as such it is easy to set prior distribution 
parameters (shown below).
Prior of the model parameters is set under the following guidelines:

Model-predicted response rate at each dose level matches the expected rate.

A 97.5% quantile of the response rate at the lowest dose is around 0.4.

A 2.5% quantile of the response rate at the highest dose is around 0.35.

Extremely small probability for β2 being negative




















,
~
,
Binomial
~
))
75
log(
)
(log(
1
log
1
0
1
0






N
p
n
y
d
p
p
i
i
i
i
i
i
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It is assumed that the response rate at dose of 75mg, 225mg, 675mg, and 1500mg to be 0.2, 0.4, 
0.55 and 0.7 respectively. A linear regression using the above data will give prior mean μ to be ( 
-1.33, 0.72) with rounding error. The second and third bullets of the guidelines would make the 
stand deviation of β1 to be 0.45, and β2 to be 0.2. Prior distributions of β1 and β2 are assumed to 
be independent. A 95% credible interval of response rates under prior and without observation 
data is shown in Figure 1, where the top curve is the upper 97.5% quantile, the center is the 
mean, and the bottom is the lower 2.5% quantile. The circles represent the expected response 
rates at the selected doses. It can be seen that the chosen prior would lead to a mean response rate 
estimate being very close to the expected or assumed, and at the same time the wide region of 
95% credible interval indicates that the prior’s weak impact on the posterior estimation of 
response rate when data are observed.
Figure 1:
95% Credible Interval of Response Rate under Prior Only
Special consideration for titration
Non-responders at each cohort other than the maximum 1500mg cohort would be administered 
higher dose with the hope of becoming responders. Therefore, two response status data may be 
observed for those non-responders. Due to relative small sample size of each cohort, making use 
of status data after the titration dose is believed to increase the accuracy of model-based 
prediction under some reasonable assumptions. Listed in the below are two assumptions used in 
the adaptive dose selection:

If a subject responses to a dose, the subject would respond to higher dose with probability 1.
200
400
600
800
1000
1200
1400
0.0
0.2
0.4
0.6
0.8
1.0
dose (mg)
response rate
o
o
o
o
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
If a subject does not respond to a dose after 3 administrations, additional dosing at the same 
dose would not make a subject change from non-responder to responder.
Based on the above assumptions, a new approach is proposed to combine the subjects at two 
adjacent cohorts to estimate the response rate at the higher dose which is shared by the two 
cohorts.
Simulation
Trial simulation is done to show the performance of logistic regression and Bayesian logistic 
regression with starting dose data only or with titration data included. The Settings of simulation 
parameters are listed below for convenience:

Doses: 75, 225, 675, 1500

Rate: 0.2, 0.4, 0.55, 0.7

Conditional response rate for non-responder after titration:0.25, 0.25, 0.33

Response rate used to predict dose: 0.7 (equivalently the fourth cohort)

Number of simulated trials: 1000
Prediction results from four different methods are compared with each other.

SLogit: Logistic regression with response status from starting dose only

SBayLogit: Bayesian logistic regression with response status from starting dose only

DLogit: Logistic regression with response status from both starting dose and titration dose

DBayLogit: Bayesian logistic regression with response status from both starting dose and 
titration dose
Simulation results are shown in Figure 2. It can be seen that Bayesian modeling provides less 
variant and seemingly closer-to-true-value predictions compared to the usual logistic regression. 
In addition, variation of the predicted dose is smaller by including titration data when same 
modeling is used.
Figure 2:
Predicted Dose from Different Methods
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APPENDIX 3
INTERPRETATION OF HEPATITIS B SEROLOGICAL TEST
RESULTS
As our study drug is expected to demonstrate immunosuppressive effects, we find it necessary to 
carefully evaluate and exclude subjects with potentially active Hepatitis B infection. For this 
reason, in order to fully evaluate subject’s eligibility for enrollment, Exclusion Criterion 3f  
requires interpretation of data from three standard tests for hepatitis B i.e. measurement of 
hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs) and Hepatitis B 
core antibody (anti-HBc).
Subject’s eligibility for enrollment should be assessed as described below: 

Subjects that are negative for all three markers are allowed into the study

Subjects that are HBsAg (neg), anti-HBc (neg) and anti-HBs (pos) are allowed into the 
study (immunized subjects)

Subjects that are HBsAg (neg), anti-HBc (pos) and anti-HBs (pos) are allowed into the 
study (Hep B immune most likely due to natural exposure) 

Subjects that are HBsAg (pos) are excluded from the study

Subjects that are HBsAg (neg), anti-HBc (pos) and anti-HBs (neg) may be included after 
additional discussion with Medical Monitor in order to evaluate subject’s full clinical 
status and medical history. 
Please also refer to the below “Interpretation of Hepatitis B Serologic Test Results” provided by 
the Department of Health and Human Services, CDC.  
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