Longitudinal Assessment of Cardiovascular and Renal Health in Patients With Hepatitis-C (CARE-Hep C)
Conditions: Hepatitis C
Sponsor: Duke University

CONFIDENTIAL 
This document is confidential and the property of Duke Clinical Research Institute (DCRI). No 
part of it may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the DCRI. This document may be disclosed to the appropriate IECs / 
IRBs or to duly authorized representatives of the US Food and Drug Administration or other 
regulatory authority under the condition that they maintain confidentiality. 
Observational Study Protocol 
Longitudinal Assessment of Cardiovascular and Renal Health 
in Patients with Hepatitis-C (CARE-Hep C) 
Protocol Version/ Date:  Version 3.0, September 18, 2013 
Sponsor: 
Bristol-Myers Squibb 
Principal Investigator: 
Adrian Hernandez, MD, MHS 
Associate Professor of Medicine, Cardiology 
Director, Outcomes Research  
Associate Director, Duke Clinical Research Institute 
Co-Investigators: 
Pamela Douglas, MD, MACC, FASE 
Professor of Medicine, Cardiology 
Director, Cardiovascular Imaging Program 
Duke Clinical Research Institute 
Andrew Muir, MD, MHS 
Associate Professor of Medicine, Gastroenterology 
Director, Gastroenterology and Hepatology Research 
Duke Clinical Research Institute 
Tariq Ahmad, MD, MPH 
Fellow, Cardiovascular Research 
Duke Clinical Research Institute 
NCT01846494

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PROTOCOL SYNOPSIS  
Protocol Title 
Longitudinal Assessment of Cardiovascular and Renal Health 
in Patients with Hepatitis-C (CARE-Hep C) 
Indication 
Increased risk of cardiac and renal dysfunction may be associated with 
investigational drug (BMS-986094) 
Location 
Approximately 16 US sites where Phase 1 and Phase 2 studies of BMS-986094 
were conducted and sites where those subjects have been or will be further 
evaluated.   
Brief Rationale 
 
 
 
 
BMS-986094 is a hepatitis C virus (HCV) NS5B nucleotide analog polymerase 
inhibitor that was developed for the treatment of chronic HCV infection. It was 
administered to subjects as part of a Phase 1 multiple-dose study, as well as a 
12-week study looking at combination therapy in HCV-infected subjects (Phase 
2; Part A, and Part B). During follow-up, cases of cardiac and renal dysfunction 
were identified and subjects were discontinued on study drug. The purpose of 
this study will be to monitor the cardiovascular and renal health of subjects 
exposed to the study medication and characterize subjects’ clinical status in 
comparison to a cohort of HCV-infected patients without exposure to 
BMS-986094.  
Study Design 
 
This will be a multi-center, prospective, observational study designed to assess 
the cardiovascular and renal health of study participants. The study will enroll 
up to 500 subjects, including 291 of the subjects previously exposed to 
BMS-986094 in the Phase 1 or Phase 2 studies of BMS-986094 and 
approximately 200 control subjects that include subjects with hepatitis C 
without exposure to BMS-986094 and those who received placebo in the 
BMS-986094 studies (N=50). Study participants will be followed for presence 
of cardiac or renal dysfunction via regularly scheduled clinical- and 
telephone-based assessments. The follow-up period will be up to 5 years.  
Objectives 
To assess the longitudinal cardiovascular and renal health of subjects exposed 
to BMS-986094.  
Abbreviated 
Study Flow 
Written informed consent will be obtained prior to inclusion in this study.  
After consent, the following will be obtained at baseline: medical history, 
physical examination, current medications, comprehensive metabolic panel, 
complete blood counts, cardiovascular, renal and hepatic biomarkers (blood 
and urine based), electrocardiogram (ECG), and transthoracic echocardiogram 
(TTE). 
Telephone interviews will be performed at regularly scheduled intervals, 
during which a health status survey will be administered and the subject will 
be assessed for interim changes in health status including hospitalizations and 
clinic visits.   
The subjects will visit the site for regularly scheduled visits for continued 
clinical assessments of cardiovascular, renal and liver abnormalities with 
laboratory measurements, ECGs, and TTEs.  
If a subject is found to have any evidence of cardiac or renal dysfunction, they 
will be referred to a cardiovascular or renal specialist.  

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There may be a few subjects who do not have a study site and who will be 
followed by phone only.  

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Investigator Protocol Signature Page 
 
I have read and understand the protocol and agree that it contains all the ethical, legal, and scientific 
information necessary to conduct this study. I will personally conduct the study as described. I will 
provide copies of the protocol to all physicians, nurses, and other professional personnel responsible to 
me who will participate in the study. I am aware that this protocol must be approved by the Institutional 
Review Board or Ethics Committee. I agree to adhere strictly to the attached protocol. I agree that 
clinical data entered on case report forms by me and my staff will be supplied to the DCRI and may be 
utilized by the DCRI in various ways such as for submission to governmental regulatory authorities 
and/or in combination with clinical data gathered from other research sites, whenever applicable. I 
agree to allow DCRI monitors and auditors full access to all medical records at the research facility for 
subjects screened or randomized in the study. I agree to provide all subjects with informed consent 
forms, as required by government regulations and International Conference on Harmonization 
guidelines. 
 
I, the undersigned, have read and approve this protocol and agree on its content. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator (print name) 
 
 
Site Name and Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator (signature) 
 
 
Date 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS............................................................................................................. 2 
INVESTIGATOR PROTOCOL SIGNATURE PAGE .............................................................. 4 
TABLE OF CONTENTS .............................................................................................................. 5 
LIST OF FIGURES AND TABLES ............................................................................................ 7 
LIST OF ABBREVIATIONS ........................................................................................................ 8 
1. 
INTRODUCTION AND STUDY RATIONALE ............................................................... 10 
1.1 
Background Information ................................................................................................... 10 
1.2 
Study Rationale ................................................................................................................. 13 
2. 
OBJECTIVES ..................................................................................................................... 14 
2.1 
Primary Objective .............................................................................................................. 14 
3. 
STUDY DESIGN AND DURATION ................................................................................ 15 
3.1 
Overview of Study Design ................................................................................................ 15 
3.2 
Study Population ............................................................................................................... 15 
3.2.1 Inclusion Criteria ................................................................................................... 15 
3.2.2 Exclusion Criteria .................................................................................................. 15 
3.2.3 Discontinuation of Subjects from Study ............................................................ 16 
4. 
STUDY PROCEDURES ................................................................................................... 17 
4.1 
Summary of Procedures ................................................................................................... 17 
4.2 
Schedule of Assessments ................................................................................................ 17 
4.3 
Study Site Visits ................................................................................................................. 20 
4.3.1 Baseline (Initial Visit) ............................................................................................ 20 
4.3.2 Follow-up ............................................................................................................... 20 
4.4 
Telephone Interviews with Health Status Survey ......................................................... 20 
4.5 
History and Physical.......................................................................................................... 21 
4.6 
Routine Laboratory Assessments ................................................................................... 21 
4.7 
Biomarker Assessment ..................................................................................................... 21 
4.8 
Electrocardiograms and Echocardiograms ................................................................... 22 
4.9 
Evidence of Cardiac Dysfunction .................................................................................... 23 
4.10 
Evidence of Renal Dysfunction ....................................................................................... 23 
4.11  Hospitalizations .................................................................................................................. 24 
4.12 
Subject Withdrawal ........................................................................................................... 24 

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4.13 
DCRI Call Center Follow-up only .................................................................................... 24 
5. 
SAFETY EVALUATIONS ................................................................................................. 25 
5.1 
Definitions ........................................................................................................................... 25 
5.1.1 Adverse Events ..................................................................................................... 25 
5.1.2 Serious Adverse Events ...................................................................................... 25 
5.2 
Collection of Adverse Events ........................................................................................... 25 
5.3 
Assessment of Serious Adverse Events ........................................................................ 25 
5.3.1 Assessment of SAE  Severity ............................................................................. 25 
5.3.2 SAE Collection and reporting ............................................................................. 26 
5.3.3 Laboratory Test Abnormalities ........................................................................... 26 
5.3.4 Follow-up of SAEs ................................................................................................ 26 
5.4 
Expedited events/ SUSAR ............................................................................................... 26 
6. 
STATISTICAL CONSIDERATIONS ............................................................................... 27 
6.1 
Population for Analysis ..................................................................................................... 27 
6.2 
Statistical Analysis ............................................................................................................. 27 
6.3 
Primary Objective and Endpoints .................................................................................... 27 
7. 
STUDY RESPONSIBILITIES .......................................................................................... 28 
7.1 
Compliance with the Protocol and Protocol Revisions ................................................ 28 
7.2 
Training ............................................................................................................................... 28 
7.3 
Monitoring ........................................................................................................................... 28 
7.4 
Remote Monitoring and Site Training ............................................................................. 28 
7.1 
Audits/Inspections ............................................................................................................. 28 
7.2 
Clinical Study Report and Subsequent Publications .................................................... 29 
7.3 
Study Closeout ................................................................................................................... 29 
8. 
ETHICAL CONSIDERATIONS........................................................................................ 30 
8.1 
Ethics and Good Clinical Practice ................................................................................... 30 
8.2 
Institutional Review Board/Independent Ethics Committee ........................................ 30 
8.3 
Informed Consent .............................................................................................................. 30 
8.4 
Observational Study Monitoring Board .......................................................................... 31 
8.5 
Study Documentation........................................................................................................ 31 
8.6 
Source Documentation ..................................................................................................... 31 
8.7 
Modification of the Protocol.............................................................................................. 32 
8.8 
Deviations to the Protocol ................................................................................................ 32 
 

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LIST OF FIGURES AND TABLES 
TABLE 1 
PHASE 1 AND PHASE 2 STUDIES OF BMS-986094 ................................... 12 
TABLE 2 
SCHEDULE OF ASSESSMENTS ...................................................................... 18 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
BMS 
Bristol Myers Squibb 
BNP 
B‐type Natriuretic Peptide 
BUN 
blood urea nitrogen 
CMP 
comprehensive metabolic panel 
Cr 
creatinine 
DCRI 
Duke Clinical Research Institute 
DCV 
daclactasvir 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCRF 
electronic Case Report Form 
EC90 
90% maximal effect 
EDC 
electronic data capture 
EF 
ejection fraction 
HCV 
hepatitis C virus 
HCV RNA 
hepatitis C virus ribonucleic acid  
HR 
heart rate  
hs-cTn 
high sensitivity cardiac troponin 
HV 
healthy volunteer 
IRB 
institutional review board 
JVP 
jugular venous pressure 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
MRI 
magnetic resonance imaging 
NS5B 
nonstructural protein 5B 
OSMB 
Observational Study Monitoring Board 
PegIFN α 
pegylated interferon alpha 
P-gp 
P-glycoprotein 
PMI 
point of maximal impact 
QD 
once daily 

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RBV 
ribavirin 
RdRp 
ribonucleic acid (RNA)-dependent RNA polymerase 
RGT 
response-guided therapy 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
TTE 
transthoracic echocardiogram 
 
 
 

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1. INTRODUCTION AND STUDY RATIONALE  
1.1 
Background Information 
BMS-986094 (previously known as INX-08189) is a novel nucleotide analogue polymerase inhibitor 
developed for the treatment of chronic hepatitis C virus (HCV) infection. BMS-986094 inhibits the HCV 
ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), encoded by nonstructural protein 5B (NS5B). 
In replicon cell culture systems, BMS-986094 was found to be a highly potent inhibitor of replication 
with a concentration resulting in 90% maximal effect (EC90) of 0.038 M against HCV genotype (GT)-1. 
BMS-986094 has similar potency against HCV across all genotypes tested. Combination studies using the 
replicon assay have suggested that BMS-986094 can be dosed with other HCV-targeting inhibitors with 
additive and/or synergistic responses.  
BMS-986094 has been tested in healthy volunteers (HVs) and HCV-infected individuals (Table 1). To 
date, 293 subjects have received at least 1 dose of BMS-986094; of these, 291 subjects are alive. The 
Phase 1 studies included both HVs and HCV-infected subjects, with favorable safety profiles. In the HVs, 
single doses (up to 100 mg) and multiple doses (50 mg once daily [QD] for 7 days), were used, and no 
clinically relevant trends in adverse events (AEs), vital sign changes, electrocardiogram (ECG) changes, 
physical examinations, or laboratory values, have been noted. There have been no deaths in the Phase 1 
studies. Two serious adverse events (SAEs) noted were not felt to be related to study drug. Two of the 
Phase 1 studies, BMS-986094 monotherapy (up to 200 mg QD) and BMS-986094 (up to 100 mg) in 
combination with Ribavirin (RBV) for 7 days, had a favorable safety profile in subjects with HCV. There 
were no clinically relevant trends in AEs, vital sign changes, ECG changes, physical examinations, or 
laboratory values. Also, there were no deaths. One subject (placebo + RBV group), who had a history of 
hypertension and atrial fibrillation experienced an SAE of atrial fibrillation. Another subject 
(BMS-986094 200 mg group) with a medical history of seizure disorder had an AE (seizure; not related to 
BMS-986094 by investigator assessment) that led to discontinuation of study drug. Most AEs were mild 
in intensity. 
In the Phase 2 study (AI472003), BMS-986094 (25, 50, and 100 mg) was dosed in combination with 
pegylated interferon (PegIFN α ) and ribavirin (RBV) for 12 weeks in Part A, at doses of 50, 100, and 
200 mg with or without daclactasvir (DCV, BMS-790052) and/or RBV for 12 weeks in Part B (Table 1). 
Bristol Myers Squibb (BMS) suspended all subject dosing on August 1, 2012 after notification of a SAE of 
heart failure that occurred during the trial and led to the demise of the subject. Subsequently, several 
other potential cases of drug-related cardiac and renal toxicity were identified. At time of study 
discontinuation, 79 subjects in Part A of the study had completed 12 weeks of dosing with BMS-986094 
(combined with PegIFN α/RBV), while 34 subjects in Part B had received 1 to 6 weeks of BMS-986094 
(combined with RBV and/or daclatasvir, a first in class HCV NS5A replication complex inhibitor in Phase 3 
development). The majority of subjects with evidence of cardiac and renal dysfunction are from Part B 
of the Phase 2 clinical trial (AI472-003). Since then, retrospective evaluation of subjects in Part A of 
Study AI472-003 has identified additional cases of interest. No definitive evidence of cardiac or renal 
dysfunction has yet been identified in the Phase 1 subjects, but comprehensive evaluations are ongoing. 

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Subsequent to identification of the potential cardiac and renal toxicity of BMS-986094, BMS has been 
working in close collaboration with the FDA and clinical study investigators to conduct comprehensive 
safety assessments and close follow-up of all BMS-986094 study subjects. Duke Clinical Research 
Institute (DCRI) is creating an observational registry of subjects who were exposed to BMS-986094 for 
purposes of understanding the incidence of cardiac and renal dysfunction associated with the study drug 
and facilitating referral to subspecialists when appropriate.   

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Table 1 
Phase 1 and Phase 2 Studies of BMS-986094 
Study Treatments 
Study  
Number 
Phase 1 Studies 
Active 
Treatment 
Subjects 
Placebo 
Subjects 
Single dose:  
094 alone 
INH-189-001 
(1 day dosing; 3, 9, 25, 50, 100 mg of 094) 
 Single Ascending Dose Study in 
Healthy Volunteers 
32 
10 
Multiple dose: 
094 (or PBO) alone,  
 
or  
094 (or PBO) + RBV 
INH-189-002 
(7 days dosing; 9, 25, 50, 100 mg of 094) 
 7-Day Multiple Dose Study in GT1 HCV 
Subjects  
(5 cohorts: 094 monotherapy/  
 2 cohorts:  094 in combination with RBV) 
56 
14 
Multiple dose: 
094 (or PBO) alone,  
 
or 
094 (or PBO) + 
Victrelis (boceprevir) 
INH-189-004 
(5 - 8 days dosing; 50 mg of 094) 
 Drug-Drug Interaction Study with 
Victrelis (boceprevir) in Healthy 
Volunteers 
28 
4 
Day 0:  
Single dose 094; 
Days 6 – 11:  
 verapamil HCl ER QD 
Day 12:  
Single dose 094 + 
verapamil HCl ER 
INH-189-005 
(single sequence:  
094 50 mg x1 on Day 0,  
verapamil 240 mg QD on Days 6 - 11, then 
094 + verapamil on Day 12) 
 Drug-Drug interaction Study with  
P-gp inhibitor (verapamil ER)  
in Healthy Volunteers 
24 
0 
Multiple dose: 
094 alone or 
094 + RBV 
INH-189-006 
(7 days dosing; 100, 200 mg of 094) 
 7 Day Multiple Dose Study in GT1 HCV 
Subjects (Additional work on dose 
response and effect of food) 
40 
10 
Study Treatments 
Study  
Number 
PHASE 2 
Active 
Treatment 
Subjects 
Placebo 
Subjects 
Multiple dose: 
094 added on to 
pegIFNα + RBV 
INH-189-003/ 
A1472003 
(Part A, GT 2/3 –  
12 weeks, RGT + 25, 50, or 100 mg of 094) 
79 
12 
(Part B, GT 2/3 and GT1–  
dosing interrupted;  
50, 100, 200 mg of 094) 
34 
0 
 
 
 Efficacy Study in GT 2/3 and GT1 
Treatment-Naïve Subjects 
 
 
Definitions: PBO=placebo; mg=milligrams; 094=BMS-986094; GT1=HCV genotype 1; HCV=hepatitis C virus; 
RBV=ribavirin; P-gp=P-glycoprotein; ER=extended release; RGT=response-guided therapy; GT2/3=HCV genotype 2 or 
3. 

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1.2 
Study Rationale 
To describe cardiovascular and renal health among subjects exposed to BMS-986094 and to monitor 
their liver disease, a registry is being created that will enroll and follow subjects who were exposed to 
BMS-986094 and still alive, as well as subjects either with known HCV infection who have no history of 
exposure to BMS-986094, including  subjects in the prior studies who received placebo. The aims of this 
study are to (1) perform frequent evaluations for the detection of cardiac and renal dysfunction and (2) 
arrange for appropriate referral if evidence of dysfunction is found. This study will include those subjects 
within the Phase 1 trials with varying amounts of exposure (N=180), as well as both Part A (79) and Part 
B (34) of the Phase 2 trial.  
These evaluations will consist of a phone call screening for symptoms, physician visits for medical 
histories, physical examinations, laboratory testing, ECGs, and transthoracic echocardiograms (TTEs) to 
screen for evidence of cardiac dysfunction. Referrals to cardiologists and nephrologists at pre-specified 
centers may be facilitated, based on these results.  

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2. OBJECTIVES 
2.1 
Primary Objective 
To describe the longitudinal cardiovascular and renal health of subjects exposed to BMS-986094.    
Overall Risk Benefit 
No study drug(s) will be administered and no experimental procedures will be performed as part of this 
study. The procedures performed in this protocol will include clinical screens for signs and symptoms of 
cardiovascular or renal disease, and medical procedures that include phlebotomy, ECGs, and TTEs. These 
procedures have minimal associated risk, and will inform subjects of their cardiovascular status; thus, 
the benefits of inclusion into the study are expected to outweigh the risks. 

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3. STUDY DESIGN AND DURATION 
3.1 
Overview of Study Design 
This will be a multi-center, prospective, observational study designed to assess the cardiovascular and 
renal health of previous BMS-986094 study participants who received study drug in comparison to HCV 
infected subjects without exposure to BMS-986094, as well as participants in the prior studies who 
received placebo (some of whom were healthy controls).  Study participants will be followed via 
regularly scheduled site and telephone based assessments. The follow-up period will be up to 5 years 
from last inclusion in the registry. This registry is designed to be observational and the clinical 
management of these subjects remains the responsibility of the usual care physician. 
The schedule of assessments is summarized in Table 2. 
3.2 
Study Population 
3.2.1 
Inclusion Criteria 
Subjects will be enrolled based on prior enrollment in the BMS-986094 studies or treatment-naïve 
HCV subjects with no known cardiovascular abnormalities. 
1. All Subjects must give informed consent prior to participation in the study.  
2. Subject participated in the Phase 1 or Phase 2 trials with BMS-986094 (including placebo arm) 
 
 
 
OR 
3. Subject with known hepatitis C (Control) 
a. No previous exposure to BMS-986094 
b. Treatment naive at study entry (No prior hepatitis C treatment experience at the time 
of enrollment, including but not limited to: standard interferon, pegylated interferon, 
ribavirin, boceprevir, telaprevir, or other experimental drugs for hepatitis C). 
 
3.2.2 
Exclusion Criteria  
1. For subjects who participated in the Phase 1 or Phase 2 trials with BMS-986094, there are no 
exclusion criteria  
2. For the control group of subjects without exposure to BMS-986094, the following exclusion 
criteria, based on clinically available data, apply: 
a. Signs or symptoms of decompensated liver disease such as variceal bleeding, ascites, 
hepatic encephalopathy, active jaundice defined by an indirect bilirubin >2, ALT or AST 
laboratory values ≥ 10 times the upper limit of normal, or other evidence of 
decompensated liver disease or hepatocellular carcinoma 
b. Chronic liver disease other than HCV not limited to Hepatitis B virus (positive test for 
HBsAg), hemochromatosis, auto-immune hepatitis, alcoholic liver disease or non-
alcoholic fatty liver disease 
c. History of liver transplantation 

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d. Co-infection with HIV (positive test for anti-HIV Ab) 
e. Prior history of cardiomyopathy (ejection fraction ≤ 50%) or history of heart failure 
f. Signs or symptoms of decompensated heart failure or  
g. Prior history of coronary artery disease, acute myocardial infarction or coronary artery 
revascularization (percutaneous or coronary artery bypass grafting) 
3.2.3 
Discontinuation of Subjects from Study 
Subjects will discontinue from the study if they withdraw informed consent or are unable to freely 
provide consent.  

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4. STUDY PROCEDURES 
4.1 
Summary of Procedures 
Subjects who participated in a Phase 1 or Phase 2 trial with BMS-986094 and received study drug as well 
as control subjects that include patients with known hepatitis C (see criteria above) and those in the 
placebo arms of the prior trials will be contacted and asked to give informed consent for enrollment into 
the study.  Subjects will be enrolled based on existing medical records or clinical site data that supports 
the inclusion/exclusion criteria. If subjects meet exclusion criteria after enrollment (e.g. ALT or AST 
laboratory values ≥ 10 times the upper limit of normal) upon receipt of baseline labs, the subject may 
stay in the study. Once consented, all subjects will complete an initial study visit at Day 1 at the study 
site. Relevant previous data collected during the subject’s participation in a Phase 1 or 2 study of 
BMS-986094 may be transferred from BMS to DCRI and entered into the study database, as needed.  All 
enrollees will undergo baseline assessment (see section 4.3.1). Schedule of assessments for subjects in 
either arm of the registry will be identical (See Table 2). 
Subjects who do not have a study site, due to relocation or for other reason(s), may be followed by 
phone only by the DCRI Call Center according to Table 3.  The other procedures outlined in this protocol 
do not apply to this subset of subjects.   
4.2 
Schedule of Assessments 
The schedule of assessments is shown in Table 2. Decisions about modification to schedule of 
assessments will be made during annual Observational Study Monitoring Board (OSMB) meetings and 
review of data.   The proposed duration of follow up, from time of initial assessment by a physician, is up 
to 5 years for each subject enrolled in the registry. 

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Table 2 
Schedule of Assessments 
 
 
Years 1-2 
Years 3-5 
Assessment 
Baseline 
3mo 
6mo 
9mo 
12mo 
15mo 
18mo 
21mo 
24mo 
30mo 
36mo 
42mo 
48mo 
54mo 
60mo 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History & 
Physical Exam 
(including vital 
signs) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Phone Call to 
Subject for Health 
Status Survey 
 
X 
 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
 
X 
X* 
X 
X* 
Medications 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CMP, CBC 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
FibroSURE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Disease 
Assessment** 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Cardiac and Renal 
Biomarkers*** 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
ECG 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Transthoracic 
Echo 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
* DCRI call center may contact subject by phone call if he/she misses in-person assessment. 
** Liver Disease Assessment includes: HCV RNA, PT/PTT/INR 
*** See Section 4.7 for details 

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Table 3  
Schedule of Assessments for Subject Follow-up by DCRI Call Center Only (subjects without a site) 
 
Years 1-2 
Years 3-5 
Assessment 
Baseline 
3mo 
6mo 
9mo 
12mo 
15mo 
18mo 
21mo 
24mo 
30mo 
36mo 
42mo 
48mo 
54mo 
60mo 
Informed 
Consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Call to 
Subject for Health 
Status Survey 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Collection of 
Medical Recordsb 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
a  Informed consent forms will be mailed to the subjects, discussed over the phone with the DCRI Call Center, and signed and mailed back to the DCRI Call Center.  
b  Collection of medical records if subject signs medical release form that will be mailed with the informed consent form. Preferably the treating physician should send the 
medical records to DCRI Call Center including records of physical exams, medications, lab results, safety event information, results of any cardiac procedures and any other 
relevant information. Medical records may also be collected at other times should phone interviews trigger the need for supporting information. 

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4.3 
Study Site Visits 
4.3.1 
Baseline (Initial Visit) 
Baseline assessments will occur at the time of first study visit (Day 1) and will include: 
• 
Comprehensive physical examination, including vital signs 
• 
Past Medical History 
• 
Cardiovascular, renal and hepatic concomitant medications 
• 
Local Laboratory Tests: comprehensive metabolic panel (CMP), complete blood count 
(CBC)  
• 
Central Laboratory Tests 
o Liver Disease Assessment: HCV RNA, PT/PTT/INR (see Section 4.7) 
o FibroSURE 
o Cardiac Biomarkers (see Section 4.7) 
o Renal Biomarkers (see Section 4.7) 
• 
Electrocardiogram (ECG) 
• 
Transthoracic echocardiogram (TTE) 
4.3.2 
Follow-up 
Follow up in-person visits will occur according to year of study and will include: 
• 
Focused physical examination 
• 
Interval medical history 
• 
Changes in cardiac, renal, and hepatic medications 
• 
Local Laboratory Tests: comprehensive metabolic panel (CMP), complete blood count 
(CBC)  
• 
Central Laboratory Tests 
o Liver Disease Assessment: HCV RNA, PT/PTT/ INR (see Section 4.7) Note:  Liver 
Disease Assessment only conducted at months 12, 24, 36, 48 and 60. 
o Cardiac Biomarkers (see Section 4.7) 
o Renal Biomarkers (see Section 4.7) 
• 
Electrocardiogram (ECG) 
• 
Transthoracic echocardiogram (TTE) 
Telephone visits will include: 
• 
Interval medical history 
• 
Health Status Survey 
4.4 
Telephone Interviews with Health Status Survey 
All subjects will be contacted by telephone for structured interviews by trained DCRI personnel who are 
part of the DCRI Outcomes call center to provide surveillance for any cardiovascular and renal 
symptoms. Questions will be included to allow for discerning between cardiac or pulmonary etiology of 
symptoms. The telephone visits will be done at standard intervals between site visits. During years 1-2, 
the telephone visits will be done every 6 months and during years 3-5, the telephone visits will be done 
every 12 months. Telephone visits will also be used to contact subjects if they miss scheduled clinic 

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visits. Any change in subject’s cardiovascular or renal health status will result in notification of the site 
investigator and the medical monitor. The primary responsibility for following up on the notification will 
lie with the site investigator. In the future, if yet known symptoms or organ toxicities that may be 
related to BMS-986094 are identified, health status surveys might be modified to include relevant 
questions.  
4.5 
History and Physical  
All study participants will undergo medical history and physical exam on initial visit, along with a review 
of current medications related to cardiovascular, renal or hepatic disease.  During subsequent visits, 
subjects will undergo a focused history and physical exam that aims to uncover signs and symptoms of 
cardiac or renal dysfunction. Additionally, changes in medications, as well as recent hospitalizations, 
specifically for cardiovascular or renal causes will be documented. Subjects will be queried about any 
significant changes in clinical care such as need for dialysis or episodes of acute kidney injury. In the 
future, if yet known symptoms or organ toxicities that may be related to BMS-986094 come to light, 
history and physicals might be modified to include relevant questions.   
4.6 
Routine Laboratory Assessments 
Study participants will have laboratory values checked at the local laboratory according to the schedule 
of assessments. These will include comprehensive metabolic panel and complete blood count. Any 
clinical interventions indicated by laboratory results will be at the discretion of the site PI.  In all 
circumstances, the sites will be responsible for modifying clinical care based on these results per 
standard of care.  HCV RNA, PT/PTT/INR, and FibroSURE will be done at a central laboratory (see Section 
4.7). The DCRI coordinating PI and co-Investigators will be available for follow up and consultation with 
the site as needed.    
4.7 
Biomarker Assessment 
Subjects enrolled in the study will be asked to provide blood and urine samples for biomarker analyses 
as well as storage for future use. These will be performed at a central laboratory. Ongoing testing of 
biomarkers will include those that may indicate pathophysiological changes to cardiovascular, renal, or 
hepatic status and include: 
Cardiovascular biomarkers: 
• 
B-type natriuretic peptide  [BNP] 
• 
High sensitivity cardiac troponin (hs-cTn) 
• 
Storage for future use (optional) 
Renal Biomarkers: 
• 
Cystatin-C   
• 
Albumin  
• 
Storage for future use (optional) 

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Hepatic Biomarkers:  
• 
FibroSURE (baseline only) 
• 
PT/PTT/ INR 
• 
Hepatitis C RNA 
A central laboratory will provide all labels, tubes and requisitions necessary for the above mentioned 
biomarkers and samples for storage.  Sites will have access to all central laboratory results and will also 
be informed of certain abnormal values.  In all circumstances, the sites will be responsible for modifying 
clinical care based on these results per standard of care. The DCRI coordinating PI and co-Investigators 
will be available for follow up and consultation with the site as needed.    
If the subject consents, blood and urine samples will be collected and stored for future use. 
4.8 
Electrocardiograms and Echocardiograms 
Resting transthoracic two-dimensional (2-D) and Doppler echocardiograms and static 12-lead ECGs will 
be performed according to the schedule of assessments in Table 2.  
Protocols and procedures for acquiring and transmitting detailed resting, transthoracic 2-D, and Doppler 
echocardiogram and standard 12-lead ECG image acquisition are included in the study manual of 
procedures. Each study site will identify their preferred echocardiography laboratory. The echo lab, as 
well as the study site, will be trained and qualified before any subject may be enrolled. The echo lab will 
be expected to maintain minimal quality standards throughout the study. Importantly, images and ECGs 
should be acquired using only subject study number, initials, and date of study. Sites will transfer study 
echocardiograms on a CD-ROM or DVD and paper ECGs via courier to DCRI Imaging Core Laboratory 
(Core Lab), within three business days.   
All study echocardiograms and ECGs will be independently analyzed by the DCRI Imaging Core Lab. Upon 
arrival in the Core Lab, echocardiograms will be de-identified by removing or masking all protected 
health information on the images and will undergo quality review with feedback returned to the site’s 
clinical echo lab.  
Echocardiograms will be analyzed for systolic and diastolic left ventricular (LV) function, anatomic 
measurement of LV and atrial volumes, valvular regurgitation, wall thickness, wall motion score and LV 
mass index. Electrocardiograms will also undergo quality review and feedback and will be analyzed for 
rhythm, intervals, and evidence of ischemia or hypertrophy.   
All echocardiograms and ECGs will be analyzed by the core lab within 7 business days of resolution of 
any queries.  A report will be communicated to the study site within one business day of physician 
interpretation. 
In addition sites will identify any clinical echocardiograms or ECGs obtained during the study period with  
significantly abnormal findings (evidence of cardiac function, as defined below)  and send the images 
and/or ECG to the DCRI Imaging Core Lab, along with the clinical report (site interpretation).  

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4.9 
Evidence of Cardiac Dysfunction   
Any of the following findings will be considered potentially indicative of cardiac dysfunction/heart 
failure and would prompt referral to cardiovascular specialist, closer follow-up, and/or hospitalization. 
The decision will be left to the discretion of the treating physician. Abnormal responses to the 
cardiovascular questionnaire or testing will be evaluated by the medical monitor at DCRI and results 
reported to the site for further evaluation as clinically indicated.  
a) Abnormalities on history and physical exam may include: 
• 
Symptoms of cardiovascular disease or heart failure such as increasing shortness of 
breath, chest pain, fatigue, orthopnea, paroxysmal nocturnal dyspnea, syncope or 
presyncope.  
• 
Physical exam findings concerning for heart failure such as hypotension (systolic blood 
pressure [SBP] < 90 mm Hg), tachycardia (heart rate [HR] > 100 bpm), elevated jugular 
venous pressure (JVP > 10 cm H20 while sitting upright), rales or crackles on pulmonary 
exam, extra heart sounds (S3 or S4), murmurs (holosystolic or diastolic murmur), lower 
extremity edema, decreased distal pulses, and cool extremities. 
• 
Hospitalization for any cardiac cause. 
b) Abnormalities in laboratory values (defined as >upper limit of normal defined by laboratory 
in subjects with normal baseline values and >25% change from previous visit in those with 
abnormal values): 
• 
Evidence of myocardial injury, as noted by abnormal level of hs-cTn. 
• 
Evidence of myocardial stress, as noted by abnormal levels of BNP. 
c) Abnormalities on ECG: 
• 
Evidence of any ECG abnormalities new from baseline (or most recent) ECG. 
d) Abnormalities on TTE: 
• 
Evidence of new myocardial dysfunction on imaging, defined as left ventricular ejection 
fraction (LVEF) < 50% or any regional wall motion abnormality. 
• 
New moderate or greater valvular regurgitation. 
• 
New moderate or greater chamber enlargement. 
4.10 Evidence of Renal Dysfunction 
Any of the following findings will be considered potentially indicative of renal dysfunction failure and 
would prompt referral to renal specialist, closer follow-up, and/or hospitalization. The decision will be 
left to the discretion of the usual care physician.  
a) Abnormalities on history and physical exam: 
• 
Symptoms of renal failure such as reduce urine output, flank plain, rash, abdominal 
pain.   
• 
Hospitalization for any renal cause. 

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b) Abnormalities in laboratory values (defined as >upper limit of normal defined by laboratory 
in subjects with normal baseline values and >25% change from previous visit in those with 
abnormal values): 
• 
Evidence of renal dysfunction, as noted by significant increases in BUN, Cr, cystatin C. 
• 
Abnormal urine albumin level as defined as a spot urine albumin creatinine ratio >300 
mg/g.   
4.11  Hospitalizations 
Hospitalization is defined as inpatient admission to a hospital for a period greater than 24 hours.  
All hospitalizations, regardless of whether it was associated with a reportable SAE (defined as an SAE 
related to cardiac or renal dysfunction or resulting in death), will be collected and recorded on the  
appropriate module of the eCRF.  If the primary diagnosis of admission was a reportable SAE, the SAE  
eCRF will also be completed. Hospitalizations not associated with a reportable SAE should not be  
reported as an SAE. 
 
4.12 
Subject Withdrawal 
Subjects have the right to withdraw from the study at any time and for any reason without prejudice to 
his or her future medical care. In the case of subject withdrawal, the investigator will discuss with the 
subject the most appropriate way to terminate study participation to ensure the subject’s health. All 
efforts will be made to complete and report the observations as thoroughly as possible up to the date of 
study withdrawal. Subjects will have the right to return to the study after withdrawal at any time.  
4.13 
DCRI Call Center Follow-up only 
Subjects who do not have a study site may be followed by the call center through phone follow-up.  
These subjects must have a local treating physician in order to be followed by the call center. They will 
continue to receive all care and treatment from their local healthcare provider.  The call center staff will 
provide a brief explanation regarding the observational/telephone only follow up to the subject and 
then mail the consent form, medical release form and patient contact information sheet to the subject.  
Approximately one week later, the subject will be called and the consent form and medical release form 
will be reviewed over the phone.  If the subject agrees to participate, they will sign the forms and send 
back to the call center.  Once the documents are received; the call center will request medical records 
from the subject’s healthcare provider to assist in establishing baseline medical history.  Any data that 
can be extrapolated from these records will be entered into the database. 
This small group of subjects will have telephone visits done at 3 month intervals during years 1-2 and 
every 6 months during years 3-5.  The subjects will be informed of any changes in their health that 
warrant seeking advice and care from their local physician.  It will be explained that the survey in no way 
takes the place of the need for physician follow up and does not provide any treatment if there can be 
no site follow up.  The survey will be for data collection only in these cases. 
 

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5. SAFETY EVALUATIONS 
5.1 
Definitions 
5.1.1 
Adverse Events  
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigational subject 
administered an investigational intervention and which does not necessarily have a causal relationship 
with study treatment. An AE can be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with use of the study drug, whether or 
not considered related to an investigational intervention.  
5.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that may result in any of the 
following outcomes: 
• 
Death 
• 
Is life-threatening 
• 
In-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, 
it may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes.  
5.2 
Collection of Adverse Events 
This is a long-term observational, non-interventional study. For this study, non-serious AEs will not be 
collected.  
5.3 
Assessment of Serious Adverse Events 
As this is a long-term observational, non-interventional study, temporal association with the use of 
study drug, as referenced in 5.1.1, is not applicable.  Collection, evaluation, and reporting of SAEs will be 
limited to SAEs related to cardiac or renal dysfunction and SAEs resulting in death.  
 
5.3.1 Assessment of SAE  Severity  
The determination of SAE severity rests on medical judgment of a medically-qualified investigator. The 
severity of SAEs will be graded using the following definitions:  
• 
Mild: awareness of sign, symptom, or event, but easily tolerated;  
• 
Moderate: discomfort enough to cause interference with usual activity and may warrant 
intervention;  

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• 
Severe: incapacitating with inability to do usual activities or significantly affects clinical 
status, and warrants intervention. 
5.3.2 SAE Collection and reporting 
Collection, evaluation, and reporting of SAEs will be limited to SAEs related to cardiac and renal 
dysfunction and SAEs resulting in death. In the future, if symptoms or organ toxicities that may be 
related to BMS-986094 are identified, the reporting of SAEs may change. SAEs will be collected and 
recorded on the SAE page of the eCRF from the signing of informed consent to the end of the follow-up 
period.  
SAEs related to cardiac dysfunction, renal dysfunction and SAEs resulting in death, regardless of 
causality, must be reported by the investigator or qualified designee as soon as they become aware of 
the event. The investigator/qualified designee will enter the required information regarding the SAE into 
the appropriate module of the eCRF. DCRI Safety Surveillance will be notified of SAEs via an electronic 
data capture (EDC)-generated email. DCRI Safety Surveillance will perform a review of all SAE forms to 
verify that all sections are complete and consistent and will issue queries on the SAE panel in the EDC 
system for incomplete or inaccurate information. If the eCRF system is temporarily unavailable, the 
event should be reported via a paper back-up SAE form to the DCRI Safety Surveillance. Upon return of 
the availability of the EDC system, the SAE information must be entered into the eCRF. DCRI will send 
reported SAEs to BMS in aggregate approximately every 6 months. 
Additional details regarding the collection and reporting of SAEs will be documented in the safety plan. 
5.3.3 Laboratory Test Abnormalities 
For laboratory test abnormalities that meet the definition of an SAE and that required the subject to 
receive specific corrective therapy, the clinical diagnosis, rather than the laboratory term, will be used 
by the reporting investigator (e.g., elevated BUN and creatinine versus renal insufficiency/renal failure). 
5.3.4 Follow-up of SAEs 
When additional relevant information becomes available, the investigator will record follow-up 
information according to the same process used for reporting the initial event as described above. The 
investigator will follow all events until resolution, stabilization or the event is otherwise explained. DCRI 
Safety Surveillance will follow all SAEs until resolution/stabilization/until the event is otherwise 
explained/ or until the last subject completes the final follow-up, whichever occurs first. DCRI will report 
SAEs to BMS in aggregate approximately every 6 months.   
5.4 
Expedited events/ SUSAR 
BMS will evaluate the SAE data for regulatory reporting criteria and will be responsible for submission to 
the appropriate authorities. 
 

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6. STATISTICAL CONSIDERATIONS 
6.1 
Population for Analysis 
This will be a multi-center, prospective, observational study designed to assess study participants for 
signs and symptoms of cardiovascular and renal dysfunction. The study will aim to enroll 291 of the 
subjects originally treated in Phase 1 and Phase 2 of the BMS-986094 studies, as well as approximately 
200 unexposed subjects with HCV and subjects enrolled in the original trial but who received placebo, 
who will serve as controls.  
6.2 
Statistical Analysis 
As the primary objective, measures of cardiovascular and renal dysfunction among subjects exposed to 
BMS-986094 will be summarized in aggregate and will include exploration of trends observed during the 
long term follow-up period.  Primary measures will include subject symptoms, findings on physical 
examination, laboratory measures including a range of biomarkers related to cardiac and renal 
dysfunction, ECG changes, development of new cardiovascular-related adverse events, and findings 
from transthoracic echocardiography.   
As a secondary objective, the evolution and status of underlying liver disease in this population will also 
be summarized.  This will include trends in HCV RNA as well as changes in clinical laboratory measures of 
liver function and coagulation observed through the follow-up period. 
Statistical analyses will be presented largely as descriptive statistics as well as tabular and graphic 
formats reflecting trends over time.  In addition to the data elements gathered during this study of long 
term safety surveillance, study data collected as part of the initial study enrollment and treatment will 
be combined and analyzed when appropriate for a thorough analysis of the study population.  
Further analytic detail will be provided in a statistical analysis plan.  The plan will describe the planned 
statistical analyses for presentation to the Observational Study Monitoring Board (OSMB) as well as at 
the conclusion of the study.  Agreement to the statistical analysis plan will be required prior to 
distribution of study results. 
6.3 
Primary Objective and Endpoints 
The primary endpoint will be to assess incidence of cardiovascular and renal dysfunction among subjects 
exposed to BMS-986094 and compare with a similar population of HCV subjects who were not exposed 
to BMS-986094. Recommendations will be made for referral to appropriate cardiovascular and renal 
specialists when concerning abnormalities are identified.  Statistical analysis will focus on collected data 
related to prior and ongoing subject assessments and performing descriptive statistics on the cohort at 
regular intervals.   
 
 

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7. STUDY RESPONSIBILITIES 
7.1 
Compliance with the Protocol and Protocol Revisions 
The study must be conducted as described in this approved protocol. The Investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB of an Amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects. Documentation of approval signed by the chairperson or 
designee of the IRB(s)/IEC(s) must be sent to DCRI.  If the revision is an Administrative Letter, 
Investigators must inform their IRB(s)/IEC(s). 
7.2 
Training 
Prior to the start of enrollment, the physician investigators and study coordinators at each site will be 
trained on the clinical protocol and data collection procedures, including how to use the eCRF system. 
Initial investigator and coordinator training will occur with an InForm trainer and hands‐on database 
interaction. This trainer will present slides, demonstrate key InForm functionality and guide attendees 
through practice exercises. Follow‐up training and training for new study personnel will be conducted by 
DCRI personnel who will present slides, demonstrate the system and guide attendees through practice 
exercises using on‐line web‐based teleconferences. 
7.3 
Monitoring 
The DCRI will ensure that data collection is being handled properly, will provide in service training, and 
address questions from site investigators and coordinators. Data quality and completeness will be 
reviewed by the DCRI team on a regular and ongoing basis, and any issues noted will be addressed with 
the site. Monitoring visits will be completed as described in the Clinical Monitoring Plan. 
7.4 
Remote Monitoring and Site Training 
The study will be monitored remotely by representatives of the DCRI or its designee according to the 
prospective clinical monitoring plan for real-time monitoring of compliance with study protocol.  
7.1 
Audits/Inspections 
DCRI Quality Assurance personnel, or a qualified designee, may conduct audits at the study site.  Audits 
will include, but not be limited to: audit trail of data handling and processes, presence of required 
documents, the informed consent process, and comparison of case report forms/database with source 
documents.  The investigator agrees to accommodate and participate in audits conducted at a 
reasonable time in a reasonable manner, as needed. Regulatory authorities may also audit an 
investigator during or after the study. The site investigator should contact the Principal Investigator(s) as 
well as their IRB/IEC, immediately if this occurs, and must fully cooperate with governmental (e.g. FDA) 
audits conducted at a reasonable time in a reasonable manner. 

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7.2 
Clinical Study Report and Subsequent Publications 
DCRI will reserve the right to publish manuscripts or abstracts arising from this study after approval by 
BMS prior to publication or presentation and will adhere to BMS’s publication requirements. Study 
records will be maintained by the site investigators until told otherwise by DCRI and/or BMS. 
7.3 
Study Closeout 
Upon completion of the study (defined by all subjects have completed all follow-up visits, all CRFs are 
complete, and all queries have been resolved), DCRI will notify the site of closeout and a study closeout 
visit will be performed. All CRFs will be collected and any unused study materials will be destroyed.   The 
DCRI monitor will ensure that the Investigator’s regulatory files are up to date and complete, and that 
any outstanding issues from previous visits have been resolved. Other issues to be reviewed at the 
closeout visit include: discussing retention of study files, possibility of site audits, publication policy, and 
notifying the IRB of study closure. 
 
 

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8. ETHICAL CONSIDERATIONS 
8.1 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and in accordance with DCRI standard 
operating procedures. These procedures are designed to ensure adherence to Good Clinical Practice, as 
described in the following documents: 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996, (which incorporate the 
principles of the Declaration of Helsinki)  
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
8.2 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form, and other 
information for subjects must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee (IRB/IEC). A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to the Coordinating Center (DCRI) 
before study initiation. The name and occupation of the chairman and the members of the IRB/IEC must 
be supplied to the Coordinating Center if this information is released by IRB/IEC. Any amendments to 
the protocol, other than administrative ones, must be approved by this committee. 
8.3 
Informed Consent 
The investigator or designee must explain to each subject (or legally authorized representative) the 
nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that participation in 
the study is voluntary and that he/she may withdraw from the study at any time and that withdrawal of 
consent will not affect his/her subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating it, and 
should be given a copy of the signed document. If written consent is not possible, oral consent can be 
obtained if witnessed by a signed statement from one or more persons not involved in the study, 
mentioning why the subject was unable to sign the form. No subject can enter the study before his/her 
informed consent has been obtained. The informed consent forms are part of the protocol, and must be 
submitted by the investigator with it for IRB/IEC approval. The Coordinating Center will supply proposed 
informed consent forms, which comply with regulatory requirements, and are considered appropriate 
for the study. Any changes to the proposed consent form suggested by the Investigator must be agreed 
to by the Coordinating Center before submission to the IRB/IEC, and a copy of the approved version 
must be provided to the Coordinating Center after IRB/IEC approval. 

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8.4 
Observational Study Monitoring Board 
An independent Observational Study Monitoring Board (OSMB) will review accumulating data at regular 
intervals (at least every 12 months) and provide a recommendation to the study leadership following 
each planned review.   The primary focus of the board will be to identify unanticipated safety concerns 
or trends felt to warrant action prior to the expected termination of the registry, as well as to make 
recommendations regarding the frequency of subject assessment.  Procedural details of the structure 
and function, frequency of meetings, and data planned for review will be included in an OSMB charter, 
which will be finalized prior to the first OSMB review meeting. 
8.5 
Study Documentation 
Study documentation includes all case report forms, data correction forms, source documents, 
monitoring logs and appointment schedules, Sponsor-investigator correspondence and regulatory 
documents (e.g., signed protocol and amendments, Ethics or Institutional Review Committee 
correspondence and approval, approved and signed subject consent forms, Statement of Investigator 
form, and clinical supplies receipts and distribution records). 
The investigator will prepare and maintain complete and accurate study documentation in compliance 
with Good Clinical Practice standards and applicable federal, state, and local laws, rules and regulations; 
and, for each subject participating in the study, promptly complete all original case report forms and 
such other reports as required by this protocol following completion or termination of the clinical study 
or as otherwise required pursuant to any agreement with DCRI. 
By signing the protocol, the investigator acknowledges that, within legal and regulatory restrictions and 
institutional and ethical considerations, study documentation will be promptly and fully disclosed to 
DCRI by the investigator upon request and also shall be made available at the investigator’s site upon 
request for inspection, copying, review and audit at reasonable times by representatives of DCRI or 
responsible government agencies as required by law.  
The investigator agrees to promptly take any reasonable steps that are requested by DCRI as a result of 
an audit to cure deficiencies in the study documentation and case report forms. 
8.6 
Source Documentation 
Source documents include all original recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical study.  Accordingly, 
source documents include, but are not limited to, laboratory reports, ECG tracings, X rays, radiologist 
reports, subject diaries, biopsy reports, ultrasound photographs, subject progress notes, hospital charts 
or pharmacy records and any other similar reports or records of any procedure performed in accordance 
with the protocol. 
Whenever possible, the original recording of an observation should be retained as the source document; 
however, a photocopy is acceptable provided that it is a clear, legible, and exact duplication of the 
original certified document. All laboratory source documents will be available for all normal and 
abnormal results. 

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Regulations require that Investigators maintain information in the study subject’s medical records which 
corroborate data collected on the CRF. In order to comply with these regulatory requirements, the 
following information will be maintained and made available as required by DCRI monitors, or 
designees, and/or regulatory inspectors: 
• 
Medical history/physical condition of the study subject prior to involvement in the study 
sufficient to verify protocol entry criteria. 
• 
Medical record documenting that informed consent was obtained for the subject’s 
participation in the study. 
• 
Dated and signed notes for each subject visit including results of examinations. 
• 
Notations on abnormal lab results and their resolution. 
• 
Dated printouts or reports of special assessments, (e.g., ECG reports). 
• 
Description of adverse events and follow-up of the adverse events (minimally event 
description, severity, onset date, duration, relation to study treatment, outcome and 
treatment for adverse event). 
• 
Notes regarding concomitant medications taken during the study (including start and stop 
dates). 
• 
Subject’s condition upon completion of or withdrawal from the study. 
8.7 
Modification of the Protocol 
The Investigator must not implement changes of the protocol without prior written agreement by the 
DCRI and prior review and documented approval/favorable agreement by the IRB of an amendment, 
except where necessary to eliminate an immediate hazard(s) to study subjects, or when the changes 
involve only logistical or administrative aspects of the study (e.g., changes in research personnel or 
change in phone numbers). 
8.8 
Deviations to the Protocol 
Deviations to the protocol must be documented and reported to the DCRI. Protocol deviations should be 
reported to the site IRB per their guidelines.