Conditions: Hepatitis C, Chronic Hepatitis C Opiate Dependence
Keywords: HCV Suboxone Epclusa psychiatrist
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
The main purpose of this pilot study is to investigate the safety, effectiveness and tolerability of the study medication in the treatment of people with chronic hepatitis C virus infection who regularly attend a psychiatrist-staffed clinic for opiate addiction treatment.

Detailed description:
An estimated 3.2 million people in the United States are currently infected with hepatitis C virus (HCV). Since 1990, when the US introduced screening of the blood supply for HCV, injection drug use has been the primary mode of HCV transmission in the United States. It is widely recognized that addressing the HCV epidemic among people who inject drugs (PWID) depends on increasing access to: 1) clean injection equipment; 2) opiate substitution therapy (OST); 3) curative HCV treatment; and 4) assistance with comorbid psychiatric conditions and social issues (Robaeys, C et al, 2013).

Nevertheless, access to HCV treatment among current and former injection drug users is thought to be limited by several factors including: 1) insufficient number of infectious disease and gastroenterology providers and 2) provider and third-party payor concerns about adherence to medication and the risk of reinfection (Aspinall, EJ et al, 2013). Strategies to increase access among current and former injection drug users to direct acting antiviral drugs are urgently needed. The purpose of the current study is to assess the impact of co-treating chronic hepatitis C infection and opiate dependence within the context of an outpatient addiction clinic staffed by psychiatrists. The beneficial impact of co-treating opiate dependence and an infectious illness has been demonstrated in the case of HIV infection. Altice and colleagues conducted an observational study of HIV-infected opiate-dependent patients who were offered OST with buprenorphine/naloxone at 10 different HIV clinics. Subjects initiating buprenorphine/naloxone were more likely to initiate or remain on ART (antiretroviral therapy) (Altice, 2011).

The Extension for Community Healthcare Outcomes (ECHO) program has demonstrated that with proper training and mentorship, primary care providers with no prior experience in managing HCV are able to treat the disease effectively (Arora et al, 2011). Since the publication of the ECHO study, the treatment of HCV has become considerably less complicated due to the widespread availability of safe, highly effective single tablet regimens, such as Epclusa. The investigators believe that treatment of HCV is now well within the grasp of physicians and other healthcare providers without training in internal or family medicine.

This single arm pilot study will assess HCV treatment with Epclusa at an outpatient addiction clinic staffed by psychiatrists. The investigators hypothesize that with proper training and mentorship, psychiatrists who are also a licensed buprenorphine/naloxone providers will be able to effectively assess liver health and treat chronic hepatitis C infection with Epclusa. Further, the investigators hypothesize that patients with chronic hepatitis C infection on buprenorphine/naloxone maintenance therapy who are treated for HCV by a psychiatrist during regularly scheduled visits to an addiction clinic will have high rates of adherence to HCV treatment and achieve SVR12 (sustained virologic response, 12 weeks post-treatment).

Given that subjects will receive standard of care evaluation and treatment for their chronic hepatitis C infection, the investigators believe that study participation poses minimal risk. Indeed, The investigators believe that subjects will benefit from improved access to this important treatment which will be provided at a convenient location by a known physician under the guidance of an infectious disease physician with extensive experience treating HCV infection.

Arms:
arm 1: In this open label, single arm study, all subjects will receive the intervention as prescribed by psychiatrists in the office based opiate addition treatment program.

Interventions: intervention 1: sofosbuvir/velpatasvir
Intervention descriptions: intervention 1: 12 week treatment with once daily sofosbuvir/velpatasvir fixed dose combination therapy. Tablets are formulated with 400mg sofosbuvir and 100mg velpatasvir in pink, diamond-shaped, film coated tablets.

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
Protocol: 
Sponsor-Investigator Initiated CRI #15-05 
Title: 
Bridging Care to HCV Treatment Among Opioid Dependent 
Patients on Buprenorphine/naloxone Maintenance Therapy: A 
Pilot Study of Treating HCV with Epclusa at a Psychiatrist-staffed 
Outpatient Addiction Clinic 
Protocol: 
V7.0  September 13, 2017 
NCT03235154 


 
 
1 
 
CLINICAL STUDY PROTOCOL --- CONFIDENTIAL 
 
Protocol: 
Sponsor-Investigator Initiated CRI #15-05 
 
Title: 
Bridging Care to HCV Treatment Among Opioid Dependent Patients on 
Buprenorphine/naloxone Maintenance Therapy: A Pilot Study of Treating HCV with 
Epclusa at a Psychiatrist-staffed Outpatient Addiction Clinic 
 
Protocol: 
V7.0  September 13, 2017 
 
Sponsor: 
Community Research Initiative of New England 
529 Main Street 
Boston, MA  02129 
Tel: 617-502-1700 
 
Funder:  
Gilead Sciences, Inc. 
 
Sponsor- 
Investigator: 
Amy Colson, MD MPH 
Principal Investigator 
Community Research Initiative of New England 
529 Main Street 
Boston, MA  02129 
Tel: 617-502-1700 
Email: acolson@crine.org 
 
Sub- 
Investigators: 
Zev Schuman-Olivier, MD 
 
Outpatient Addiction Services 
 
Cambridge Health Alliance 
 
26 Central Street 
 
Somerville, MA  02143 
 
Tel: 617-665-1000 
 
Email: zschuman@challiance.org 
 
 
Hannah B. Olivet, MD 
Senior Clinical Investigator 
529 Main Street 
Boston, MA  02129 
Tel: 617-502-1700 
 
Email: holivet@crine.org 
 
Medical 
Monitor: 
Jonathan S. Appelbaum, MD, FACP, AAHIVS 
Laurie L. Dozier, Jr., MD, Education Director and Professor of Internal Medicine 
Chair, Department of Clinical Sciences 
Florida State University College of Medicine 
1115 West Call Street, Suite 3140-F 
Tallahassee, FL  32306-4300 
Tel:  (617) 502-1799 
jonathan.appelbaum@med.fsu.edu 
 


CRI 15-05 Protocol 13SEP2017 
Page 2 
 
 
Table of Contents 
1 
PROTOCOL SYNOPSIS .................................................................................................................. 5 
2 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................... 10 
3 
INTRODUCTION ........................................................................................................................ 13 
3.1 
BACKGROUND AND RATIONALE .......................................................................................................... 13 
3.2 
EPCLUSA ......................................................................................................................................... 14 
3.3 
BUPRENORPHINE/NALOXONE ............................................................................................................. 16 
3.4 
COMPLIANCE ................................................................................................................................... 17 
4 
OBJECTIVES ............................................................................................................................... 17 
4.1 
PRIMARY OBJECTIVE: ........................................................................................................................ 17 
4.2 
SECONDARY OBJECTIVES: .................................................................................................................. 18 
4.3 
EXPLORATORY OBJECTIVE: ................................................................................................................. 18 
5 
STUDY DESIGN .......................................................................................................................... 18 
5.1 
TREATMENT PLAN AND REGIMEN ....................................................................................................... 18 
5.2 
SUBJECT RECRUITMENT ..................................................................................................................... 18 
5.3 
VISIT SCHEDULE ............................................................................................................................... 18 
5.4 
HCV VIROLOGIC RESPONSE-BASED TREATMENT STOPPING CRITERIA ....................................................... 19 
5.5 
TREATMENT DISCONTINUATION CRITERIA ............................................................................................ 19 
6 
SUBJECT POPULATION............................................................................................................... 19 
6.1 
NUMBER OF SUBJECTS AND SUBJECT SELECTION ................................................................................... 19 
6.2 
INCLUSION CRITERIA FOR CLINICAL SUBJECTS ........................................................................................ 19 
6.3 
EXCLUSION CRITERIA FOR CLINICAL SUBJECTS ........................................................................................ 20 
6.4 
ELIGIBILITY CRITERIA FOR PROVIDER PARTICIPANTS ................................................................................ 21 
7 
MEDICINAL PRODUCT ............................................................................................................... 21 
7.1 
ENROLLMENT AND TREATMENT .......................................................................................................... 21 
7.2 
DESCRIPTION AND HANDLING OF EPCLUSA ........................................................................................... 21 
7.2.1 
Formulation ......................................................................................................................... 21 
7.2.2 
Packaging and Labeling ....................................................................................................... 22 
7.2.3 
Storage and Handling .......................................................................................................... 22 
7.2.4 
Dosage and Administration of Epclusa ................................................................................ 22 
7.3 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................................................... 22 
7.4 
MONITORING ACCOUNTABILITY AND STUDY DRUG ADHERENCE FOR EPCLUSA ........................................... 23 
8 
STUDY PROCEDURES ................................................................................................................. 24 
8.1 
INFORMED CONSENT ........................................................................................................................ 24 
8.2 
SCREENING VISIT (DAY -28 TO DAY 0) ................................................................................................ 25 
8.3 
TREATMENT ASSESSMENTS ................................................................................................................ 26 
8.3.1 
Baseline/Day 1 Visit ............................................................................................................. 26 
8.3.2 
Weeks 2, 4, 6, 8, 10 (+/-3 days) ........................................................................................... 26 
8.3.3 
End of Treatment (+/-3 days) .............................................................................................. 26 
8.3.4 
Early Termination Visit ........................................................................................................ 26 
8.4 
POST-TREATMENT ASSESSMENTS ....................................................................................................... 27 
8.4.1 
Post-Treatment Week 4 and 12 (+/- 5 days) ....................................................................... 27 
8.5 
UNSCHEDULED VISIT......................................................................................................................... 27 


CRI 15-05 Protocol 13SEP2017 
Page 3 
 
 
8.6 
ASSESSMENTS FOR PREMATURE DISCONTINUATION FROM STUDY DOSING ................................................ 27 
8.7 
PROCEDURES AND SPECIFICATIONS ..................................................................................................... 27 
8.7.1 
Clinical Laboratory Analytes ................................................................................................ 27 
8.7.2 
Medical History .................................................................................................................... 28 
8.7.3 
Quality of Life Surveys ......................................................................................................... 28 
8.7.4 
Missed Visits ........................................................................................................................ 28 
8.7.5 
Mentorship .......................................................................................................................... 28 
8.7.6 
Location of Study Activities.................................................................................................. 29 
9 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ....................................................................... 30 
9.1 
DEFINITIONS OF ADVERSE EVENTS, ADVERSE REACTIONS, AND SERIOUS ADVERSE EVENTS ........................... 30 
9.1.1 
Adverse Events ..................................................................................................................... 30 
9.1.2 
Serious Adverse Events ........................................................................................................ 30 
9.1.3 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events ........................................................................................................................ 32 
9.2 
ASSESSMENT OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .......................................................... 32 
9.2.1 
Assessment of Causality for Study Drugs and Procedures................................................... 32 
9.2.2 
Assessment of Severity ........................................................................................................ 32 
9.3 
SPONSOR-INVESTIGATOR REQUIREMENTS AND INSTRUCTIONS FOR REPORTING ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS ......................................................................................................................................... 33 
9.4 
CRI REPORTING REQUIREMENTS ........................................................................................................ 34 
9.5 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE EVENTS OR 
SERIOUS ADVERSE EVENTS ............................................................................................................................ 34 
9.6 
SUBJECT STOPPING RULES ................................................................................................................. 34 
9.7 
SPECIAL SITUATIONS REPORTS ............................................................................................................ 35 
9.7.1 
Definitions of Special Situations .......................................................................................... 35 
9.8 
REPORTING SPECIAL SITUATIONS ........................................................................................................ 35 
9.8.1 
Instructions for Reporting Pregnancies ............................................................................... 35 
9.8.2 
Reporting Other Special Situations ...................................................................................... 36 
10 
STATISTICAL CONSIDERATIONS .............................................................................................. 37 
10.1 
ANALYSIS OBJECTIVES AND ENDPOINTS ............................................................................................... 37 
10.1.1 
Analysis Objectives .............................................................................................................. 37 
10.1.2 
Primary Endpoint ................................................................................................................. 37 
10.1.3 
Secondary Endpoints ........................................................................................................... 37 
10.1.4 
Safety Endpoints .................................................................................................................. 37 
10.1.5 
Other Endpoints of Interest ................................................................................................. 37 
10.2 
ANALYSIS CONVENTIONS ................................................................................................................... 38 
10.2.1 
Analysis Sets ........................................................................................................................ 38 
10.3 
DATA HANDLING CONVENTIONS ......................................................................................................... 38 
10.4 
DEMOGRAPHIC DATA AND BASELINE CHARACTERISTICS .......................................................................... 38 
10.5 
PRIMARY ANALYSIS .......................................................................................................................... 38 
10.6 
SECONDARY ANALYSIS ...................................................................................................................... 38 
10.7 
OTHER ANALYSES ............................................................................................................................. 39 
11 
SPONSOR-INVESTIGATOR RESPONSIBILITIES .......................................................................... 39 
11.1 
GOOD CLINICAL PRACTICE ................................................................................................................. 39 
11.2 
INSTITUTIONAL REVIEW BOARD (IRB)/INDEPENDENT ETHICS COMMITTEE (IEC) REVIEW AND APPROVAL ...... 39 
11.3 
INFORMED CONSENT ........................................................................................................................ 40 


CRI 15-05 Protocol 13SEP2017 
Page 4 
 
 
11.4 
CONFIDENTIALITY ............................................................................................................................. 40 
11.5 
STUDY FILES AND RETENTION OF RECORDS ........................................................................................... 40 
11.6 
CASE REPORT FORMS ....................................................................................................................... 41 
11.7 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY AND RETURN ................................................... 41 
11.8 
PROTOCOL COMPLIANCE ................................................................................................................... 42 
11.9 
PROTOCOL MODIFICATIONS ............................................................................................................... 42 
11.10 
STUDY MONITORING .................................................................................................................... 42 
11.11 
STUDY AUDITING OR INSPECTIONS .................................................................................................. 42 
11.12 
STUDY DISCONTINUATION ............................................................................................................. 42 
11.13 
FINANCE AND INSURANCE.............................................................................................................. 42 
11.14 
STUDY REPORT AND PUBLICATIONS ................................................................................................. 42 
12 
REFERENCES .......................................................................................................................... 44 
13 
APPENDICES .......................................................................................................................... 45 
APPENDIX 1: 
INVESTIGATOR SIGNATURE PAGE ............................................................................................ 46 
APPENDIX 2: 
STUDY PROCEDURES TABLE ................................................................................................... 47 
APPENDIX 3: 
QUESTIONNAIRE TO DETERMINE THE PARTICIPATING PSYCHIATRISTS’ COMFORT WITH HCV 
MANAGEMENT 49 
APPENDIX 4: 
GSI GRADING SCALE FOR SEVERITY OF ADVERSE EVENTS AND LABORATORY ABNORMALITIES ........... 50 
APPENDIX 5: 
PREGNANCY PRECAUTIONS, DEFINITION FOR FEMALE OF CHILDBEARING POTENTIAL, AND 
CONTRACEPTIVE RECOMMENDATIONS ............................................................................................................. 73 
APPENDIX 6: 
HCV TREATMENT CURRICULUM ............................................................................................. 75 
 
 
 


CRI 15-05 Protocol 13SEP2017 
Page 5 
 
 
1 Protocol Synopsis 
 
Sponsor: 
Community Research Initiative of New England 
529 Main Street 
Boston, MA  02129 
Study Title: 
Bridging Care to HCV Treatment Among Opioid Dependent Patients on 
Buprenorphine/naloxone Maintenance Therapy: A Pilot Study of Treating HCV 
with Epclusa at a Psychiatrist-staffed Outpatient Addiction Clinic 
ClinicalTrials.gov 
Identifier: 
 
NCT03235154 
Study Design: 
This is an open label, single center, pilot study to evaluate the efficacy, safety 
and tolerability of Epclusa treatment in naïve and treatment-experienced 
(including treatment intolerant) subjects with chronic HCV infection genotypes 
1, 2, 3, 4, 5 and 6 in the context of a psychiatrist-staffed 
buprenorphine/naloxone clinic. 
Study Centers: 
One study center in North America. 
 
Objectives: 
Primary Objective: 
To assess the effectiveness, as measured by SVR12, of HCV treatment with 
Epclusa administered by a psychiatrist/licensed buprenorphine/naloxone 
provider during regularly scheduled visits to an outpatient addiction clinic for 
buprenorphine/naloxone replacement therapy and mental healthcare. 
Secondary Objectives: To assess the impact of HCV treatment on health-related quality of life among 
subjects on buprenorphine/naloxone therapy. 
 
To assess adherence to Epclusa therapy among subjects administered treatment 
in the context of visits to an outpatient addiction clinic for 
buprenorphine/naloxone replacement therapy and mental healthcare. 
Exploratory Objective: To design and assess a curriculum and mentorship program to support 
psychiatrists with managing HCV infection.  For the purpose of this study, the 
curriculum will be tailored to the management of HCV with Epclusa. 
 
Number of Subjects: 
20 
Target Population: 
Approximately 20 subjects with chronic HCV infection genotypes 1, 2, 3, 4, 5 or 6 
will be enrolled. 
Study Product: 
Epclusa (sofosbuvir/velpatasvir) fixed dose combination tablets are pink, 
diamond-shaped, film-coated tablets containing 400 mg of sofosbuvir and 100 
mg of velpatasvir.  Subjects will take one tablet daily with or without food. 
Epclusa was approved by the FDA in 2016 for the treatment of adult patients 
with chronic hepatitis C infection genotypes 1, 2, 3, 4, 5, 6.  It is recommended as 
first line therapy for treatment naïve and pegylated-ribavirin-experienced adults 


CRI 15-05 Protocol 13SEP2017 
Page 6 
 
 
with chronic hepatitis C infection genotypes 1-6 (AASLD and IDSA HCV 
Guidelines, October, 2016) 
 
Duration of treatment: Subjects will be treated for 12 weeks. 
 
Main Eligibility 
Criteria: 
Inclusion Criteria for clinical subjects: 
Subjects must meet all of the following inclusion criteria to be eligible for 
participation in this study. 
1. Willing and able to provide written informed consent 
2. Age ≥ 18 years 
3. Confirmation of chronic HCV infection as documented by a positive HCV 
antibody test at least 6 months prior to the Baseline/Day 1 visit OR by 
patient report of infection for at least 6 months prior to the baseline/day 1 
visit AND positive HCV RNA test at screening 
4. HCV genotype 1, 2, 3, 4, 5 or 6 
5. In stable remission from opioid use on buprenorphine/naloxone for at least 
12 weeks 
6. Within the following laboratory parameters as assessed at the screening 
visit: 
a. HCV RNA quantifiable 
b. Screening rhythm strip without bradycardia (heart rate > 60 or, if on 
beta blocker, > 55 BPM) 
c. ALT ≤ 10 x ULN 
d. AST ≤ 10 x ULN 
e. Direct bilirubin ≤ 1.5 x ULN 
f. Platelets > 60,000 
g. HbA1c ≤ 13% 
h. Creatinine clearance ≥ 30 mL/min, as calculated by the Cockcroft-
Gault equation 
i. 
Albumin ≥ 3g/dL 
j. 
INR ≤ 1.5 x ULN or on an anticoagulant regimen affecting INR 
7. Female subject is eligible to enter if it is confirmed that she is: 
a. Not pregnant or nursing 
b. Not of childbearing potential (i.e. s/p hysterectomy, oophorectomy 
or has medically documented ovarian failure, or are postmenopausal 
women > 50 years of age with cessation of menses for 12 months or 
greater) 
OR 
Of childbearing potential with a negative serum pregnancy test 
within 2 weeks of screening, a negative urine pregnancy test on Day 
1, and a commitment to either abstain from intercourse or 
consistently use an acceptable method of birth control (Appendix 4) 


CRI 15-05 Protocol 13SEP2017 
Page 7 
 
 
in addition to condom use by her male partner(s) from the date of 
screening until 30 days after the last dose of study drug 
8. All male study participants must agree to consistently and correctly use 
condoms with their female partner(s) of childbearing potential and such 
female partner(s) must agree to use an acceptable method of birth control 
(listed) from the date of screening until 90 days after the last dose of study 
drug 
9. Male subjects must refrain from sperm donation from the date of screening 
until 90 days after the last dose of study drug 
10. Subject must be in generally good health, with the exception of HCV, in the 
opinion of the Sponsor-Investigator or Sub-Investigator(s) 
11. Subject must be able to comply with dosing instructions for study drug 
administration and able to complete the study visits, including all required 
post-treatment visits 
Exclusion Criteria for clinical subjects: 
Subjects who meet any of the following exclusion criteria are not to be enrolled in 
this study: 
1. Presence of decompensated cirrhosis as defined by encephalopathy, ascites, 
or a history of a variceal bleed 
2. Prior treatment with direct acting antiviral hepatitis C medications 
3. Positive urine drug toxicity test at screening (except for cannabinoids and 
prescribed medications) 
4. Absence of buprenorphine in urine sample at screening 
5. Currently pregnant or breastfeeding female 
6. Detectable HIV RNA > 50 copies/ml (co-infected subjects with suppressed 
viral load ARE eligible for participation) 
7. Use of any prohibited concomitant medication within 28 days prior to day 1 
8. Chronic use of systemically administered immunosuppressive agents 
9. Difficulty with blood collection or poor venous access 
10. History of solid organ transplantation 
11. Known significant allergy to sofosbuvir or velpatasvir 
12. Current chronic liver disease of a non-HCV etiology (including 
hemochromatosis, Wilson’s disease, alfa-1 antitrypsin deficiency) 
13. Active HBV infection defined as either a positive HBV surface antigen test or 
a positive test for HBV DNA. (Subjects who are positive for HBV core 
antibody but negative for Hepatitis B sAb, sAg, and DNA ARE eligible) 
 
Eligibility Criteria for Provider Participants 
All licensed buprenorphine/naloxone providers who are also licensed staff psychiatrists at the outpatient 
addiction clinic at Cambridge Health Alliance are eligible to participate in the study. Participation will 
require 
1. Attendance at the teaching session on the evaluation and management of 
hepatitis C infection conducted by the Study Investigator, Dr. Amy Colson (see 
Appendix 6 for teaching curriculum) 


CRI 15-05 Protocol 13SEP2017 
Page 8 
 
 
2. Agreement to have weekly mentorship by telephone with Dr. Colson. 
3. Provision of written informed consent addressing survey completion 
 
Study Procedures 
/Frequency: 
All study procedures will take place at the buprenorphine-naloxone clinic at OAS. 
Subjects will be seen approximately biweekly, in conjunction with their visits to 
the outpatient addiction clinic.  Effectiveness of HCV treatment will be assessed 
at week 4 on treatment and at 4 and 12 weeks following completion of 
treatment by measuring HCV RNA using the Cobas® AmpliPrep/Cobas® TaqMan® 
HCV Test v 2.0. 
 
Liver fibrosis will be assessed by Hepatitis C Virus (HCV) FibroSure® test collected 
at the screening visit as well as by FIB-4 index calculated from ALT, AST and 
platelet count collected at the screening visit. To the extent that the two tests 
differ, the higher fibrosis score will be used to guide therapy.  Additional 
screening labs will include: ALT, AST, HgbA1C, indirect bilirubin, direct bilirubin, 
alkaline phosphatase, CBC with Platelet Count, basic metabolic panel with 
calculated GFR, Hepatitis B surface antibody, Hepatitis B core antibody, Hepatitis 
B surface antigen, Hepatitis B quantitative DNA,  HCV genotype (if not 
documented in the medical record),  urine drug screen (for natural and synthetic 
opioids, cocaine, benzodiazepines, cannabinoids, barbiturates, and 
buprenorphine), and serum pregnancy test for women of childbearing 
potential). 
 
All women of childbearing potential will be screened for pregnancy throughout 
study participation, and pregnancy prevention counseling will be offered to 
women of childbearing potential and all male participants.  Urine drug screening 
will occur at every visit.  Additional laboratory assessments may be conducted 
per standard of care for monitoring of health or adverse events, throughout the 
study.  All laboratory assessments will be conducted as standard of care 
assessments. 
 
At the screening visit, study participants will complete questionnaires assessing 
demographic characteristics.  At baseline, week 4 on-treatment, end of 
treatment (or early termination), and 12 weeks after treatment, participants will 
complete quality of life questionnaires including the Functional Assessment of 
Chronic Illness Therapy-Fatigue (FACIT-F), PROMIS v1.0  Emotional Distress – 
Depression Short Form 8a (PROMIS ED -Depression SF8a), and Short Form Health 
Survey (SF36). 
 
Adherence to Epclusa will be monitored at each study treatment visit through 
pill counts and MEMSCap™ Medication Event Monitoring System smart 
packaging that records the date and time whenever the medication vial is 
opened. 
 


CRI 15-05 Protocol 13SEP2017 
Page 9 
 
 
Fully licensed psychiatrists who are also licensed buprenorphine/naloxone 
providers who work at the Cambridge Health Alliance’s Outpatient Addiction 
Services will initiate and monitor Epclusa treatment with training and ongoing 
mentoring by Dr. Amy Colson, the Sponsor-Investigator.  Initial training prior to 
enrolling subjects will address interpretation of HCV diagnostic tests, assessment 
of liver fibrosis, selection of patients for HCV treatment, 
administration/monitoring of Epclusa therapy, and post-therapy assessment of 
treatment effectiveness.  The Sponsor-Investigator will conduct weekly 
telephone consultation and mentorship throughout the course of the study. 
 
The psychiatrists’ level of comfort with providing care for hepatitis C infection 
will be determined by a questionnaire administered before and at the 
completion of their training session and after 4 months of prescribing HCV 
therapy to study participants. 
 
 
This study will be conducted in accordance with the guidelines of Good Clinical Practices (GCPs) including 
archiving of essential documents. 
 
 


CRI 15-05 Protocol 13SEP2017 
Page 10 
 
 
2 Glossary of Abbreviations and Definition of Terms 
 
AE 
 
adverse event 
ALT 
 
alanine aminotransferase (also SGPT) 
AST 
 
aspartate aminotransferase (also SGOT) 
BID 
 
twice a day 
CD4 
 
Cluster of differentiation 4 
CI 
 
Confidence Interval 
CRF 
 
case report form(s) 
CRI 
 
Community Research Initiative of New England 
CSR 
 
clinical study report 
dL 
 
Deciliter 
DSPH 
 
Drug Safety and Public Health 
ECG 
 
Electrocardiogram 
eCRF 
 
Electronic case report form(s) 
EOT 
 
End of Treatment 
ET 
 
Early Termination 
EU 
 
European Union 
FACIT-F  
Functional Assessment of Chronic Illness Therapy-Fatigue 
FDA 
 
(United States) Food and Drug Administration 
FDC 
 
Fixed dose combination 
FEV1 
 
forced expiratory volume in one second 
GCP 
 
Good Clinical Practice (Guidelines) 
GCSF 
 
Granulocyte colony stimulating factor 
GGT 
 
gamma-glutamyl transferase 
GSI 
 
Gilead Sciences, Inc. 
Hb 
 
Hemoglobin 
HbA1c  
Hemoglobin A1c 
HBV 
 
Hepatitis B virus 
HCV 
 
Hepatitis C virus 
ICH 
 
International Conference on Harmonisation 


CRI 15-05 Protocol 13SEP2017 
Page 11 
 
 
IEC 
 
independent ethics committee 
IND 
 
Investigational New Drug (Application) 
INR 
 
International Normalized Ratio of prothrombin time 
IRB 
 
institutional review board 
IUD 
 
intrauterine device 
IU 
 
international units 
IV 
 
Intravenous 
Kg 
 
Kilogram 
L 
 
Liter 
LDL 
 
low-density lipoprotein 
LLN 
 
lower limit of the normal range 
LLOQ 
 
Lower limit of quantification 
LLT 
 
Lower-Level Term 
MCV 
 
mean corpuscular volume or mean cell volume 
Mg 
 
Milligram 
Mm 
 
Millimeter 
mL 
 
Milliliter 
Min 
 
Minute 
mmHg  
millimeters mercury 
P-gp 
 
P-glycoprotein 
PG 
 
Pharmacogenomic 
PO 
 
by mouth 
QD 
 
once daily (use only in tablets) 
PK 
 
Pharmacokinetic 
PT 
 
preferred term or prothrombin time 
RBC 
 
red blood cell count 
RNA 
 
ribonucleic acid 
RVR 
 
rapid virologic response 
SADR 
 
Serious adverse drug reaction 
SAE 
 
serious adverse event 


CRI 15-05 Protocol 13SEP2017 
Page 12 
 
 
SF36 
 
Short Form Health Survey 
SOF 
 
Sofosbuvir 
SOP 
 
Standard operating procedure 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
SVR 
 
Sustained Virologic Response 
SVR4 
 
Sustained viral response 4 weeks after discontinuation of study treatment 
SVR12  
Sustained viral response 12 weeks after discontinuation of study treatment 
SVR24  
Sustained viral response 24 weeks after discontinuation of study treatment 
ULN 
 
upper limit of the normal range 
US 
 
United States 
VEL 
 
Velpatasvir 
WBC 
 
white blood cell count 
WOCPB  
women of childbearing potential 
 
 


CRI 15-05 Protocol 13SEP2017 
Page 13 
 
 
3 INTRODUCTION 
3.1 Background and Rationale 
An estimated 3.2 million people in the United States are currently infected with hepatitis C virus (HCV).  
Since 1990, when the US introduced screening of the blood supply for HCV, injection drug use has been 
the primary mode of HCV transmission in the United States. It is widely recognized that addressing the 
HCV epidemic among people who inject drugs (PWID) depends on increasing access to: 1) clean injection 
equipment; 2) opioid substitution therapy (OST); 3) curative HCV treatment; and 4) assistance with 
comorbid psychiatric conditions and social issues (Robaeys, C et al, 2013). 
Nevertheless, access to HCV treatment among current and former injection drug users is thought to be 
limited by several factors including: 1) insufficient number of infectious disease and gastroenterology 
providers and 2) provider and third-party payor concerns about adherence to medication and the risk of 
reinfection (Aspinall, EJ et al, 2013). Strategies to increase access among current and former injection 
drug users to direct acting antiviral drugs are urgently needed. The purpose of the current study is to 
assess the impact of co-treating chronic hepatitis C infection and opioid dependence within the context 
of an outpatient addiction clinic staffed by psychiatrists. 
The partial μ-agonist, buprenorphine, is effective treatment for opioid dependence.  Buprenorphine is 
typically co-formulated with naloxone and prescribed as buprenorphine/naloxone in a physician’s office 
by providers who have undergone specialized training and licensure as proscribed by the Drug Abuse 
Treatment Act of 2000.  Currently, there are more than 20,000 licensed buprenorphine/naloxone 
providers in the United States (Anson, 2013).  Importantly, buprenorphine/naloxone patients are usually 
required to see their buprenorphine/naloxone providers for a new buprenorphine/naloxone prescription 
at least monthly, if not more frequently, and the adherence to these visits is extremely high. Moreover, 
buprenorphine/naloxone therapy is often prescribed through multidisciplinary clinics which are highly 
effective at retaining patients in care because comorbid psychiatric conditions and social problems are 
also addressed. 
The beneficial impact of co-treating opioid dependence and an infectious illness has been demonstrated 
in the case of HIV infection. Altice and colleagues conducted an observational study of HIV-infected 
opioid-dependent patients who were offered OST with buprenorphine/naloxone at 10 different HIV 
clinics. Subjects initiating buprenorphine/naloxone were more likely to initiate or remain on 
antiretroviral therapy (Altice, 2011). 
The Extension for Community Healthcare Outcomes (ECHO) program has demonstrated that with proper 
training and mentorship, primary care providers with no prior experience in managing HCV are able to 
treat the disease effectively.  The ECHO project employed video conferencing technology to provide 
specialist run didactic sessions and consultation to primary care physicians in rural areas and prisons of 
New Mexico.  Between 2004 and 2008, 146 treatment-naïve subjects were treated at the HCV clinic at 
UNM, and 261 treatment naïve subjects were treated at ECHO sites. Sustained virologic response rates 
were similar at the academic medical center clinic and ECHO sites (57.5% at UNM HCV clinic versus 
58.2% at ECHO sites, P = .89). At the UNM HCV clinic, 13.7% of patients had serious adverse events, as 
did 6.9% of those treated at ECHO sites (Arora et al, 2011). 
Since the publication of the ECHO study, the treatment of HCV has become considerably less 
complicated due to the widespread availability of safe, highly effective single tablet regimens, such as 
Epclusa. We believe that treatment of HCV is now well within the grasp of physicians and other 
healthcare providers without training in internal or family medicine.  We propose a single arm pilot study 


CRI 15-05 Protocol 13SEP2017 
Page 14 
 
 
of HCV treatment with Epclusa at an outpatient addiction clinic in Somerville, Massachusetts staffed by 
psychiatrists. 
 
We hypothesize that: 
• 
With proper training and mentorship, psychiatrists who are also licensed 
buprenorphine/naloxone providers will be able to effectively assess liver health and treat 
chronic hepatitis C infection with Epclusa 
• 
Patients with chronic hepatitis C infection on buprenorphine/naloxone maintenance therapy 
who are treated for HCV by a psychiatrist during regularly scheduled visits to an addiction clinic 
will have high rates of 
o adherence to HCV treatment 
o SVR 12 
Given that subjects will receive standard of care evaluation and treatment for their chronic hepatitis C 
infection, we believe that study participation poses minimal risk.  Indeed, we believe that subjects will 
benefit from improved access to this important treatment which will be provided at a convenient 
location by a known physician under the guidance of an infectious disease physician with extensive 
experience treating HCV infection. 
 
3.2 Epclusa 
Epclusa is a two-drug fixed-dose combination product that contains 100 mg of velpatasvir and 400 mg of 
sofosbuvir in a single tablet. The recommended dosage of Epclusa is one tablet taken orally once daily 
with or without food for 12 weeks. Velpatasvir is a pangenotypic HCV NS5A inhibitor and sofosbuvir is a 
pangenotypic nucleotide inhibitor of HCV NS5B RNA-dependent RNA polymerase. 
Epclusa was approved by the FDA in 2016 for the treatment of adult patients with chronic hepatitis C 
infection genotypes 1, 2, 3, 4, 5, and 6.  It is recommended as first line therapy for treatment naïve and 
pegylated-ribavirin-experienced adults with chronic hepatitis C infection genotypes 1-6 (AASLD and IDSA 
HCV Guidelines, October, 2016).  Safety and tolerability data for Epclusa is based on data from three 
Phase 3 clinical trials (ASTRAL-1, ASTRAL-2, and ASTRAL-3) which enrolled a total of 1035 subjects who 
either did not have cirrhosis or who had compensated cirrhosis (Epclusa Package Insert). 
Overall, 0.2% of subjects in the three studies discontinued Epclusa due to adverse events. 
The most common adverse reactions (≥10%) during 12 weeks of treatment with Epclusa were headache 
and fatigue. 
ASTRAL-1 was a randomized placebo-controlled trial which enrolled 740 subjects with genotypes 1, 2, 4, 
5, and 6 chronic HCV.  Nineteen percent of these subjects had compensated cirrhosis and 32% were 
treatment experienced. The table below lists adverse reactions (adverse events assessed as causally 
related by the Investigator, all grades) observed in ≥5% of subjects in ASTRAL-1.  The majority of adverse 
reactions were of severity grade 1. Importantly, each of these reactions occurred at a similar frequency 
or more frequently in the control arm, with the exception of asthenia which occurred in 5% subjects on 
Epclusa and 3% of subjects on placebo. 


CRI 15-05 Protocol 13SEP2017 
Page 15 
 
 
Reaction 
Frequency in ASTRAL-1 
Headache 
22% 
Fatigue 
15% 
Nausea 
9% 
Asthenia 
5% 
Insomnia 
5% 
 
Co-administration of amiodarone with Epclusa is not recommended because post-marketing cases of 
symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, 
have been reported when amiodarone is co-administered with sofosbuvir. 
The concomitant use of Epclusa with P-gp inducers and/or moderate to potent CYP2B6, CYP2C8, and 
CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may significantly decrease plasma 
concentrations of velpatasvir and/or sofosbuvir and may lead to a reduced therapeutic effect of 
EPCLUSA. Therefore, the use of Epclusa with P-gp inducers and moderate to potent CYP2B6, CYP2C8, and 
CYP3A4 is not recommended. 
Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease 
the concentration of velpatasvir. Epclusa and antacid administration must be separated by at least 4 
hours.  H-2 receptor antagonists may be administered simultaneously with or 12 hours apart from 
Epclusa at a dose that does not exceed famotidine 20 mg BID.  Co-administration of Epclusa and proton 
pump inhibitors is not recommended.  However, if it is medically necessary to administer Epclusa and a 
proton pump inhibitor, Epclusa should be taken with food 4 hours before omeprazole at a dose which 
does not exceed 20 mg. 
Epclusa interacts with several medications commonly used by our target population. Efavirenz and 
tipranavir/r should not be co-administered with Epclusa because these HIV medications decrease 
velpatasvir and/or sofosbuvir levels. Renal function should be monitored in patients taking tenofovir DF 
with Epclusa.  Epclusa increases levels of the HMG-CoA reductase inhibitors, rosuvastatin and 
atorvastatin.  Patients on atorvastatin and rosuvastatin should be monitored closely for evidence of 
myopathy; and the dose of rosuvastatin should not exceed 10 mg and the dose of atorvastatin should 
not exceed 20 mg. 
Epclusa should not be administered in conjunction with the following medications: 
− 
Proton pump inhibitors (other than omeprazole 20 mg as above) 
− 
Amiodarone 
− 
Digoxin 
− 
Topotecan 
− 
Carbamazepine 
− 
Phenytoin 
− 
Phenobarbital 
− 
Oxcarbazepine 
− 
Rifabutin 
− 
Rifampin 
− 
Rifapentine 
− 
Efavirenz 
− 
Tipranavir/ritonavir 


CRI 15-05 Protocol 13SEP2017 
Page 16 
 
 
− 
St. John’s Wort 
− 
Sofosbuvir as a single agent 
 
The efficacy of Epclusa in treatment naïve and treatment experienced (with pegylated interferon and 
RBV ± Protease inhibitor) non-cirrhotics and compensated cirrhotics was evaluated in three Phase 3 trials 
of 1035 subjects with genotypes 1, 2, 3, 4, 5 and 6. 
ASTRAL-1: Randomized placebo controlled trial of Epclusa for 12 weeks in subjects with 
genotypes 1, 2, 4, 5, 6 
ASTRAL-2: Randomized controlled open label trial of Epclusa for 12 weeks compared with 
SOF/RBV for 12 weeks in subjects with genotype 2 
ASTRAL-3: Randomized controlled open label trial of Epclusa for 12 weeks compared with 
SOF/RBV for 24 weeks in subjects with genotype 3 
 
Week 12 sustained virologic response (SVR-12) rates for subjects treated in ASTRAL-1 with Epclusa for 12 
weeks are shown in the table below 
 
 
ASTRAL-1 Virologic Outcomes 
Genotype (n) 
SVR-12 
1a (210) 
98% 
1b (118) 
99% 
2 (104) 
100% 
4 (116) 
100% 
5 (35) 
97% 
6 (41) 
100% 
 
Week 12 sustained virologic response (SVR-12) rates for genotype 3 subjects treated in ASTRAL-3 with 
Epclusa for 12 weeks or SOF/RBV for 24 weeks are shown in the table. 
 
ASTRAL-3 Virologic Outcomes 
 
SVR 12 for Epclusa for 12 weeks 
SVR 12 for SOF/RBV for 24 weeks 
Treatment class 
 
Naive 
Experienced 
Naïve 
Experienced 
Without cirrhosis 
 
98% 
94% 
90% 
71%  
With 
Compensated 
Cirrhosis 
93% 
89% 
73%  
58% 
 
3.3 Buprenorphine/naloxone 
Buprenorphine/naloxone is used to treat opioid dependence.  It is a combination of two medications, 
buprenorphine and naloxone, in a 4:1 ratio. 
Buprenorphine is a partial agonist at the μ-opioid receptor with a high affinity and slow dissociation from 
these receptors.  In individuals undergoing withdrawal from full opioid agonists, such as heroin, 
buprenorphine ameliorates withdrawal symptoms by partially activating the μ-opioid receptors. 


CRI 15-05 Protocol 13SEP2017 
Page 17 
 
 
Naloxone is a potent opioid antagonist at the μ-opioid receptor and precipitates opioid withdrawal when 
administered parenterally in individuals physically dependent on full opioid agonists.  Naloxone has 
limited sublingual absorption such that the inclusion of naloxone in buprenorphine/naloxone reduces 
the potential for parenteral abuse of buprenorphine (i.e. by crushing and dissolving tablets or dissolving 
film for intravenous injection). 
Buprenorphine/naloxone is available as both a sublingual film and a tablet. 
Buprenorphine/naloxone sublingual film is supplied as an orange rectangular sublingual film with a white 
printed logo in four dosage strengths: 
• 
buprenorphine/naloxone 2 mg/0.5 mg 
• 
buprenorphine/naloxone 4 mg/1 mg 
• 
buprenorphine/naloxone 8 mg/2 mg 
• 
buprenorphine/naloxone 12 mg/3 mg 
Buprenorphine/naloxone sublingual tablets are supplied in 2 dosage strengths: 
• 
buprenorphine/naloxone 2 mg/0.5 mg 
• 
buprenorphine/naloxone 8 mg/2 mg 
Typical maintenance doses range from 8-16 mg of buprenorphine with 2 to 4 mg of naloxone. 
The safety of buprenorphine/naloxone is supported by clinical trials of buprenorphine (Subutex) 
sublingual tablets and buprenorphine/naloxone sublingual tablets and buprenorphine/naloxone 
sublingual solution and buprenorphine/naloxone sublingual tablets.  In total, safety data from clinical 
studies are available from over 3000 opioid-dependent subjects exposed to buprenorphine at doses in 
the range used in the treatment of opioid dependence.  The most common side effects of 
buprenorphine/naloxone include dizziness, drowsiness, abdominal pain, nausea, constipation, headache, 
insomnia, hyperhidrosis, and flushing.  The sublingual film product may also cause numbness, burning, 
tingling of the mouth. 
Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other 
central nervous system (CNS) depressants (including alcohol), has been associated with significant 
respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death 
associated with the concomitant use of buprenorphine and benzodiazepines involved misuse by self-
injection. Deaths have also been reported in association with concomitant administration of 
buprenorphine with other depressants such as alcohol or other CNS depressant drugs. 
3.4 Compliance 
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), and all 
applicable regulatory requirements. 
4 OBJECTIVES 
4.1 Primary Objective: 
• 
To assess the effectiveness, as measured by SVR-12, of HCV treatment with Epclusa 
administered by psychiatrist/licensed buprenorphine/naloxone providers during regularly 


CRI 15-05 Protocol 13SEP2017 
Page 18 
 
 
scheduled visits to an outpatient addiction clinic for buprenorphine/naloxone replacement 
therapy and mental healthcare. 
4.2 Secondary Objectives: 
• 
To assess the impact of HCV treatment on health-related quality of life among subjects on 
buprenorphine/naloxone therapy. 
• 
To assess adherence to Epclusa therapy in subjects administered treatment in the context of 
visits to an outpatient addiction clinic for buprenorphine/naloxone replacement therapy and 
mental healthcare. 
4.3 Exploratory Objective: 
• 
To design and assess a curriculum and mentorship program to support psychiatrists with 
managing HCV infection.  For the purpose of this study, the curriculum will be tailored to the 
management of HCV genotypes 1, 2, 3, 4, 5 and 6 and treatment with Epclusa. 
5 STUDY DESIGN 
5.1 Treatment Plan and Regimen 
This is a single arm pilot study of administering HCV treatment at an outpatient addiction clinic staffed by 
psychiatrists at Cambridge Health Alliance. Approximately 20 subjects will be enrolled and treated with 
Epclusa tablet once daily for 12 weeks. 
5.2 Subject Recruitment 
Patients with HCV infection already engaged in addiction treatment at Cambridge Health Alliance will be 
identified by members of the study team and/or the psychiatrist-buprenorphine/naloxone providers and 
approached regarding participation. Importantly, HCV status will already be recorded in the medical 
record as all patients are routinely screened for hepatitis C infection upon entry into the OAS program. 
Psychiatrist-buprenorphine/naloxone prescribers will be approached by study investigators to 
participate based on meeting the entry criteria as providers employed at the outpatient addiction clinic 
at Cambridge Health Alliance. 
5.3 Visit Schedule 
All study visits will take place at the outpatient addiction clinic at Cambridge Health Alliance. A study 
coordinator employed by Community Research Initiative will conduct the study visits in conjunction with 
the psychiatrist-buprenorphine/naloxone provider at Cambridge Health Alliance. 
Subjects will complete all of the following visits: Screening, Baseline/Day 1, On-Treatment Visits 
approximately biweekly throughout treatment, and Post-Treatment Visits at Weeks 4 and 12 (from time 
of last dose of study drug.) 
Screening assessments will be completed within 28 days of the Baseline/Day 1 Visit. The screening 
window may be extended to 42 days prior to Day 1 for subjects with in extenuating circumstances, if 
approved by Medical Monitor. 
The assessments performed at each visit are described in Sections 8.2 and 8.3. 


CRI 15-05 Protocol 13SEP2017 
Page 19 
 
 
5.4 HCV Virologic Response-Based Treatment Stopping Criteria 
Treatment will be stopped if there is a less than 1 log10 decline in HCV RNA after 4 weeks of therapy. 
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after an 
initial observation indicating virologic failure. All subjects who terminate treatment early will complete 
the Early Termination (ET) Visit, Week 4 and Week 12 Post-Treatment Visits. 
5.5 Treatment Discontinuation Criteria 
The Medical Monitor should be consulted prior to subject discontinuation when medically feasible. Study 
drug must be discontinued in the following instances: 
• 
Unacceptable toxicity, as defined in Section 9 of the protocol, or toxicity that, in the judgment of 
the Sponsor-Investigator or Sub-Investigator(s), compromises the ability to continue study-
specific procedures or is considered to not be in the subject’s best interest 
• 
Pregnancy of female subject 
• 
HCV efficacy failure as defined in Section 5.3 
• 
Significant protocol violation 
• 
Subject request to discontinue for any reason; it is important to determine and document 
whether the withdrawal of consent is primarily due to an adverse event (AE), lack of efficacy, or 
other reason 
• 
Discontinuation of the study at the request of CRI, regulatory agency, or an Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) 
If a subject meets discontinuation criteria during treatment, an Early Termination Visit will be required 
(Section 8.2.4). Early Termination Visits should be scheduled as soon as possible following 
discontinuation of treatment. Subjects that discontinue treatment early are still required to complete 
Post-Treatment Weeks 4, and 12 Visits. 
6 SUBJECT POPULATION 
6.1 Number of Subjects and Subject Selection 
Approximately 20 subjects with chronic HCV infection will be enrolled, including individuals who have 
compensated cirrhosis and who have been previously treated with pegylated-interferon and ribavirin ± 
an HCV protease inhibitor. Due to the limited resources available for this proof of concept pilot study, 
only English-speaking participants will be considered for enrollment. 
6.2 Inclusion Criteria for clinical subjects 
1. Willing and able to provide written informed consent 
2. Age ≥ 18 years 
3. Confirmation of chronic HCV infection as documented by a positive HCV 
antibody test at least 6 months prior to the Baseline/Day 1 visit OR by 
patient report of infection for at least 6 months prior to the baseline/day 1 
visit AND positive HCV RNA test at screening 
4. HCV genotype 1, 2, 3, 4, 5 or 6 
5. In stable remission from opioid use on buprenorphine/naloxone for at least 
12 weeks 


CRI 15-05 Protocol 13SEP2017 
Page 20 
 
 
6. Within the following laboratory parameters as assessed at the screening 
visit: 
a. HCV RNA quantifiable 
b. Screening rhythm strip without bradycardia (heart rate > 60 or, if on 
beta blocker, > 55 BPM) 
c. ALT ≤ 10 x ULN 
d. AST ≤ 10 x ULN 
e. Direct bilirubin ≤ 1.5 x ULN 
f. Platelets > 60,000 
g. HbA1c ≤ 13% 
h. Creatinine clearance ≥ 30 mL/min, as calculated by the Cockcroft-
Gault equation 
i. 
Albumin ≥ 3g/dL 
j. 
INR ≤ 1.5 x ULN or on an anticoagulant regimen affecting INR 
7. Female subject is eligible to enter if it is confirmed that she is: 
a. Not pregnant or nursing 
b. Not of childbearing potential (i.e. s/p hysterectomy, oophorectomy 
or has medically documented ovarian failure, or are postmenopausal 
women > 50 years of age with cessation of menses for 12 months or 
greater) 
OR 
Of childbearing potential with a negative serum pregnancy test 
within 2 weeks of screening, a negative urine pregnancy test on Day 
1, and a commitment to either abstain from intercourse or 
consistently use an acceptable method of birth control (Appendix 4) 
in addition to condom use by her male partner(s) from the date of 
screening until 30 days after the last dose of study drug 
8. All male study participants must agree to consistently and correctly use 
condoms with their female partner(s) of childbearing potential and such 
female partner(s) must agree to use an acceptable method of birth control 
(listed) from the date of screening until 90 days after the last dose of study 
drug 
9. Male subjects must refrain from sperm donation from the date of screening 
until 90 days after the last dose of study drug 
10. Subject must be in generally good health, with the exception of HCV, in the 
opinion of the Sponsor-Investigator or Sub-Investigator(s) 
11. Subject must be able to comply with dosing instructions for study drug 
administration and able to complete the study visits, including all required 
post-treatment visits 
 
Subjects must meet all of the above inclusion criteria to be eligible for participation in this study. 
6.3 Exclusion Criteria for clinical subjects 
 
1. Presence of decompensated cirrhosis as defined by encephalopathy, ascites, 
or a history of a variceal bleed 


CRI 15-05 Protocol 13SEP2017 
Page 21 
 
 
2. Prior treatment with direct acting antiviral hepatitis C medications 
3. Positive urine drug toxicity test at screening (except for cannabinoids and 
prescribed medications) 
4. Absence of buprenorphine in urine sample at screening 
5. Currently pregnant or breastfeeding female 
6. Detectable HIV RNA > 50 copies/ml (co-infected subjects with suppressed 
viral load ARE eligible for participation) 
7. Use of any prohibited concomitant medication within 28 days prior to day 1 
8. Chronic use of systemically administered immunosuppressive agents 
9. Difficulty with blood collection or poor venous access 
10. History of solid organ transplantation 
11. Known significant allergy to sofosbuvir or velpatasvir 
12. Current chronic liver disease of a non-HCV etiology (including 
hemochromatosis, Wilson’s disease, alfa-1 antitrypsin deficiency) 
13. Active HBV infection defined as either a positive HBV surface antigen test or 
a positive test for HBV DNA. (Subjects who are positive for HBV core 
antibody but negative for Hepatitis B sAb, sAg, and DNA ARE eligible) 
6.4 Eligibility Criteria for Provider Participants 
All licensed buprenorphine/naloxone providers who are also fully licensed psychiatrists 
at the outpatient addiction clinic at Cambridge Health Alliance are eligible to participate 
in the study. Participation will require: 
1. Attendance at the teaching session on the evaluation and management of 
hepatitis C infection conducted by the Study Investigator, Dr. Amy Colson (see 
Appendix 6 for teaching curriculum) 
2. Agreement to have weekly mentorship by telephone with Dr. Colson. 
3. Provision of written informed consent addressing survey completion 
 
Given his role on the study team, Dr. Zev Schuman-Olivier will not be eligible to 
participate in the provider survey. 
7 MEDICINAL PRODUCT 
7.1 Enrollment and Treatment 
This is an open label study. 
7.2 Description and Handling of Epclusa 
7.2.1 
Formulation 
Epclusa (sofosbuvir/velpatasvir FDC) tablets are pink, diamond-shaped, film-coated tablets containing 
400 mg of sofosbuvir and 100 mg of velpatasvir. The tablets are debossed with “GSI” on one side and 
“7916” on the other side. The Epclusa tablets contain the following inactive ingredients: copovidone, 
microcrystalline cellulose, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, iron 
oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. 


CRI 15-05 Protocol 13SEP2017 
Page 22 
 
 
7.2.2 
Packaging and Labeling 
Epclusa tablets are packaged in standard 28-tablet medication vials compatible with the MEMSCap™ 
Medication Event Monitoring System that will be utilized as an adherence monitoring method in addition 
to traditional pill counts.  The TrackCap® product features integrated microcircuits that records the date 
and time whenever the medication vial is opened.  The electronic data collected in the medication event 
monitoring system will be downloaded into a designated, secured, limited access study computer for 
immediate review and later analysis. All Epclusa packaging will be labeled to meet all applicable 
requirements of the US Food and Drug Administration (FDA), Annex 13 of Good Manufacturing Practices: 
Manufacture of investigational medicinal products (July 2010) and/or other local regulations as 
applicable. 
7.2.3 
Storage and Handling 
Epclusa 28-tablet medication vials will be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25 degrees Celsius (77 degrees Fahrenheit); 
excursions are permitted between 15 and 30 degrees Celsius (59 to 86 degrees Fahrenheit). 
All drug products will be stored in a securely locked area, accessible only to authorized site personnel. To 
ensure the stability of the study drug and to ensure proper product identification, the drug product will 
not be stored in a fashion other than the blister package in which they are supplied. Consideration 
should be given to handling, preparation, and disposal through measures that minimize drug contact 
with the body. Appropriate precautions should be followed to avoid direct eye contact or exposure 
through inhalation when handling Epclusa. 
7.2.4 
Dosage and Administration of Epclusa 
One Epclusa tablet is to be administered once daily with or without food. Each subject will be given 
instructions to maintain approximately the same daily dosing interval between study drug doses. 
For a missed dose of Epclusa, subjects will be instructed to take the missed dose of study drug as soon as 
possible within 12 hours of the missed dose. Subjects will also be cautioned never to double the next 
dose with a missed dose of study drug under any circumstances. 
7.3 Prior and Concomitant Medications 
Concomitant medications taken within 30 days prior to screening, up to and including 30 days after the 
last dose of study drug, need to be recorded in the source documents and case report form(s) (CRFs). 
The following medications are prohibited during the screening period and for a minimum of 28 days 
prior to the Baseline/Day 1 Visit through the end of study: 
• 
Proton pump inhibitors (other than omeprazole 20 mg as below) 
• 
Amiodarone 
• 
Digoxin 
• 
Carbamazepine 
• 
Phenytoin 
• 
Phenobarbital 
• 
Oxcarbazepine 
• 
Rifabutin 
• 
Rifampin 
• 
Rifapentine 
• 
Efavirenz 


CRI 15-05 Protocol 13SEP2017 
Page 23 
 
 
• 
Tipranavir/ritonavir 
• 
Sofosbuvir as a single agent 
• 
St. John’s wort, echinacea, milk thistle 
• 
Rosuvastatin at a dose exceeding 10 mg 
• 
Atorvastatin at a dose exceeding 20 mg 
 
The following medications will be used with caution during the study: 
Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease 
the concentration of velpatasvir.   Therefore, patient who are currently on acid lowering therapy 
including Antacids (Tums, Mylanta, Maalox, Rolaids etc.), Famotidine/Pepcid, Ranitidine/Zantac, 
Esomeprazole/Nexium, Omeprazole/Prilosec, Lansoprazole/Prevacid, Pantoprazole/Protonix and who 
must continue acid lowering therapy must agree to one of the three acid lowering treatment regimens. 
− 
Tums as needed separated from Epclusa by at least 4 hours 
− 
Zantac at a dose no higher than 150 mg once daily to be separated from Epclusa by 12 hours 
− 
Omeprazole at a dose no higher than 20 mg once daily.  For patients on omeprazole, Epclusa 
must be taken with food 4 hours prior to omeprazole dosing. 
 
Renal function should be monitored in patients taking tenofovir DF with Epclusa. 
Epclusa increases levels of the HMG-CoA reductase inhibitors, rosuvastatin and atorvastatin. Patients on 
atorvastatin and rosuvastatin should be monitored closely for evidence of myopathy. The dose of 
rosuvastatin should not exceed 10 mg and the dose of atorvastatin should not exceed 20 mg. 
Medications for disease conditions excluded from the protocol (e.g., active cancer, transplantation) are 
not listed under this Concomitant Medication section and are disallowed in the study. 
7.4 Monitoring Accountability and Study Drug Adherence for Epclusa 
The Sponsor-Investigator is responsible for ensuring adequate accountability of all used and unused 
study drug. This includes acknowledgement of receipt of the shipment of study drug (quantity and 
condition), detailed inventory documentation, and detailed dispensation and excess medication return 
documentation 
Epclusa will be stored at the CRI facility in accordance with CRI SOPs, in a temperature controlled, 
secure, limited-access location.  Epclusa will be transported to the study conduct location, Cambridge 
Health Alliance, in a private vehicle (i.e. livery or privately owned automobile) in the direct possession of 
the study coordinator and in a securely locked carry-case. If any study drug transported to the study 
location is not dispensed, it will be returned to secure storage at CRI in the same manner.  Temperature 
of drug environment during transportation will be monitored and recorded.  Any excursion from 
acceptable storage temperature will result in quarantine from the dispensable supply. 
Subjects will be instructed to bring back all study drug original containers at every post-baseline study 
visit through the end of treatment. 
Study drug will be reconciled using study drug pill count at every post-baseline visit by the Sponsor-
Investigator, Sub-Investigator(s) or designee (i.e. study coordinator) in order to monitor the subject’s 
adherence with the study drug regimen. 


CRI 15-05 Protocol 13SEP2017 
Page 24 
 
 
Epclusa accountability records will be maintained in order to: 
• 
Record the date, subject number, subject initials, the study drug dispensed. 
• 
Record the date, quantity of used and unused study drug for returned Epclusa, along with the 
initials of the person recording the information. 
Adherence will be further monitored through MEMSCap™ Medication Event Monitoring System.  The 
TrackCap® features integrated microcircuits that records the date and time whenever the medication 
vial is opened.  The electronic data collected in the medication event monitoring system will be 
downloaded via a dedicated MEMs reader onto a designated, secured, limited access study computer for 
review during the study visit and for later analysis.  At every post-baseline study visit the Investigator or 
designee will download the electronic adherence monitoring data and review with the participant, 
providing adherence counseling as needed. 
To ensure consistent access to study drug, at baseline, a 28 day supply of medication will be dispensed 
along with a 28 day back-up supply.  In the event that a subject misses a regularly scheduled visit, s/he 
will be contacted by study staff to reschedule as soon as possible, and will be counseled on use of the 
back-up medication supply if necessary (see Section 7.2.4).  Accountability for the back-up supply will be 
monitored at each study visit, any doses taken recorded, and the back-up supply will then be 
redispensed to the subject. 
8 STUDY PROCEDURES 
The study procedures to be conducted for each subject enrolled in the study are presented in tabular 
form in Appendix 2 and described in the text that follows. 
All study procedures will take place at the outpatient addiction clinic at Cambridge Health Alliance. 
The Sponsor-Investigator must document any deviation from protocol procedures and notify the IRB, per 
the IRB’s reporting requirements. 
8.1 Informed Consent 
Prior to any protocol required procedures as outlined in Section 8, informed consent must be obtained.  
Patients identified by study team investigators or participating psychiatrist-buprenorphine/naloxone 
prescribers will be approached to potentially participate in the study.  They will be given a copy of the 
informed consent and provided the opportunity to meet with study staff as many times as they would 
like, to review the details of the study, and the consent document.  They may also take it home and 
share it with friends, family and other medical providers, as they consider participation.  Once the 
subject feels all their questions have been answered, and study staff have assessed that they 
comprehend the study information presented in the informed consent document, the consent will be 
signed by the study subject and cosigned by the study staff explaining the study.  Study staff will ensure 
that the process was compliant with CRI SOP for obtaining consent and will ensure the following 
essential components of consent: 
• 
Process was not coercive 
 
• 
Consent obtained before protocol procedures initiated 
 
• 
Information about the study including all available options was provided in a language 
understood by the subject 


CRI 15-05 Protocol 13SEP2017 
Page 25 
 
 
 
• 
Opportunity was given to the subject to consider all available options 
 
• 
Questions and concerns were addressed 
 
• 
Subject states comprehension of information 
 
• 
Consent signed and dated by subject with first and last name using ink 
 
• 
Consent signed and dated by coordinator using ink 
 
• 
Copy of signed Informed Consent was given to the subject 
 
• 
Copy of signed Informed Consent was filed in source documents 
 
8.2 Screening Visit (Day -28 to Day 0) 
Subjects will be screened within 28 days of the Baseline/Day 1 Visit to determine eligibility for 
participation in the study. The screening window may be extended to 42 days prior to Day 1 for subjects 
with extenuating circumstances if approved by the Medical Monitor. 
The following will be performed and documented at screening: 
• 
Obtain written informed consent 
• 
Determine eligibility (Reference Sections  6.2 &  6.3) 
• 
Obtain select medical history including risk factor(s) for HCV infection, estimated duration of 
HCV infection, prior assessments of fibrosis, HCV genotype if known, prior HCV treatment, 
comorbid liver diseases 
• 
Obtain details of AEs related to screening procedures (Reference Section 9) 
• 
Obtain details of concomitant medications 
• 
Pregnancy prevention counseling 
• 
Pregnancy testing for women of childbearing potential only (Reference Study Procedures Table  
Appendix 2) 
• 
Obtain blood samples (Reference Study Procedures Table  Appendix 2) 
• 
Obtain urine samples (Reference Study Procedures Table  Appendix 2) 
A single retest of screening labs is permitted only if there is reason to believe the retest value will be 
within accepted parameters (i.e. if the initial value was either due to a sample processing error or due to 
an extenuating circumstance such as intercurrent infection). 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the clinic for 
the Baseline/Day 1 Visit assessments and enrollment. 
From the time of obtaining informed consent through the first administration of study drug, all serious 
adverse events (SAEs), as well as any non-serious adverse events related to protocol-mandated 
procedures, will be recorded on the adverse events case report form (eCRF). All other untoward medical 
occurrences observed during the screening period, including exacerbation or changes in medical history, 
are to be captured on the medical history CRF/eCRF. 
See Section 9: Adverse Events and Toxicity Management for additional details. 


CRI 15-05 Protocol 13SEP2017 
Page 26 
 
 
8.3 Treatment Assessments 
8.3.1 
Baseline/Day 1 Visit 
The following baseline tests and procedures must be completed prior to enrollment and 
dosing/dispensing: 
• 
Confirm eligibility 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy Prevention Counseling 
• 
Subject completes Quality of Life Surveys (FACIT-F, PROMIS ED -Depression SF8a, SF36) 
• 
Obtain urine samples (Reference Study Procedures Table  Appendix 2) 
• 
Pregnancy testing for women of childbearing potential only (Reference Study Procedures Table  
Appendix 2) 
• 
Dispense 4 week study drug supply and backup bottle with MEMScapsTM 
• 
Instruct the subject on the packaging, storage and administration of the study drug 
8.3.2 
Weeks 2, 4, 6, 8, 10 (+/-3 days) 
The following procedures/assessments are to be completed: 
• 
Assessment of AEs and concomitant medications 
• 
Obtain blood samples (Reference Study Procedures Table  Appendix 2) 
• 
Obtain urine samples (Reference Study Procedures Table  Appendix 2) 
• 
Pregnancy testing for women of childbearing potential only (Reference Study Procedures Table  
Appendix 2) 
• 
Pregnancy Prevention Counseling 
• 
Assess compliance with study drug dosing regimen including pill count 
• 
Download MEMSCapTM Adherence Data 
• 
Dispense study drug supply (weeks 4 and week 8, or as needed for emergency supply) 
• 
Additionally, at week 4 visit only, subject will complete Quality of Life Surveys FACIT-F, PROMIS 
ED -Depression SF8a, SF36) 
 
8.3.3 
End of Treatment (+/-3 days) 
The following procedures/assessments are to be completed at the end of Epclusa treatment (Week 12): 
• 
Assessment of AEs and concomitant medications 
• 
Subject completes Quality of Life Surveys (FACIT-F, PROMIS ED -Depression SF8a, SF36) 
• 
Obtain urine samples (Reference Study Procedures Table  Appendix 2) 
• 
Pregnancy testing for women of childbearing potential only (Reference Study Procedures Table  
Appendix 2) 
• 
Pregnancy Prevention Counseling 
• 
Assess compliance with study drug dosing regimen including pill count 
• 
Download MEMSCapTM Adherence Data 
8.3.4 
Early Termination Visit 
The Sponsor-Investigator and other study staff (e.g., Medical Monitor, Sub-Investigator(s), and Clinical 
Project Manager) must be informed, as soon as possible, when a subject comes off treatment due to an 
AE. 


CRI 15-05 Protocol 13SEP2017 
Page 27 
 
 
If a subject discontinues treatment early for any reason then the following assessments for the Early 
Termination (ET) Visit must be performed: 
• 
Assessment of AEs and concomitant medications 
• 
Subject completes Quality of Life Surveys (FACIT-F, PROMIS ED -Depression SF8a, SF36) 
• 
Obtain blood samples (Reference Study Procedures Table  Appendix 2) 
• 
Obtain urine samples (Reference Study Procedures Table  Appendix 2) 
• 
Pregnancy testing for women of childbearing potential only (Reference Study Procedures Table  
Appendix 2) 
• 
Pregnancy Prevention Counseling 
• 
Assess compliance with study drug dosing regimen including pill count 
• 
Download MEMSCapTM Adherence Data 
8.4 Post-Treatment Assessments 
All subjects must complete the Post-Treatment visits 4 and 12 weeks following the last dose of study 
drug. 
8.4.1 
Post-Treatment Week 4 and 12 (+/- 5 days) 
The following procedures/assessments are to be completed: 
• 
Assessment of AEs 
• 
Pregnancy testing for women of childbearing potential only at the Post-Treatment Week 4 visit 
only (Reference Study Procedures Table  Appendix 2) 
• 
Obtain blood samples (Reference Study Procedures Table  Appendix 2) 
• 
Additionally, at post treatment week 12 visit only, subject will complete Quality of Life Surveys 
FACIT-F, PROMIS ED -Depression SF8a, SF36) 
Subjects with a HCV RNA > LLOQ at the Post-Treatment Week 12 Visit will return for confirmatory HCV 
RNA, preferably within 2 weeks. 
8.5 Unscheduled Visit 
A subject should attend an unscheduled visit if requested by the Sponsor-Investigator or Sub-
Investigator(s). The assessments are at the requestor’s discretion, and will at a minimum collect AE and 
concomitant medication information. 
8.6 Assessments for Premature Discontinuation from Study Dosing 
If a subject discontinues study drug dosing (for example, as a result of an AE), every attempt should be 
made to keep the subject in the study and continue to perform the required study-related follow-up and 
procedures. If this is not possible or acceptable to the subject or Sponsor-Investigator, the subject may 
be withdrawn from the study. 
8.7 Procedures and Specifications 
8.7.1 
Clinical Laboratory Analytes 
• 
Blood Collection 
o All required laboratory blood assessments will be conducted as described in Appendix 2, 
and per the discretion of the Sponsor-Investigator or Sub-Investigator(s).  Additional 
assessments may be conducted per standard of care at the enrolling site and per the 
discretion of the Sponsor-Investigator or Sub-Investigator(s). 


CRI 15-05 Protocol 13SEP2017 
Page 28 
 
 
• 
Urine Collection 
o Urine assessments for drug screening and pregnancy (in WOCBP) will be conducted as 
described in Appendix 2.  Additional assessments may be conducted per standard of care 
at the enrolling site and per the discretion of the Sponsor-Investigator or Sub-
Investigator(s). 
8.7.1.1 
Management of Positive Urine Drug Screening Assessment 
In the event that a study subject has a positive urine drug screen the subject will be 
managed according to the judgment of the Sub-Investigator.  Interventions may include 
increased frequency of study visits, additional remote monitoring and support, and 
enhanced supplemental services for substance use prevention. 
8.7.2 
Medical History 
Selected medical history will be collected by subject self-report and available medical records, including: 
• 
risk factor for HCV 
• 
estimated duration of HCV infection 
• 
prior assessments of fibrosis 
• 
HCV genotype if known 
• 
prior HCV treatment 
• 
comorbid liver diseases including hemochromatosis, autoimmune hepatitis, alpha-1-antitrypsin 
deficiency, obesity 
• 
history of hepatic decompensation including variceal bleed, ascites, and encephalopathy 
• 
clinically significant, active in the last year and ongoing conditions at time of enrollment 
8.7.3 
Quality of Life Surveys 
• 
Quality of life surveys included in this study are Functional Assessment of Chronic Illness 
Therapy-Fatigue (FACIT-F), PROMIS Short Form v1.0 - ED-Depression 8a (PROMIS ED -Depression 
SF8a), Short Form Health Survey (SF36) which will be completed by subjects at Baseline/Day 1, 
on treatment week 4 visit, End of Treatment/Early Termination visits and post treatment week 
12 visit. The subject should read and complete the surveys by himself/herself and write/mark 
answers directly onto the questionnaire. 
8.7.4 
Missed Visits 
In the event that a subject misses a scheduled clinic visit, the study staff will telephone the subject within 
24 hours of the missed visit.  Another study visit will be scheduled for as soon as possible.  The study 
staff will counsel subjects on how to continue study drug dosing from their back-up medication pack 
until the rescheduled visit, to ensure no missed doses. 
8.7.5 
Mentorship 
Participating psychiatrists must consent to participate in the study.  A consent form will be provided to 
the psychiatrist-buprenorphine/naloxone provider prior to the initial training session with ample time for 
the psychiatrists to read the consent and have their questions answered.  They will be offered the 
opportunity to review the consent with study investigators by telephone or in face-to-face meetings with 
a study investigator or study team member.  If they agree to consent, the signing of the consent will 
occur in the presence of a study team member, who will cosign the document.  A copy of the signed 
consent will be provided to each psychiatrist-buprenorphine/naloxone prescriber.  The original will be 
kept in a secure, locked study file at the CRI facility.  Study consent procedures consistent with CRI SOP 
for informed consent will be followed (outlined in detail in section 8.1). 


CRI 15-05 Protocol 13SEP2017 
Page 29 
 
 
After consenting to participate, but prior to screening the first subject, the psychiatrists at the outpatient 
addiction clinic will undergo a training session with the Sponsor-Investigator which will address the 
management of HCV.  The following topics will be addressed: 
• 
Pathogenesis of HCV infection 
• 
Goals of therapy/benefits of curing HCV 
• 
Pre-treatment assessment, including diagnosis of cirrhosis 
• 
Usage of Epclusa 
The session will be based on the teaching slides in Appendix 6. 
In addition, the Sponsor-Investigator will provide regularly scheduled weekly telephone support to the 
psychiatrists. 
The psychiatrists’ comfort level with providing care for patients with HCV infection will be determined by 
a questionnaire administered prior to the training session, after the training session, and after 4 months 
of actively treating subjects (Appendix 3).  All responses to these questionnaires will be kept strictly 
confidential. 
8.7.6 
Location of Study Activities 
This protocol is intended for study and implementation within the outpatient addiction clinic at 
Cambridge Health Alliance.  The Community Research Initiative Sponsor-Investigator and study team will 
collaborate with the psychiatry team at the outpatient addiction clinic to implement the study and 
collect study data at the addiction clinic location on pre-specified days. 
All procedures with study participants will take place at the outpatient addiction clinic and at a 
phlebotomy lab one flight downstairs from the addiction clinic.  No study-related records or study drug 
will be stored at the outpatient addiction clinic.  For each day session of study visits at the Sub-
Investigator’s clinic, study staff will transport documentation and study drug, on the day of the session, 
for only the subjects scheduled for visits that day.  Study staff will bring blank source documentation 
worksheets, questionnaires, and informed consents as needed.  Study staff will transport investigational 
drug securely to the clinic for the subjects scheduled, per CRI SOPs.  Refer to section 7.4 for further detail 
on storage and transportation of study-related medication. Upon completion of source documentation 
worksheets, questionnaires, and ICFs, the study coordinator will immediately transport these study 
documents and returned study medication containers to the CRI office for secure storage. 
To ensure maintenance of subject confidentiality, the following procedures with study records will be 
followed: 
• 
Any documentation from the subject medical record that contains subject identifying 
information will be faxed from the clinic to Community Research Initiative via secure fax, for 
inclusion in the subject source document.  These items will be certified copies of the original 
faxed documents. 
• 
Informed consent documents must include patient names and signatures and in accordance with 
the regulations, must be original documents.  These documents will be transported by the study 
coordinator directly from the clinic to Community Research Initiative for secure storage.  They 
will be transported in a private vehicle (i.e. livery or privately owned automobile) in the direct 
possession of the study coordinator and in a securely locked carry-case. 
• 
To maintain subject confidentiality, all other source documentation worksheets completed at 
study visits will not have patient names or identifying information.  These documents will be 


CRI 15-05 Protocol 13SEP2017 
Page 30 
 
 
completed utilizing the unique 3 letter code and study specific numeric code number assigned 
upon screening and enrollment. 
Community Research Initiative will maintain and store all essential documents and study medication for 
this study.  All study data entry into the eCRF will occur at the CRI office by trained study staff. Ongoing 
regulatory filing, maintenance of essential documents and monitoring of study data will occur at the CRI 
office and be conducted by trained study staff. 
9 ADVERSE EVENTS AND TOXICITY MANAGEMENT 
 
Given that subjects will receive standard of care evaluation and treatment for their chronic hepatitis C 
infection, we believe that study participation poses minimal excess risk.  Indeed, we believe that subjects 
will benefit from improved access to this important treatment which will be provided at a convenient 
location by a known physician under the guidance of an infectious disease physician with extensive 
experience treating HCV infection. Potential risks to study participation may include 
1. Increased frequency of appointments at the outpatient addiction clinic for those who are usually 
seen less frequently than every 2 weeks. 
2. Increased duration of the appointments at the outpatient addiction clinic for completion of 
study procedures. 
9.1 Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events 
9.1.1 
Adverse Events 
An AE is any untoward medical occurrence in a clinical study subject administered a pharmaceutical 
product, which does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. AEs may also include 
pre- or post-treatment complications that occur as a result of protocol specified procedures, lack of 
efficacy, overdose, drug abuse/misuse reports, or occupational exposure. Preexisting events that 
increase in severity or change in nature during or as a consequence of participation in the clinical study 
will also be considered AEs. 
An AE does not include the following: 
• 
Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported. 
• 
Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions) 
• 
Overdose without clinical sequelae 
• 
Any medical condition or clinically significant laboratory abnormality with an onset date before 
the consent form is signed and not related to a protocol-associated procedure is not an AE. It is 
considered to be pre-existing and should be documented on the medical history CRF. 
9.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following: 


CRI 15-05 Protocol 13SEP2017 
Page 31 
 
 
• 
Death 
• 
Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.) 
• 
In-patient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect 
• 
A medically important event or reaction: such events may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes constituting SAEs. Medical and scientific judgment must be 
exercised to determine whether such an event is a reportable under expedited reporting rules. 
Examples of medically important events include intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; and development of drug dependency or drug abuse. For the avoidance of 
doubt, infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements. 
Clarification of Serious Adverse Events: 
• 
Death is an outcome of an adverse event, and not an adverse event in itself.  In reports of death 
due to "Disease Progression", where no other information is provided, the death will be 
assumed to have resulted from progression of the disease being treated with the study drugs. 
• 
All deaths, regardless of cause, must be reported for subjects on study and for deaths occurring 
within 30 days of the last study evaluation. 
• 
"Occurring at any dose" does not imply that the subject is receiving study drug at the time of the 
event.  Dosing may have been given as treatment cycles or interrupted temporarily prior to the 
onset of the SAE, but may have contributed to the event. 
• 
"Life-threatening" means that the subject is at immediate risk of death from the event as it 
occurred.  This does not include an event that might have led to death, if it had occurred with 
greater severity. 
• 
Complications that occur during hospitalizations are AE's.  If a complication prolongs 
hospitalization, it is an SAE. 
• 
"Inpatient hospitalization" means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time.  This may or may not be overnight.  It does not include 
presentation and care within an emergency department. 
• 
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms 
and/or other clinical information.  In such cases, the diagnosis should be documented as the AE 
and/or SAE and not the individual signs/symptoms 
NOTE:  The following hospitalizations are not considered SAEs: 
• 
A visit to the emergency room or other hospital department lasting less than 24 hours that does 
not result in admission (unless considered an “important medical event” or a life-threatening 
event) 
• 
Elective surgery planned before signing consent 
• 
Admissions as per protocol for a planned medical/surgical procedure 
• 
Routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) 


CRI 15-05 Protocol 13SEP2017 
Page 32 
 
 
• 
Medical/surgical admission for purpose other than remedying ill health state that was planned 
before study entry.  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 (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative). 
9.1.3 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or Serious 
Adverse Events 
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. However, 
laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that require medical or 
surgical intervention or lead to study drug interruption, modification, or discontinuation must be 
recorded as an AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal assessments 
(e.g., electrocardiogram, x-rays, vital signs) that are associated with signs and/or symptoms must be 
recorded as an AE or SAE if they meet the definition of an AE or SAE as described in Sections  9.1.1 and 
9.1.2 If the laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., 
anemia), not the laboratory result (i.e., decreased hemoglobin). 
For specific information on handling of clinical laboratory abnormalities in this study, please refer to 
Section 9.5. 
9.2 Assessment of Adverse Events and Serious Adverse Events 
The Investigator or qualified Sub-Investigator is responsible for assessing AEs and SAEs for causality and 
severity, and for final review and confirmation of accuracy of event information and assessments. 
9.2.1 
Assessment of Causality for Study Drugs and Procedures 
The Investigator or qualified Sub-Investigator is responsible for assessing the relationship to study drug 
treatment using clinical judgment and the following considerations: 
• 
No: Evidence exists that the adverse event has an etiology other than the study drug. For SAEs, 
an alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication). 
• 
Yes: There is reasonable possibility that the event may have been caused by the investigational 
medicinal product. 
It should be emphasized that ineffective treatment should not be considered as causally related in the 
context of adverse event reporting. 
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) should 
be assessed using the following considerations: 
• 
No: Evidence exists that the adverse event has an etiology other than the study procedure. 
• 
Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture) 
9.2.2 
Assessment of Severity 
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale for Severity 
of Adverse Events and Laboratory Abnormalities (Appendix 4). 
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the clinical 
severity in the context of the underlying conditions; this may or may not be in agreement with the 
grading of the laboratory abnormality. 


CRI 15-05 Protocol 13SEP2017 
Page 33 
 
 
9.3 Sponsor-Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events 
All SAEs, regardless of cause or relationship, that occur after the subject first consents to participate in 
the study (i.e., signing the informed consent) and throughout the duration of the study, including the 
protocol-required post-treatment follow-up period, will be reported to CRI as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed from screening onwards. 
All AEs, regardless of cause or relationship, that occur from initiation of study drug until 4 weeks after 
last administration of study drug shall be reported to the CRF/eCRF database as instructed. 
Any SAEs and deaths that occur after the Post-Treatment follow-up visit OR within 30 days of the last 
dose of study drug (whichever is longer), regardless of causality, shall also be reported. 
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Investigators are not obligated to actively seek SAEs after the 30 day period. However, if the Investigator 
learns of any SAEs that occur after study participation has concluded and the event is deemed relevant 
to the use of study drug, he/she should promptly document and report the event for further assessment 
by CRI study team. 
CRI has requirements for expedited reporting of serious adverse events which meet specific 
requirements of worldwide regulatory authorities.  The reporting period begins when a subject signs the 
informed consent, and ends 30 days after discontinuation of dosing or completion of the subject’s 
participation in the study if the last scheduled visit occurs at a later time. CRI and WIRB (or local IRB if 
not using the central IRB) will be notified within 24 hours of the Sponsor-Investigator’s knowledge of an 
event. The procedures for Investigators and study staff reporting all serious adverse events, regardless of 
causal relationship, are as follows: 
• 
Study staff notify the CRI Medical Monitor and Principal Investigator via 617-502-1799. 
• 
The study staff will complete the IRB Promptly Reportable Information Form and MedWatch 
3500A. The Principal or Sub-Investigator must sign and date the form.  If only limited information 
is available, follow up reports are required.  If the Investigator believes that an SAE is not related 
to the investigational product but is potentially related to the conditions of the study (such as 
withdrawal of previous therapy, or a complication of a study procedure), the potential 
relationship should be specified in the narrative section of the SAE report.  If an ongoing SAE 
changes in its intensity or relationship to the investigational product, a follow up SAE report will 
be filed within 24 hours of awareness.  As follow-up information becomes available, it should be 
sent immediately using the same procedure used for transmitting the initial SAE report.  All SAEs 
should be followed to resolution or stabilization. The original SAE form must be kept on file at 
the study site. 
• 
Record the event on the AE eCRF 
• 
For fatal or life-threatening events, also fax copies of hospital case reports, autopsy reports, and 
other documents with subject personal identifying information redacted. 
• 
Additional information may be requested to ensure the timely completion of accurate safety 
reports. 
Any medications necessary for treatment of the SAE must be recorded onto the concomitant medication 
section of the subject’s eCRF and the event description section of the SAE form. 


CRI 15-05 Protocol 13SEP2017 
Page 34 
 
 
9.4 CRI Reporting Requirements 
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, 
or evaluation of a subject.  To prevent reporting bias, subjects should not be questioned regarding the 
specific occurrence of one or more adverse events. 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its individual 
symptoms.  The following information should be captured for all AEs:  onset, duration, intensity, 
seriousness, relationship to study drug, action taken, and treatment required.  If treatment for the event 
was administered, it should be recorded in the medical record.  The Sponsor-Investigator must retain 
and notify the IRB with any additional information requested, notably for reported deaths of subjects. 
In accordance with relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the Sponsor-Investigator will report all serious adverse events, including reports of 
pregnancies, overdose and cancer that may or may not be associated with an adverse event to the FDA 
via filing of a FDA MedWatch 3500A form. 
 
Assessment of expectedness for SAEs will be determined using reference safety information specified in 
the Investigator’s Brochure. 
Gilead Sciences, Inc. will provide timeline notification of relevant SUSAR reports.  The Sponsor-
Investigator must ensure notification of all study staff of the contents of the SUSAR reports, and will 
notify the IRB/IEC of SUSAR reports in accordance with the IRB/IEC policy. 
9.5 Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse 
Events or Serious Adverse Events 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory abnormalities 
(e.g. clinical chemistry, hematology, and urinalysis) independent of the underlying medical condition that 
require medical or surgical intervention or lead to investigational medicinal product interruption or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, laboratory or 
other abnormal assessments (e.g., electrocardiogram, X-rays, vital signs) that are associated with signs 
and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or SAE) as 
described in Sections  9.1.1 and 9.1.2. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (i.e., anemia) not the laboratory result (i.e., decreased hemoglobin). 
Severity should be recorded and graded according to the GSI Grading Scale for Severity of AEs and 
Laboratory Abnormalities (Appendix 4). For AEs associated with laboratory abnormalities, the event 
should be graded on the basis of the clinical severity in the context of the underlying conditions; this may 
or may not be in agreement with the grading of the laboratory abnormality. 
9.6 Subject Stopping Rules 
The Medical Monitor should be consulted prior to dose discontinuation of Epclusa unless the 
Investigator believes that immediate action is warranted to ensure the continued safety of the subject. 
Due to a clinical or laboratory event, administration of all study drugs(s) may be discontinued. There is 
no option for Epclusa dose reduction. If Epclusa is stopped for toxicity, it must not be restarted Post-
Treatment Weeks 4 and 12 Visits must also be scheduled. 
Subjects who meet any of the following laboratory criteria must stop all study drug(s): 
• 
Elevation of ALT and/or AST >5x Baseline/Day 1 or nadir, confirmed by immediate repeat testing 


CRI 15-05 Protocol 13SEP2017 
Page 35 
 
 
• 
Abnormal elevation of ALT >3x Baseline/Day 1 and total bilirubin >2 x ULN, confirmed by 
immediate repeat testing 
• 
Elevation of ALT >15 x ULN, confirmed by immediate repeat testing 
• 
Any Grade 3 or greater rash associated with constitutional symptoms 
• 
Any Grade 4 adverse event or laboratory abnormality assessed as related to Epclusa 
9.7 Special Situations Reports 
9.7.1 
Definitions of Special Situations 
Special situation reports include all reports of medication error, abuse, misuse, overdose reports and 
pregnancy reports regardless of an associated AE. These also include reports of adverse reactions in 
infants following exposure from breastfeeding, and reports of adverse reactions associated with product 
complaints and reports arising from occupational exposure. 
• 
A pregnancy report is used to report any pregnancy following maternal or paternal exposure to 
the medicinal product. 
• 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer. 
• 
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject. 
• 
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information. 
• 
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labeling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the Investigator 
has reason to suspect that the subject has taken the additional dose(s). 
• 
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product. 
9.8 Reporting Special Situations 
9.8.1 
Instructions for Reporting Pregnancies 
Any pregnancy of a woman participant or female partner of a male study participant should be 
immediately reported to the Medical Monitor and Sponsor-Investigator.  All pregnancies will be reported 
to the IRB/IEC within 24 hours of notification, and followed-up through the end of the pregnancy.  
Pregnancy outcomes will be recorded and reported to the IRB/IEC. 
The Sponsor-Investigator will collect information on all pregnancies that are identified after the subject 
first consents to participate in the study (i.e., signs the informed consent) and throughout the study, 
including the post study drug follow-up period. 
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons. 
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic abortion 
due to complications or other medical reasons) will be reported by the Sponsor-Investigator within 24 


CRI 15-05 Protocol 13SEP2017 
Page 36 
 
 
hours as an SAE to the IRB/IEC. The underlying medical reason for this procedure should be recorded as 
the AE term. 
A spontaneous abortion is always considered to be an SAE and will be reported as an SAE to the IRB/IEC. 
Furthermore, any SAE occurring as an adverse pregnancy outcome post study will be reported to the 
IRB/IEC. 
The subject should receive appropriate monitoring and care until the conclusion of the pregnancy. The 
outcome of the pregnancy, whether the end of the pregnancy occurs after the study has been completed 
or during study participation, will be recorded.  Outcomes that meet the definition of reportable to the 
IRB/IEC and FDA will be reported by CRI. 
Pregnancies of female partners of male study subjects exposed to the study drug will also be followed 
closely and relevant information will be collected. Monitoring of the partner will continue until the 
conclusion of the pregnancy. The outcome will be collected and may be reported to the IRB/IEC and FDA. 
Refer to the study operations manual for pregnancy information collection and reporting instructions. 
AEs and SAEs related to the pregnancy that affect the mother and/or the fetus will be reported via FDA 
MedWatch Form 3500a when the Sponsor-Investigator assesses the adverse even to be possibly 
associated with the study product used during pregnancy.  Instances of reportable pregnancy related 
SAE/AEs include but are not limited to: fetal death, miscarriage, spontaneous abortion, fetal adverse 
reaction, congenital anomaly and defect. 
Additional reporting of pregnancy and outcomes to the study drug manufacturer may also occur. 
9.8.2 
Reporting Other Special Situations 
All other special situation reports must be reported on the special situations report form and forwarded 
to the CRI Medical Monitor within 24 hours of becoming aware of the situation. These reports must 
consist of situations that involve study drug, but do not apply to concomitant medications. Except for 
situations that result in AEs, special situations involving concomitant medications will not be reported. 
Any inappropriate use of medications prohibited by this protocol should not be reported as “misuse,” 
but may be more appropriately documented as a protocol deviation. 
Refer to the study operational manual for full instructions on the mechanism of special situation capture 
and collection. 
Note: All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs at 
the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available. 
In addition to reporting SAEs and special situations to the IRB/IEC and regulatory authorities per the 
applicable recommendations and regulations, the Sponsor-Investigator will notify Gilead Sciences, Inc. of 
all safety information, including SAEs and special situation reports within 15 days of awareness of the 
safety information and in accordance with applicable laws and regulations.  All reports will be addressed 
to Gilead at the attention of: 
Gilead Sciences, Inc. 
Drug Safety & Public Health 
333 Lakeside Dr. 
Foster City, CA 94404 
Fax: 650-522-5477 


CRI 15-05 Protocol 13SEP2017 
Page 37 
 
 
Tel: 650-522-5114 
E-mail: Safety_FC@Gilead.com 
10 STATISTICAL CONSIDERATIONS 
10.1 Analysis Objectives and Endpoints 
10.1.1 Analysis Objectives 
Primary Objective: 
• 
To assess the effectiveness, as measured by SVR12, of HCV treatment with Epclusa administered 
by an internal medicine physician/licensed buprenorphine/naloxone provider during regularly 
scheduled office visits for buprenorphine/naloxone maintenance therapy. 
Secondary Objectives: 
• 
To assess the impact of HCV treatment on health-related quality of life among subjects on 
buprenorphine/naloxone therapy. 
• 
To assess adherence to Epclusa Therapy in subjects administered treatment in the context of 
visits to a buprenorphine/naloxone clinic. 
Exploratory Objective: 
• 
To design and assess a curriculum and mentorship program to support internal medicine 
providers with managing HCV infection.  The curriculum for the purpose of this study will be 
tailored to the management of HCV genotype 1 and treatment with Epclusa. 
10.1.2 Primary Endpoint 
The primary efficacy endpoint is rate of SVR-12 (HCV RNA <LLOQ 12 weeks after discontinuation of study 
treatment). 
10.1.3 Secondary Endpoints 
Secondary efficacy endpoints include the following: 
• 
Adherence to Epclusa expressed as percentage of patients who miss 1-4% of doses, 5-9% of 
doses, 10-20% of doses and > 20% of doses 
• 
Overall ratio of doses taken/doses prescribed in the study population 
• 
Change in scores of QOL questionnaires 
10.1.4 Safety Endpoints 
The primary safety endpoint is any AE leading to permanent discontinuation of study drug(s). 
10.1.5 Other Endpoints of Interest 
The Internal Medicine Physician’s change in comfort level with providing HCV care over course of study. 


CRI 15-05 Protocol 13SEP2017 
Page 38 
 
 
10.2 Analysis Conventions 
10.2.1 Analysis Sets 
10.2.1.1 Efficacy 
The analysis set for antiviral activity analyses will be subjects who were enrolled into the study and 
received at least one dose of study drugs. 
10.2.1.2 Safety 
The primary analysis set for safety analyses will include subjects who received at least one dose of study 
drug. 
Treatment-emergent data will be analyzed and defined as data collected from the first dose of study 
drug through the date of last dose of study drug plus 30 days. 
10.3 Data Handling Conventions 
Missing data can have an impact upon the interpretation of the trial data. Other than the endpoints 
discussed below, values for missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and is preceded 
and followed in time by values that are deemed successes, then the missing data point will be termed a 
success; otherwise the data point will be termed a failure. 
Any subject with missing data due to premature discontinuation of the study drug will be considered a 
failure at the date of premature discontinuation and all time points subsequent to the date of premature 
discontinuation if there are no observed values available. If no HCV RNA values are obtained after the 
last dose of study drug, the subject will be considered a treatment failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in summary 
statistics. 
10.4 Demographic Data and Baseline Characteristics 
Demographic data will include sex, self-identified race, self-identified ethnicity, and age. 
Baseline characteristic data will include HCV RNA level, calculated FIB-4 index, and Fibrosis Score on 
FibroSure®.  Demographic and baseline characteristics will be summarized using descriptive statistics: 
means and standard deviations for continuous characteristics such as age and frequencies/percentages 
for categorical measures such as sex and race. HCV RNA level will be reported as the categories “below 
LLOQ” or “detectable.” 
10.5 Primary Analysis 
The primary efficacy endpoint is SVR-12 (HCV RNA < LLOQ 12 weeks after discontinuation of study 
treatment). The percent of patients achieving SVR-12 and its 95% confidence interval of SVR-12 will be 
reported. 
10.6 Secondary Analysis 
Adherence: 
• 
Percentage of patients who miss 1-4% of doses, 5-9% of doses, and 10-20% of doses and > 20% 
of doses and the 95% confidence interval will be reported. The percentage of doses taken out of 
total doses prescribed will be reported with its 95% confidence interval. 


CRI 15-05 Protocol 13SEP2017 
Page 39 
 
 
Quality of Life: 
• 
Mean in QOL scores from baseline to EOT will be reported with its 95% confidence interval. 
 
Safety Analysis 
• 
All safety data collected on or after the first dose of study drug administration up to 30 days 
after the last dose of study drug will be summarized. All AE’s of each level severity will be 
reported with the number and percent who experienced them.  The number and percent of 
patients who stopped the study because of SAE’s will be reported, with the 95% confidence 
interval. 
10.7  Other Analyses 
The Internal Medicine Physician’s change in comfort level with providing HCV care over course of study 
will be reported descriptively, with a graph of the comfort level on each of six areas of counseling at each 
time point measured. In addition, a qualitative description of the Internal Medicine Physician’s 
experience with the training will be reported. 
11 SPONSOR-INVESTIGATOR RESPONSIBILITIES 
11.1 Good Clinical Practice 
The Sponsor-Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South Africa), 
International Conference on Harmonization (ICH) guidelines, or with the laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to the study 
subject. 
The Sponsor-Investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators”, 21 CFR, part 50, and 
21 CFR, part 56. 
The Sponsor-Investigator and all applicable Sub-Investigators will comply with 21 CFR, Part 54, providing 
documentation of their financial interest or arrangements with Gilead, or proprietary interests in the 
investigational drug under study. This documentation must be provided prior to the Sponsor-
Investigator’s (and any Sub-Investigator’s) participation in the study. The Sponsor-Investigator and Sub-
Investigator(s) agree to file any change in reportable interests during the study and for 1 year following 
completion of the study per CRI SOPs. Study completion is defined as the date when the last subject 
completes the protocol-defined activities. 
11.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Review and 
Approval 
The Sponsor-Investigator will submit this protocol, informed consent form, and any accompanying 
material to be provided to the subject (such as advertisements, subject information sheets, or 
descriptions of the study used to obtain informed consent) to an IRB/IEC. The Sponsor-Investigator will 
not begin any study subject activities until approval from the IRB/IEC has been documented and 
provided as a letter to the Sponsor-Investigator. 


CRI 15-05 Protocol 13SEP2017 
Page 40 
 
 
Before implementation, the Sponsor-Investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be provided to the 
subject after initial IRB/IEC approval, with the exception of those necessary to reduce immediate risk to 
study subjects. 
11.3 Informed Consent 
The Sponsor-Investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and potential 
hazards of the study and before undertaking any study -related procedures. The Sponsor-Investigator 
must use the most current IRB/IEC-approved consent form for documenting written informed consent. 
Each informed consent (or assent as applicable) will be appropriately signed and dated by the subject or 
the subject’s legally authorized representative and the person conducting the consent discussion, and 
also by an impartial witness if required by IRB/IEC of local requirements. 
11.4 Confidentiality 
The Sponsor-Investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another unique 
identifier (as allowed by local law) and an identification code will be recorded on any form submitted to 
the Sponsor-Investigator or IRB/IEC. NOTE: The Sponsor-Investigator must keep a screening log showing 
codes, names, and addresses for all subjects screened and for all subjects enrolled in the trial. Subject 
data will be processed in accordance with all applicable regulations. 
The Sponsor-Investigator agrees that all confidential study information, including but not limited to the 
Investigator Brochure, this protocol, eCRF, the study drug, and any other study information, remain the 
sole and exclusive property of the Sponsor-Investigator during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly involved in 
the conduct of the study or as required by law). The Sponsor-Investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to any third 
party or otherwise into the public domain. 
11.5 Study Files and Retention of Records 
The Sponsor-Investigator will maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: 
• 
Sponsor-Investigator’s study file, and 
• 
Subject clinical source documents. 
The Sponsor-Investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence. 
The required source data should include sequential notes containing at least the following information 
for each subject: 
• 
Subject identification (name, date of birth, gender); 
• 
Original, signed informed consent form with documentation that the consent was signed prior to 
initiating any study procedures; 


CRI 15-05 Protocol 13SEP2017 
Page 41 
 
 
• 
Documentation that subject meets eligibility criteria, i.e. history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria); 
• 
Documentation of the reason(s) a consented subject is not enrolled 
• 
Participation in study (including study number); 
• 
Study discussed and date of informed consent; 
• 
Dates of all visits; 
• 
Documentation that protocol specific procedures were performed; 
• 
Results of efficacy parameters, as required by the protocol; 
• 
Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return; 
• 
Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity); 
• 
Concomitant medication (including start and end date, dose if relevant, dose changes); 
• 
Date of study completion and reason for early discontinuation, if it occurs. 
All clinical study documents will be retained by the Sponsor-Investigator until 2 years after the 
investigation is discontinued and regulatory authorities have been notified. 
11.6 Case Report Forms 
For each subject consented, an eCRF will be completed by an authorized study staff member whose 
training for this function is documented according to study procedures. eCRF will be completed within 
three days of the subject visit to enable the Sponsor-Investigator to perform central monitoring of safety 
data. Subsequent to data entry, a study monitor will perform source data verification for select data 
points in accordance with the monitoring plan within the EDC system. Original entries as well as any 
changes to data fields will be stored in the audit trail of the system. Prior to database lock (or any interim 
time points as described in the clinical data management plan), the Sponsor-Investigator will use his/her 
log in credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol schedule 
of events and procedures. System-generated or manual queries will be issued to the investigative site 
staff as data discrepancies are identified by the monitor or internal CRI staff, who routinely review the 
data for completeness, correctness, and consistency. A read-only archive copy of the case report form 
will be stored in accordance with the records retention requirements outlined in Section 11.5. 
Study data will be collected and managed using REDCap electronic data capture tools hosted by Boston 
Computing Network (Harris et al. 2009). REDCap (Research Electronic Data Capture) is a secure, web-
based application designed to support data capture for research studies, providing: 1) an intuitive 
interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) 
automated export procedures for seamless data downloads to common statistical packages; and 4) 
procedures for importing data from external sources. It satisfies HIPAA-Security guidelines and is 21 CFR 
Part 11 capable, with compliance assured by the Community Research Initiative Information Technology 
Department and Boston Computing Network.  Data will be exported from REDCap to the statistician for 
statistical analysis will be de-identified. 
11.7 Investigational Medicinal Product Accountability and Return 
All used and unused study drug supplies will be destroyed by the study monitor or designee in 
accordance to the Sponsor-Investigator standard operating procedures. The Sponsor-Investigator must 
maintain accurate records for all study drug destroyed. Records must show the identification and 


CRI 15-05 Protocol 13SEP2017 
Page 42 
 
 
quantity of each unit destroyed, the method of destruction, and the person who disposed of the study 
drug. Upon study completion, copies of the study drug accountability records must be filed at the site. 
11.8 Protocol Compliance 
The Sponsor-Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
11.9 Protocol Modifications 
All protocol modifications will be submitted to the IRB/IEC in accordance with local requirements and 
receive documented IRB/IEC approval before modifications can be implemented. 
11.10 Study Monitoring 
In accordance with regulations and guidelines, the Sponsor-Investigator is responsible for assuring 
ongoing monitoring of the study.  The designated study monitor will have direct access to the Sponsor-
Investigator’s source documentation in order to verify the accuracy of the data recorded in the eCRF. 
The monitor is responsible for routine review of the eCRF at regular intervals throughout the study to 
verify adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered on them. The monitor will have access to any subject records needed to verify the entries on the 
eCRF. 
11.11 Study Auditing or Inspections 
Representatives of regulatory authorities may conduct inspections or audits of the clinical study. If the 
Sponsor-Investigator is notified of an inspection by a regulatory authority the Sponsor-Investigator will 
notify the CRI Medical Monitor and Regulatory Sponsor staff immediately.  The Sponsor-Investigator will 
make available all source documents and other records for this trial to appointed study monitors, to 
IRBs/IECs or to regulatory authority or health authority inspectors. 
11.12 Study Discontinuation 
The Sponsor-Investigator reserves the right to terminate the study at any time. Should this be necessary, 
discontinuation procedures will be arranged and the appropriate regulatory authority(ies), IRBs, and IECs 
will be notified. In terminating the study, the Sponsor-Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. 
11.13 Finance and Insurance 
No funds have been set aside for payment of treatment of any injury or illness that occurs as a direct 
result in a subject’s participation in this study.  No funds have been appropriated for other associated 
losses such as lost wages, disability or discomfort related to an injury or illness as a result of a subject’s 
participation in this study.  In the event that a subject experiences an injury or illness as described above, 
they should be immediately referred to their primary care provider for treatment.  The subject will be 
responsible for payment of cost of treatment. 
11.14 Study Report and Publications 
A clinical study report will be prepared and provided to the regulatory agency(ies). The Sponsor-
Investigator will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 


CRI 15-05 Protocol 13SEP2017 
Page 43 
 
 
The Sponsor-Investigator may communicate, orally present, or publish in scientific journals or other 
scholarly media. 
 


CRI 15-05 Protocol 13SEP2017 
Page 44 
 
 
12 References 
 
Altice FL, Bruce RD, Lucas GM et al, HIV Treatment Outcomes Among HIV-Infected, Opioid-Dependent 
Patients Receiving Buprenorphine/Naloxone Treatment within HIV Clinical Care Settings: Result 
from a Multisite Study, J Acquir Immune Defic Syndr: 2011 March; 56 (suppl 1) S22-S32 
Anson P, National Pain Report, September 13, 2013 
Arora S, Thornton K, Murata G, Deming P, Kalishman S, Dion D, Parish B, Burke T, Pak W, Dundelberg J, 
Kistin M, Brown J, Jenkusky S, Komoromy M, Qualls C. Outcomes of treatment for hepatitis C 
virus infection by primary care providers. N Engl J Med. 2011364(23):2199-207. doi: 
10.1056/NEJMoa1009370. Epub 2011 Jun 1. 
Aspinall EJ, Corson S, Doyle JS et. al., Clin Infect Dis: 1013 57 (suppl 2) 580-589. 
Barnes, HN, (2015). Hijacked Brains: The Experience and Science of Chronic Addiction.  Dartmouth 
College Press, Lebanon, NH. 
Harris AP, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG.  Research electronic data capture (REDCap) 
- A metadata-driven methodology and workflow process for providing translational research 
informatics support, J Biomed Inform. 2009 Apr;42(2):377-81. 
Epclusa® (Sofosbuvir/velpatasvir fixed dose combination) tablets.  US Prescribing Information.  Gilead 
Sciences, Inc. Foster City, CA.  2016. 
Robaeys C, Grebely J, Mauss S et al., Recommendations for the Management of Hepatitis C Virus 
Infection Among People Who Use Injection Drugs, Clin Infect Dis: 2013 57 (suppl 2) S129-137 
Buprenorphine/naloxone® (bupenorphone and naloxone) sublingual film. Reckitt Benckiser 
Pharmaceuticals, Inc. Richmond, VA. April 2014. 
Sanjeev Arora, M.D., Karla Thornton, M.D., Glen Murata, M.D., Paulina Deming, Pharm.D., Summers 
Kalishman, Ph.D., Denise Dion, Ph.D., Brooke Parish, M.D., Thomas Burke, B.S., Wesley Pak, 
M.B.A., Jeffrey Dunkelberg, M.D., Martin Kistin, M.D., John Brown, M.A., Steven Jenkusky, M.D., 
Miriam Komaromy, M.D., and Clifford Qualls, Ph.D. N Engl J Med 2011; 364:2199-2207June 9, 
2011DOI: 10.1056/NEJMoa1009370 
 
American Association for the Study of Liver Diseases and Infectious Diseases Society of American HCV 
Guidelines for the Testing, Managing and Treating HCV, October, 2016. 
 
 


CRI 15-05 Protocol 13SEP2017 
Page 45 
 
 
13 Appendices 
 
Appendix 1 
Investigator Signature Page 
Appendix 2 
Study Procedures Table 
Appendix 3 
Questionnaire to Determine Psychiatrist Sub-Investigator Comfort with HCV 
Management 
Appendix 4 
GSI Grading Scale 
Appendix 5 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations 
Appendix 6 
HCV Treatment Curriculum 
 
 


CRI 15-05 Protocol 13SEP2017 
Page 46 
 
 
 
Appendix 1: Investigator Signature Page 
 
Bridging Care to HCV Treatment Among Opioid Dependent Patients on Buprenorphine/naloxone 
Maintenance Therapy: A Pilot Study of Treating HCV with Epclusa at a Psychiatrist-staffed Outpatient 
Addiction Clinic Clinic 
September 13, 2017 V7.0 
 
Investigator Statement 
I have read the protocol, including all appendices, and I agree that it contains all necessary details or my 
staff to conduct this study as described.  I will conduct his study as outlined herein and will make a 
reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all study-
related information.  I will discuss this material with them to ensure that they are fully informed about 
the drugs and the study. 
I affirm that the protocol, GCP guidelines and applicable regulatory requirements will be followed. 
I will not initiate any study activities until the IRB/IEC and other required regulatory approvals are 
obtained. 
 
__________________________________________ 
 
_________________________________ 
Principal Investigator Name (Printed) 
 
 
 
Signature 
 
_______________________________ 
Date 


CRI 15-05 Protocol 13SEP2017 
Page 47 
 
 
Appendix 2: 
Study Procedures Table 
 
Screening Baseline Biweekly Visits on 
Treatmenth 
Unscheduled 
Visit 
EOT or early 
termination 
Post-Treatment 
weeks 4 and 12 
Clinical Assessments: 
Informed Consent 
X 
 
 
 
 
 
Eligibility Review 
X 
X 
 
 
 
 
Medical Historya 
X 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
 
Pregnancy Prevention Counseling for 
WOCBP 
X 
X 
X 
X 
X 
 
Health Related QOL Surveysb 
 
X 
X (week 4 only) 
 
X 
X (post treatment 
week 12 only) 
Drug Dispensing 
 
X 
Xi 
 
 
 
Instruct the subject on the packaging, 
storage and administration of study 
drug 
 
X 
 
 
 
 
Pill count 
 
 
X 
X 
X 
 
Download MEMSCapTM adherence data 
 
 
X 
X 
X 
 
Laboratory Assessments:g 
Hepatic Function Testsc 
X 
 
Xd 
 
 
 
CBC with Platelet Countc 
X 
 
 
 
 
 
BMP with eGFR 
X 
 
 
 
 
 
HgbA1C 
x 
 
 
 
 
 
HCV RNAd 
X 
 
Xd 
 
 
X 
HCV genotype if not documented in 
medical record 
X 
 
 
 
 
 
FibroSure® 
X 
 
 
 
 
 
Hepatitis B surface antibody, core 
antibody, surface antigen 
X 
 
 
 
 
 
Hepatitis B quantitative DNA PCR test 
X 
 
Xd  
 
 
 
Urine drug screen  
X 
X 
X 
 
X 
 
Urine screen for buprenorphine 
X 
X 
X 
 
X 
 


CRI 15-05 Protocol 13SEP2017 
Page 48 
 
 
 
Screening Baseline Biweekly Visits on 
Treatmenth 
Unscheduled 
Visit 
EOT or early 
termination 
Post-Treatment 
weeks 4 and 12 
Serum Pregnancy Test for WOCBP 
X 
 
 
 
 
 
Urine Pregnancy Test for WOCBP 
 
X 
X 
 
X (post treatment 
week 4 only) 
 
Internal Medicine Mentorship and Assessments: 
Psychiatrist Sub-Investigator 
Mentorship e 
X 
X 
X 
X 
X 
X 
Psychiatrist Sub-Investigator 
Questionnaire f 
X 
 
Xf 
 
 
 
 
a Select Medical History to include: risk factor(S) for HCV, estimated duration of HCV, prior assessments of fibrosis, HCV genotype if known, prior 
HCV treatment, comorbid liver diseases 
b FACIT-F, PROMIS ED -Depression SF8a, SF36 
c ALT, AST, and platelet count will be used to calculate FIB-4 Index 
d HCV RNA, HBV DNA and HFT to be assessed at week 4 on treatment but not at other biweekly on treatment visits unless clinically indicated 
e Detailed teaching session prior to screening 
f Administered before and at the completion of the training session and after 4 months of prescribing of HCV therapy to study participants. 
g Additional safety laboratory assessments may be assessed per the clinical judgement of the Sponsor-Investigator or Sub-Investigator. 
h While the goal is for all visits to be within +/-3 days of the target visit date, study visits will be accepted outside of the window as required by the 
patient and the operational flow of the clinic. 
I Study drug will be dispensed at the week 4 and week 8 study visits, and as needed at other visits for emergency resupply. 
 
 


CRI 15-05 Protocol 13SEP2017 
Page 49 
 
 
Appendix 3: 
Questionnaire to Determine the Participating Psychiatrists’ Comfort with HCV Management 
 
 
Not at all comfortable 
Somewhat comfortable 
Comfortable 
Very Comfortable 
Counseling patients on 
natural history of HCV 
infection 
 
 
 
 
Counseling patients on 
benefits of treatment 
 
 
 
 
Assessing fibrosis and 
diagnosing cirrhosis 
 
 
 
 
Counseling patients on 
proper usage of 
Epclusa 
 
 
 
 
Counseling patients on 
drug interactions with 
Epclusa 
 
 
 
 
Counseling patients on 
efficacy of Epclusa 
 
 
 
 
 
 


CRI 15-05 Protocol 13SEP2017 
Page 50 
 
 
 
Appendix 4: 
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
Version 18June2012 
 
 
 
HEMATOLOGY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
HIV POSITIVE 
8.5 to 10.0 g/dL 
7.5 to < 8.5 g/dL 
6.5 to < 7.5 g/dL 
< 6.5 g/dL 
Adult and Pediatric ≥ 57 Days 
85 to 100 g/L 
75 to < 85 g/L 
65 to < 75 g/L 
< 65 g/L 
HIV NEGATIVE 
10.0 to 10.9 g/dL 
9.0 to < 10.0 g/dL 
7.0 to < 9.0 g/dL 
< 7.0 g/dL 
Adult and Pediatric ≥ 57 Days 
100 to 109 g/L 
90 to < 100 g/L 
70 to < 90 g/L 
< 70 g/L 
OR 
OR 
OR 
Any decrease from Baseline 
Any decrease from Baseline 
Any decrease from Baseline 
2.5 to < 3.5 g/dL 
3.5 to < 4.5 g/dL 
≥ 4.5 g/dL 
25 to < 35 g/L 
35 to < 45 g/L 
≥ 45 g/L 
Infant, 36–56 Days 
8.5 to 9.4 g/dL 
7.0 to < 8.5 g/dL 
6.0 to < 7.0 g/dL 
< 6.0 g/dL 
(HIV POSITIVE OR 
85 to 94 g/L 
70 to < 85 g/L 
60 to < 70 g/L 
< 60 g/L 
NEGATIVE) 
Infant, 22–35 Days 
9.5 to 10.5 g/dL 
8.0 to < 9.5 g/dL 
7.0 to < 8.0 g/dL 
< 7.0 g/dL 
(HIV POSITIVE OR 
95 to 105 g/L 
80 to < 95 g/L 
70 to < 80 g/L 
< 70 g/L 
NEGATIVE) 
Infant, 1–21 Days 
12.0 to 13.0 g/dL 
10.0 to < 12.0 g/dL 
9.0 to < 10.0 g/dL 
< 9.0 g/dL 
(HIV POSITIVE OR 
120 to 130 g/L 
100 to < 120 g/L 
90 to < 100 g/L 
< 90 g/L 
NEGATIVE) 
 


CRI 15-05 Protocol 13SEP2017 
Page 51 
 
 
 
 
 
 
HEMATOLOGY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Absolute Neutrophil Count 
1000 to 1300/mm3 
750 to < 1000/mm3 
500 to < 750/mm3 
< 500/mm3 
(ANC) 
Adult and Pediatric, > 7 Days 
1.00 to 1.30 GI/L 
0.75 to < 1.00 GI/L 
0.50 to < 0.75 GI/L 
< 0.50 GI/L 
Infant, 2 – ≤ 7 Days 
1250 to 1500/mm3 
1000 to < 1250/mm3 
750 to < 1000/mm3 
< 750/mm3 
1.25 to 1.50 GI/L 
1.00 to < 1.25 GI/L 
0.75 to < 1.00 GI/L 
< 0.75 GI/L 
Infant, 1 Day 
4000 to 5000/mm3 
3000 to < 4000/mm3 
1500 to < 3000/mm3 
< 1500/mm3 
4.00 to 5.00 GI/L 
3.00 to < 4.00 GI/L 
1.50 to < 3.00 GI/L 
< 1.50 GI/L 
Absolute CD4+ Count 
HIV NEGATIVE ONLY 
300 to 400/mm3 
200 to < 300/mm3 
100 to < 200/mm3 
< 100/mm3 
Adult and Pediatric 
> 13 Years 
300 to 400/μL 
200 to < 300/μL 
100 to < 200/μL 
< 100/μL 
Absolute Lymphocyte Count 
HIV NEGATIVE ONLY 
600 to 650/mm3 
500 to < 600/mm3 
350 to < 500/mm3 
< 350/mm3 
Adult and Pediatric 
> 13 Years 
0.60 to 0.65 GI/L 
0.50 to < 0.60 GI/L 
0.35 to < 0.50 GI/L 
< 0.35 GI/L 
Platelets 
100,000 to < 125,000/mm3 
50,000 to < 100,000/mm3 
25,000 to < 50,000/mm3 
< 25,000/mm3 
100 to < 125 GI/L 
50 to < 100 GI/L 
25 to < 50 GI/L 
< 25 GI/L 
WBCs 
2000/mm3 to 2500/mm3 
1,500 to < 2,000/mm3 
1000 to < 1,500/mm3 
< 1000/mm3 
2.00 GI/L to 2.50 GI/L 
1.50 to < 2.00 GI/L 
1.00 to < 1.50 GI/L 
< 1.00 GI/L 
Hypofibrinogenemia 
100 to 200 mg/dL 
75 to < 100 mg/dL 
50 to < 75 mg/dL 
< 50 mg/dL 
1.00 to 2.00 g/L 
0.75 to < 1.00 g/L 
0.50 to < 0.75 g/L 
< 0.50 g/L 


CRI 15-05 Protocol 13SEP2017 
Page 52 
 
 
 
 
 
 
HEMATOLOGY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyperfibrinogenemia 
> ULN to 600 mg/dL 
> 600 mg/dL 
— 
— 
> ULN to 6.0 g/L 
> 6.0 g/L 
— 
— 
Fibrin Split Product 
20 to 40 μg/mL 
> 40 to 50 μg/mL 
> 50 to 60 μg/mL 
> 60 μg/mL 
20 to 40 mg/L 
> 40 to 50 mg/L 
> 50 to 60 mg/L 
> 60 mg/L 
Prothrombin Time (PT) 
> 1.00 to 1.25 × ULN 
> 1.25 to 1.50 × ULN 
> 1.50 to 3.00 × ULN 
> 3.00 × ULN 
International Normalized Ratio 
1.1 to 1.5 x ULN 
>1.5 to 2.0 x ULN 
>2.0 to 3.0 x ULN 
>3.0 x ULN 
of prothrombin time (INR) 
Activated Partial 
Thromboplastin Time (APTT) 
> 1.00 to 1.66 × ULN 
> 1.66 to 2.33 × ULN 
> 2.33 to 3.00 × ULN 
> 3.00 × ULN 
Methemoglobin 
5.0 to 10.0% 
> 10.0 to 15.0% 
> 15.0 to 20.0% 
> 20.0% 


CRI 15-05 Protocol 13SEP2017 
Page 53 
 
 
 
CHEMISTRY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130 to <LLN mEq/L 
125 to < 130 mEq/L 
121 to < 125 mEq/L 
< 121 mEq/L 
130 to <LLN mmol/L 
125 to < 130 mmol/L 
121 to < 125 mmol/L 
< 121 mmol/L 
Hypernatremia 
146  to 150 mEq/L 
> 150 to 154 mEq/L 
> 154 to 159 mEq/L 
> 159 mEq/L 
146  to 150 mmol/L 
> 150 to 154 mmol/L 
> 154 to 159 mmol/L 
> 159 mmol/L 
Hypokalemia 
3.0 to 3.4 mEq/L 
2.5 to < 3.0 mEq/L 
2.0 to < 2.5 mEq/L 
< 2.0 mEq/L 
3.0 to 3.4 mmol/L 
2.5 to < 3.0 mmol/L 
2.0 to < 2.5 mmol/L 
< 2.0 mmol/L 
Hyperkalemia 
5.6 to 6.0 mEq/L 
> 6.0 to 6.5 mEq/L 
> 6.5 to 7.0 mEq/L 
> 7.0 mEq/L 
5.6 to 6.0 mmol/L 
> 6.0 to 6.5 mmol/L 
> 6.5 to 7.0 mmol/L 
> 7.0 mmol/L 
Hypoglycemia 
Adult and Pediatric 
55 to 64 mg/dL 
40 to < 55 mg/dL 
30 to < 40 mg/dL 
< 30 mg/dL 
≥ 1 Month 
3.03 to 3.58 mmol/L 
2.20 to < 3.03 mmol/L 
1.64 to < 2.20 mmol/L 
< 1.64 mmol/L 
Infant, < 1 Month 
50 to 54 mg/dL 
40 to < 50 mg/dL 
30 to < 40 mg/dL 
< 30 mg/dL 
2.8 to 3.0 mmol/L 
2.2 to < 2.8 mmol/L 
1.7 to < 2.2 mmol/L 
< 1.7 mmol/L 
Hyperglycemia, Nonfasting 
116 to 160 mg/dL 
> 160 to 250 mg/dL 
> 250 to 500 mg/dL 
> 500 mg/dL 
6.42 to 8.91 mmol/L 
> 8.91 to 13.90 mmol/L 
> 13.90 to 27.79 mmol/L 
> 27.79 mmol/L 
Hyperglycemia, Fasting 
110 to 125 mg/dL 
>125 to 250 mg/dL 
>250 to 500 mg/dL 
>500 mg/dL 
6.08 to 6.96 mmol/L 
>6.96 to 13.90 mmol/L 
>13.90 to 27.79 mmol/L 
>27.79 mmol/L 
Hypocalcemia 
(corrected for albumin if 
7.8 to 8.4  mg/dL 
7.0 to < 7.8 mg/dL 
6.1 to < 7.0 mg/dL 
< 6.1 mg/dL 
appropriate*) 
1.94 to 2.10 mmol/L 
1.74 to < 1.94 mmol/L 
1.51 to < 1.74 mmol/L 
< 1.51 mmol/L 
Adult and Pediatric 
≥ 7 Days 
Infant, < 7 Days 
6.5 to 7.5 mg/dL 
6.0 to < 6.5 mg/dL 
5.5 to < 6.0 mg/dL 
< 5.5 mg/dL 
1.61 to 1.88  mmol/L 
1.49 to < 1.61 mmol/L 
1.36 to < 1.49 mmol/L 
< 1.36 mmol/L 


CRI 15-05 Protocol 13SEP2017 
Page 54 
 
 
 
 
 
 
CHEMISTRY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypercalcemia (corrected 
for albumin if appropriate*) 
>ULN to 11.5 mg/dL 
> 11.5 to 12.5 mg/dL 
> 12.5 to 13.5 mg/dL 
> 13.5 mg/dL 
Adult and Pediatric ≥ 
>ULN to 2.88 mmol/L 
> 2.88 to 3.13 mmol/L 
> 3.13 to 3.38 mmol/L 
> 3.38 mmol/L 
7 Days 
Infant, < 7 Days 
11.5 to 12.4 mg/dL 
> 12.4 to 12.9 mg/dL 
> 12.9 to 13.5 mg/dL 
> 13.5 mg/dL 
2.86 to 3.10  mmol/L 
> 3.10 to 3.23  mmol/L 
> 3.23 to 3.38  mmol/L 
> 3.38 mmol/L 
Hypocalcemia (ionized) 
3.0 mg/dL to < LLN 
2.5 to < 3.0 mg/dL 
2.0 to < 2.5 mg/dL 
< 2.0 mg/dL 
0.74 mmol/L to < LLN 
0.62 to < 0.74 mmol/L 
0.49 to < 0.62 mmol/L 
< 0.49 mmol/L 
Hypercalcemia (ionized) 
> ULN to 6.0 mg/dL 
> 6.0 to 6.5 mg/dL 
> 6.5 to 7.0 mg/dL 
> 7.0 mg/dL 
> ULN to 1.50 mmol/L 
> 1.50 to 1.63 mmol/L 
> 1.63 to 1.75 mmol/L 
> 1.75 mmol/L 
Hypomagnesemia 
1.40 to <LLN mg/dL 
1.04 to < 1.40 mg/dL 
0.67 to < 1.04 mg/dL 
< 0.67 mg/dL 
1.2 to <LLN mEq/L 
0.9 to < 1.2 mEq/L 
0.6 to < 0.9 mEq/L 
< 0.6 mEq/L 
0.58 to <LLN mmol/L 
0.43 to < 0.58 mmol/L 
0.28 to < 0.43 mmol/L 
< 0.28 mmol/L 
Hypophosphatemia 
2.0 to < LLN mg/dL 
Adult and Pediatric 
1.5 to < 2.0 mg/dL 
1.0 to < 1.5 mg/dL 
< 1.0 mg/dL 
> 14 Years 
0.63  to < LLN mmol/L 
0.47 to < 0.63 mmol/L 
0.31 to < 0.47 mmol/L 
< 0.31 mmol/L 
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL 
2.5 to < 3.0 mg/dL 
1.5 to < 2.5 mg/dL 
< 1.5 mg/dL 
0.96 to 1.12 mmol/L 
0.80 to < 0.96 mmol/L 
0.47 to < 0.80 mmol/L 
< 0.47 mmol/L 
Pediatric < 1 Year 
3.5 to 4.5 mg/dL 
2.5 to < 3.5 mg/dL 
1.5 to < 2.5 mg/dL 
< 1.5 mg/dL 
1.12 to 1.46 mmol/L 
0.80 to < 1.12 mmol/L 
0.47 to < 0.80 mmol/L 
< 0.47 mmol/L 


CRI 15-05 Protocol 13SEP2017 
Page 55 
 
 
CHEMISTRY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyperbilirubinemia 
Adult and Pediatric 
> 1.0 to 1.5 × ULN 
> 1.5 to 2.5 × ULN 
> 2.5 to 5.0 × ULN 
> 5.0 × ULN 
> 14 Days 
Infant, ≤ 14 Days 
NA 
20.0 to 25.0 mg/dL 
> 25.0 to 30.0 mg/dL 
> 30.0 mg/dL 
(non-hemolytic) 
342 to 428 μmol/L 
> 428 to 513 μmol/L 
> 513 μmol/L 
Infant, ≤ 14 Days 
NA 
NA 
20.0 to 25.0 mg/dL 
> 25.0 mg/dL 
(hemolytic) 
342 to 428 μmol/L 
> 428 μmol/L 
Blood Urea Nitrogen 
1.25 to 2.50 × ULN 
> 2.50 to 5.00 × ULN 
> 5.00 to 10.00 × ULN 
> 10.00 × ULN 
Hyperuricemia 
>ULN to 10.0 mg/dL 
> 10.0 to 12.0 mg/dL 
> 12.0 to 15.0 mg/dL 
> 15.0 mg/dL 
>ULN to 597 μmol/L 
> 597 to 716 μmol/L 
> 716 to 895 μmol/L 
> 895 μmol/L 
Hypouricemia 
1.5 mg/dL to < LLN 
1.0 to < 1.5 mg/dL 
0.5 to < 1.0 mg/dL 
< 0.5 mg/dL 
87 μmol/L to < LLN 
57 to < 87 μmol/L 
27 to < 57 μmol/L 
< 27 μmol/L 
Creatinine 
> 1.50 to 2.00 mg/dL 
> 2.00 to 3.00 mg/dL 
> 3.00 to 6.00 mg/dL 
> 6.00 mg/dL 
> 133 to 177 μmol/L 
> 177 to 265 μmol/L 
> 265 to 530 μmol/L 
> 530 μmol/L 
Bicarbonate 
16.0 mEq/L to < LLN 
11.0 to < 16.0 mEq/L 
8.0 to < 11.0 mEq/L 
< 8.0 mEq/L 
16.0 mmol/L to < LLN 
11.0 to < 16.0 mmol/L 
8.0 to < 11.0 mmol/L 
< 8.0 mmol/L 
Triglycerides 
NA 
500 to 750 mg/dL 
> 750 to 1200 mg/dL 
> 1200 mg/dL 
(Fasting) 
5.64–8.47 mmol/L 
> 8.47–13.55 mmol/L 
> 13.55 mmol/L 
LDL 
130 to 160 mg/dL 
>160 to 190 mg/dL 
> 190 mg/dL 
NA 
(Fasting) 
3.35 to 4.15 mmol/L 
>4.15 to 4.92 mmol/L 
>4.92 mmol/L 


CRI 15-05 Protocol 13SEP2017 
Page 56 
 
 
 
 
CHEMISTRY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Pediatric >2 to <18 years 
110 to 130 mg/dL 
>130 to 190 mg/dL 
> 190 mg/dL 
NA 
2.84 to 3.37 mmol/L 
>3.37 to 4.92 mmol/L 
>4.92 mmol/L 
Hypercholesterolemia 
200 to 239 mg/dL 
> 239 to 300 mg/dL 
> 300 mg/dL 
NA 
(Fasting) 
5.16 to 6.19 mmol/L 
> 6.19 to 7.77 mmol/L 
> 7.77 mmol/L 
Pediatric < 18 Years 
170 to 199 mg/dL 
> 199 to 300 mg/dL 
> 300 mg/dL 
NA 
4.39 to 5.15 mmol/L 
> 5.15 to 7.77 mmol/L 
> 7.77 mmol/L 
Creatine Kinase 
3.0 to < 6.0 × ULN 
6.0 to < 10.0 × ULN 
10.0 to < 20.0 × ULN 
≥ 20.0 × ULN 
 
 
* 
Calcium should be corrected for albumin if albumin is < 4.0 g/dL 


CRI 15-05 Protocol 13SEP2017 
Page 57 
 
 
 
ENZYMES 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.25 to 2.50 × ULN 
> 2.50 to 5.00 × ULN 
> 5.00 to 10.00 × ULN 
> 10.00 × ULN 
ALT (SGPT) 
1.25 to 2.50 × ULN 
> 2.50 to 5.00 × ULN 
> 5.00 to 10.00 × ULN 
> 10.00 × ULN 
GGT 
1.25 to 2.50 × ULN 
> 2.50 to 5.00 × ULN 
> 5.00 to 10.00 × ULN 
> 10.00 × ULN 
Alkaline Phosphatase 
1.25 to 2.50 × ULN 
> 2.50 to 5.00 × ULN 
> 5.00 to 10.00 × ULN 
> 10.00 × ULN 
Total Amylase 
> 1.0 to 1.5 × ULN 
> 1.5 to 2.0 × ULN 
> 2.0 to 5.0 × ULN 
> 5.0 × ULN 
Pancreatic Amylase 
> 1.0 to 1.5 × ULN 
> 1.5 to 2.0 × ULN 
> 2.0 to 5.0 × ULN 
> 5.0 × ULN 
Lipase 
> 1.0 to 1.5 × ULN 
> 1.5 to 3.0 × ULN 
> 3.0 to 5.0 × ULN 
> 5.0 × ULN 
Albumin 
3.0 g/dL to < LLN 
2.0 to < 3.0 g/dL 
< 2.0 g/dL 
NA 
30 g/L to < LLN 
20 to < 30 g/L 
< 20 g/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CRI 15-05 Protocol 13SEP2017 
Page 58 
 
 
 
 
 
URINALYSIS 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hematuria (Dipstick) 
1+ 
2+ 
3-4+ 
NA 
Hematuria (Quantitative) 
See Note below 
>ULN - 10 RBC/HPF 
> 10-75 RBC/HPF 
> 75 RBC/HPF 
NA 
Females 
Males 
6-10 RBC/HPF 
> 10-75 RBC/HPF 
> 75 RBC/HPF 
NA 
Proteinuria (Dipstick) 
1+ 
2–3+ 
4+ 
NA 
Proteinuria, 24 Hour Collection 
Adult and Pediatric 
200 to 999 mg/24 h 
>999 to 1999 mg/24 h 
>1999 to 3500 mg/24 h 
> 3500 mg/24 h 
≥ 10 Years 
Pediatric > 3 Mo to 
201 to 499 mg/m2/24 h 
>499 to 799 mg/m2/24 h 
>799 to 1000 mg/m2/24 h 
> 1000 mg/ m2/24 h 
< 10 Years 
Glycosuria (Dipstick) 
1+ 
2-3+ 
4+ 
NA 
 
Notes: 
 
Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to Dipstick 
Hematuria. 
 
With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0. 
 
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE. 


CRI 15-05 Protocol 13SEP2017 
Page 59 
 
 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Arrhythmia (general) 
Asymptomatic AND No 
Asymptomatic AND Non- 
Symptomatic, non-life- 
Life-threatening arrhythmia 
(By ECG or physical exam) 
intervention indicated 
urgent medical intervention 
threatening AND Non- 
OR Urgent intervention 
indicated 
urgent medical intervention 
indicated 
indicated 
Cardiac-ischemia/Infarction 
NA 
NA 
Symptomatic ischemia 
Unstable angina OR Acute 
(stable angina) OR Testing 
myocardial infarction 
consistent with ischemia 
Hemorrhage (significant acute 
NA 
Symptomatic AND No 
Symptomatic AND 
Life-threatening hypotension 
blood loss) 
transfusion indicated 
Transfusion of ≤ 2 units 
OR Transfusion of > 2 units 
packed RBCs (for children 
packed RBCs indicated (for 
≤ 10 cc/kg) indicated 
children ≤ 10 cc/kg) indicated 
Hypertension (with repeat 
140–159 mmHg systolic 
> 159–179 mmHg systolic 
> 179 mmHg systolic 
Life-threatening consequences 
testing at same visit) 
OR 
OR 
OR 
(eg, malignant hypertension) 
90–99 mmHg diastolic 
> 99–109 mmHg diastolic 
> 109 mmHg diastolic 
OR Hospitalization (other than 
ER visit) indicated 
Pediatric ≤ 17 Years (with 
NA 
91st–94th percentile adjusted 
≥ 95th percentile adjusted 
Life-threatening consequences 
repeat testing at same visit) 
for age, height, and gender 
for age, height, and gender 
(eg, malignant hypertension) 
(systolic and/or diastolic) 
(systolic and/or diastolic) 
OR Hospitalization indicated 
(other than emergency room 
visit) 
Hypotension 
NA 
Symptomatic, corrected with 
Symptomatic, IV fluids 
Shock requiring use of 
oral fluid replacement 
indicated 
vasopressors or mechanical 
assistance to maintain blood 
pressure 
Pericardial Effusion 
Asymptomatic, small 
Asymptomatic, moderate or 
Effusion with non-life- 
Life-threatening consequences 
effusion requiring no 
larger effusion requiring no 
threatening physiologic 
(eg, tamponade) OR Urgent 
intervention 
intervention 
consequences OR Effusion 
intervention indicated 
with nonurgent intervention 
indicated 


CRI 15-05 Protocol 13SEP2017 
Page 60 
 
 
 
 
 
 
 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Prolonged PR Interval 
PR interval 
PR interval 
Type II 2nd degree AV 
Complete AV block 
0.21 to 0.25 sec 
> 0.25 sec 
block OR Ventricular pause 
> 3.0 sec 
Pediatric ≤ 16 Years 
1st degree AV block 
Type I 2nd degree AV block 
Type II 2nd degree AV 
Complete AV block 
(PR > normal for age and 
block 
rate) 
Prolonged QTc 
Asymptomatic, QTc interval 
Asymptomatic, QTc interval 
Asymptomatic, QTc interval 
Life-threatening 
0.45 to 0.47 sec OR Increase 
0.48 to 0.49 sec OR Increase 
≥ 0.50 sec OR Increase in 
consequences, eg, Torsade de 
interval < 0.03 sec above 
in interval 0.03 to 0.05 sec 
interval ≥ 0.06 sec above 
pointes or other associated 
baseline 
above baseline 
baseline 
serious ventricular 
dysrhythmia 
Pediatric ≤ 16 Years 
Asymptomatic, QTc interval 
Asymptomatic, QTc interval 
Asymptomatic, QTc interval 
Life-threatening 
0.450 to 0.464 sec 
0.465 to 0.479 sec 
≥ 0.480 sec 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia 
Thrombosis/Embolism 
NA 
Deep vein thrombosis AND 
Deep vein thrombosis AND 
Embolic event (eg, pulmonary 
No intervention indicated (eg, 
Intervention indicated (eg, 
embolism, life-threatening 
anticoagulation, lysis filter, 
anticoagulation, lysis filter, 
thrombus) 
invasive procedure) 
invasive procedure) 
Vasovagal Episode (associated 
Present without loss of 
Present with transient loss of 
NA 
NA 
with a procedure of any kind) 
consciousness 
consciousness 
Ventricular Dysfunction 
NA 
Asymptomatic diagnostic 
New onset with symptoms 
Life-threatening CHF 
(congestive heart failure, 
finding AND intervention 
OR Worsening symptomatic 
CHF) 
indicated 
CHF 


CRI 15-05 Protocol 13SEP2017 
Page 61 
 
 
 
 
 
RESPIRATORY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Bronchospasm (acute) 
FEV1 or peak flow reduced to 
FEV1 or peak flow 50% to 69% 
FEV1 or peak flow 25% to 
Cyanosis OR FEV1 or peak flow 
70% to 80% 
49% 
< 25% OR Intubation 
Dyspnea or Respiratory 
Dyspnea on exertion with no 
Dyspnea on exertion causing 
Dyspnea at rest causing 
Respiratory failure with 
Distress 
or minimal interference with 
greater than minimal interference inability to perform usual 
ventilatory support indicated 
usual social & functional 
with usual social & functional 
social & functional activities 
activities 
activities 
Pediatric < 14 Years 
Wheezing OR minimal 
Nasal flaring OR Intercostal 
Dyspnea at rest causing 
Respiratory failure with 
increase in respiratory rate for 
retractions OR Pulse oximetry 
inability to perform usual 
ventilatory support indicated 
age 
90% to 95% 
social & functional activities 
OR Pulse oximetry < 90% 
OCULAR/VISUAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Uveitis 
Asymptomatic but detectable 
Symptomatic anterior uveitis OR 
Posterior or pan-uveitis OR 
Disabling visual loss in affected 
on exam 
Medical intervention indicated 
Operative intervention 
eye(s) 
indicated 
Visual Changes (from 
Visual changes causing no or 
Visual changes causing greater 
Visual changes causing 
Disabling visual loss in affected 
baseline) 
minimal interference with 
than minimal interference with 
inability to perform usual 
eye(s) 
usual social & functional 
usual social & functional 
social & functional activities 
activities 
activities 


CRI 15-05 Protocol 13SEP2017 
Page 62 
 
 
 
SKIN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Alopecia 
Thinning detectable by 
Thinning or patchy hair loss 
Complete hair loss 
NA 
study participant or 
detectable by health care 
caregiver (for disabled 
provider 
adults) 
Cutaneous Reaction – Rash 
Localized macular rash 
Diffuse macular, 
Diffuse macular, 
Extensive or generalized 
maculopapular, or 
maculopapular, or morbilliform 
bullous lesions OR 
morbilliform rash OR Target 
rash with vesicles or limited 
Stevens-Johnson syndrome 
lesions 
number of bullae OR 
OR Ulceration of mucous 
Superficial ulcerations of 
membrane involving two 
mucous membrane limited to 
or more distinct mucosal 
one site 
sites OR Toxic epidermal 
necrolysis (TEN) 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Hypopigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Pruritis (itching – no skin 
Itching causing no or 
Itching causing greater than 
Itching causing inability to 
NA 
lesions) 
minimal interference with 
minimal interference with 
perform usual social & 
(See also Injection Site 
usual social & functional 
usual social & functional 
functional activities 
Reactions: Pruritis associated 
activities 
activities 
with injection) 


CRI 15-05 Protocol 13SEP2017 
Page 63 
 
 
 
GASTROINTESTINAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Anorexia 
Loss of appetite without 
Loss of appetite associated with 
Loss of appetite associated 
Life-threatening consequences 
decreased oral intake 
decreased oral intake without 
with significant weight loss 
OR Aggressive intervention 
significant weight loss 
indicated [eg, tube feeding or 
total parenteral nutrition] 
Ascites 
Asymptomatic 
Symptomatic AND Intervention 
Symptomatic despite 
Life-threatening consequences 
indicated (eg, diuretics or 
intervention 
therapeutic paracentesis) 
Cholecystitis 
NA 
Symptomatic AND Medical 
Radiologic, endoscopic, or 
Life-threatening consequences 
intervention indicated 
operative intervention 
(eg, sepsis or perforation) 
indicated 
Constipation 
NA 
Persistent constipation requiring 
Obstipation with manual 
Life-threatening consequences 
regular use of dietary 
evacuation indicated 
(eg, obstruction) 
modifications, laxatives, or 
enemas 
Diarrhea 
Transient or intermittent 
Persistent episodes of unformed 
Bloody diarrhea OR Increase 
Life-threatening consequences 
Adult and Pediatric 
≥ 1 Year 
episodes of unformed stools 
to watery stools OR Increase of 
of ≥ 7 stools per 24-hour 
(eg, hypotensive shock) 
OR Increase of ≤ 3 stools 
4–6 stools over baseline per 
period OR IV fluid 
over baseline/24 hr 
24 hrs. 
replacement indicated 
Pediatric < 1 Year 
Liquid stools (more 
Liquid stools with increased 
Liquid stools with moderate 
Liquid stools resulting in 
unformed than usual) but 
number of stools OR Mild 
dehydration 
severe dehydration with 
usual number of stools 
dehydration 
aggressive rehydration 
indicated OR Hypotensive 
shock 


CRI 15-05 Protocol 13SEP2017 
Page 64 
 
 
 
 
 
 
GASTROINTESTINAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Dysphagia-Odynophagia 
Symptomatic but able to eat 
Symptoms causing altered 
Symptoms causing severely 
Life-threatening reduction in 
usual diet 
dietary intake without medical 
altered dietary intake with 
oral intake 
intervention indicated 
medical intervention indicated 
Mucositis/Stomatitis 
Erythema of the mucosa 
Patchy pseudomembranes or 
Confluent pseudomembranes 
Tissue necrosis OR Diffuse 
(clinical exam) 
ulcerations 
or ulcerations OR Mucosal 
spontaneous mucosal bleeding 
See also Proctitis, 
bleeding with minor trauma 
OR Life-threatening 
Dysphagia-Odynophagia 
consequences (eg, aspiration, 
choking) 
Nausea 
Transient (< 24 hours) or 
Persistent nausea resulting in 
Persistent nausea resulting in 
Life-threatening consequences 
intermittent nausea with no 
decreased oral intake for 24–48 
minimal oral intake for > 48 
(eg, hypotensive shock) 
or minimal interference with 
hours 
hours OR Aggressive 
oral intake 
rehydration indicated (eg, 
IV fluids) 
Pancreatitis 
NA 
Symptomatic AND 
Symptomatic AND 
Life-threatening consequences 
Hospitalization not indicated 
Hospitalization indicated 
(eg, sepsis, circulatory failure, 
(other than ER visit) 
(other than ER visit) 
hemorrhage) 
Proctitis (functional- 
Rectal discomfort AND No 
Symptoms causing greater than 
Symptoms causing inability to 
Life-threatening consequences 
symptomatic) 
intervention indicated 
minimal interference with usual 
perform usual social/ 
(eg, perforation) 
Also see Mucositis/ 
social & functional activities OR 
functional activities OR 
Stomatitis for Clinical 
Medical intervention indicated 
Operative intervention 
Exam 
indicated 
Vomiting 
Transient or intermittent 
Frequent episodes of vomiting 
Persistent vomiting resulting 
Life-threatening consequences 
vomiting with no or 
with no or mild dehydration 
in orthostatic hypotension OR 
(eg, hypotensive shock) 
minimal interference with 
Aggressive rehydration 
oral intake 
indicated 


CRI 15-05 Protocol 13SEP2017 
Page 65 
 
 
 
 
 
 
NEUROLOGICAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Alteration in Personality- 
Alteration causing no or 
Alteration causing greater than 
Alteration causing inability to 
Behavior potentially harmful 
Behavior or in Mood (eg, 
minimal interference with 
minimal interference with 
perform usual social & 
to self or others (eg, 
agitation, anxiety, 
usual social & functional 
usual social & functional 
functional activities 
suicidal/homicidal ideation or 
depression, mania, 
activities 
activities 
attempt, acute psychosis) OR 
psychosis) 
Causing inability to perform 
basic self-care functions 
Altered Mental Status 
Changes causing no or 
Mild lethargy or somnolence 
Confusion, memory 
Delirium OR obtundation, OR 
For Dementia, see Cognitive 
minimal interference with 
causing greater than minimal 
impairment, lethargy, or 
coma 
and Behavioral/Attentional 
usual social & functional 
interference with usual social 
somnolence causing inability 
Disturbance (including 
activities 
& functional activities 
to perform usual social & 
dementia and ADD) 
functional activities 
Ataxia 
Asymptomatic ataxia 
Symptomatic ataxia causing 
Symptomatic ataxia causing 
Disabling ataxia causing 
detectable on exam OR 
greater than minimal 
inability to perform usual 
inability to perform basic self- 
Minimal ataxia causing no 
interference with usual social 
social & functional activities 
care functions 
or minimal interference with 
& functional activities 
usual social & functional 
activities 
Cognitive and 
Disability causing no or 
Disability causing greater than 
Disability causing inability to 
Disability causing inability to 
Behavioral/Attentional 
minimal interference with 
minimal interference with 
perform usual social & 
perform basic self-care 
Disturbance (including 
usual social & functional 
usual social & functional 
functional activities OR 
functions OR 
dementia and Attention 
activities OR Specialized 
activities OR Specialized 
Specialized resources on a 
Institutionalization indicated 
Deficit Disorder) 
resources not indicated 
resources on part-time basis 
full-time basis indicated 
indicated 
CNS Ischemia 
NA 
NA 
Transient ischemic attack 
Cerebral vascular accident 
(acute) 
(CVA, stroke) with 
neurological deficit 


CRI 15-05 Protocol 13SEP2017 
Page 66 
 
 
 
 
 
 
NEUROLOGICAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Developmental delay – 
Mild developmental delay, 
Moderate developmental 
Severe developmental delay, 
Developmental regression, 
Pediatric  16 Years 
either motor or cognitive, as 
delay, either motor or 
either motor or cognitive, as 
either motor or cognitive, as 
determined by comparison 
cognitive, as determined by 
determined by comparison 
determined by comparison 
with a developmental 
comparison with a 
with a developmental 
with a developmental 
screening tool appropriate 
developmental screening tool 
screening tool appropriate for 
screening tool appropriate for 
for the setting 
appropriate for the setting 
the setting 
the setting 
Headache 
Symptoms causing no or 
Symptoms causing greater 
Symptoms causing inability to 
Symptoms causing inability to 
minimal interference with 
than minimal interference with 
perform usual social & 
perform basic self-care 
usual social & functional 
usual social & functional 
functional activities 
functions OR Hospitalization 
activities 
activities 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or 
other neurologic function 
Insomnia 
NA 
Difficulty sleeping causing 
Difficulty sleeping causing 
Disabling insomnia causing 
greater than minimal 
inability to perform usual 
inability to perform basic self- 
interference with usual 
social & functional activities 
care functions 
social/functional activities 
Neuromuscular Weakness 
Asymptomatic with 
Muscle weakness causing 
Muscle weakness causing 
Disabling muscle weakness 
(including myopathy & 
decreased strength on exam 
greater than minimal 
inability to perform usual 
causing inability to perform 
neuropathy) 
OR Minimal muscle weak- 
interference with usual social 
social & functional activities 
basic self-care functions OR 
ness causing no or minimal 
& functional activities 
Respiratory muscle weakness 
interference with usual 
impairing ventilation 
social & functional activities 
Neurosensory Alteration 
Asymptomatic with sensory 
Sensory alteration or 
Sensory alteration or 
Disabling sensory alteration or 
(including paresthesia and 
alteration on exam or 
paresthesia causing greater 
paresthesia causing inability to 
paresthesia causing inability to 
painful neuropathy) 
minimal paresthesia causing 
than minimal interference with 
perform usual social & 
perform basic self-care 
no or minimal interference 
usual social & functional 
functional activities 
functions 
with usual social & 
activities 
functional activities 


CRI 15-05 Protocol 13SEP2017 
Page 67 
 
 
 
 
NEUROLOGICAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Seizure: (new onset) 
NA 
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy) 
Seizure: (pre-existing) 
NA 
Increased frequency of pre- 
Change in seizure character 
Seizures of any kind that are 
For Worsening of Existing 
existing seizures (non- 
from baseline either in 
prolonged, repetitive (eg, 
Epilepsy the Grades Should 
repetitive) without change in 
duration or quality (eg, 
status epilepticus), or difficult 
Be Based on an Increase 
seizure character OR 
severity or focality) 
to control (eg, refractory 
from Previous Level of 
infrequent breakthrough 
epilepsy) 
Control to Any of These 
seizures while on stable meds 
Levels 
in a previously controlled 
seizure disorder 
Seizure 
Seizure, generalized onset 
Seizure, generalized onset 
Seizure, generalized onset 
Seizure, generalized onset 
– Pediatric  18 Years 
with or without secondary 
with or without secondary 
with or without secondary 
with or without secondary 
generalization, lasting 
generalization, lasting 5–20 
generalization, lasting 
generalization, requiring 
< 5 minutes with < 24 hours 
minutes with 
> 20 minutes 
intubation and sedation 
post ictal state 
< 24 hours post ictal state 
Syncope (not associated 
NA 
Present 
NA 
NA 
with a procedure) 
Vertigo 
Vertigo causing no or 
Vertigo causing greater than 
Vertigo causing inability to 
Disabling vertigo causing 
minimal interference with 
minimal interference with 
perform usual social & 
inability to perform basic self- 
usual social & functional 
usual social & functional 
functional activities 
care functions 
activities 
activities 


CRI 15-05 Protocol 13SEP2017 
Page 68 
 
 
 
 
MUSCULOSKELETAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia 
Joint pain causing no or 
Joint pain causing greater than 
Joint pain causing inability 
Disabling joint pain causing 
See also Arthritis 
minimal interference with 
minimal interference with usual 
to perform usual social & 
inability to perform basic self- 
usual social & functional 
social & functional activities 
functional activities 
care functions 
activities 
Arthritis 
Stiffness or joint swelling 
Stiffness or joint swelling causing 
Stiffness or joint swelling 
Disabling joint stiffness or 
See also Arthralgia 
causing no or minimal 
greater than minimal interference 
causing inability to perform 
swelling causing inability to 
interference with usual 
with usual social & functional 
usual social & functional 
perform basic self-care 
social & functional activities 
activities 
activities 
functions 
Bone Mineral Loss 
BMD t-score or z-score 
BMD t-score or z-score < –2.5 
Pathological fracture 
Pathologic fracture causing 
–2.5 to –1.0 
(including loss of vertebral 
life-threatening consequences 
height) 
Pediatric < 21 Years 
BMD z-score 
BMD z-score < –2.5 
Pathological fracture 
Pathologic fracture causing 
–2.5 to –1.0 
(including loss of vertebral 
life-threatening consequences 
height) 
Myalgia 
Muscle pain causing no or 
Muscle pain causing greater than 
Muscle pain causing 
Disabling muscle pain causing 
(non-injection site) 
minimal interference with 
minimal interference with usual 
inability to perform usual 
inability to perform basic self- 
usual social & functional 
social & functional activities 
social & functional activities care functions 
activities 
Osteonecrosis 
NA 
Asymptomatic with radiographic 
Symptomatic bone pain with Disabling bone pain with 
findings AND No operative 
radiographic findings OR 
radiographic findings causing 
intervention indicated 
Operative intervention 
inability to perform basic self- 
indicated 
care functions 


CRI 15-05 Protocol 13SEP2017 
Page 69 
 
 
SYSTEMIC 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Acute Systemic Allergic 
Localized urticaria 
Localized urticaria with medical 
Generalized urticaria OR 
Acute anaphylaxis OR Life- 
Reaction 
(wheals) with no medical 
intervention indicated OR Mild 
Angioedema with medical 
threatening bronchospasm OR 
intervention indicated 
angioedema with no medical 
intervention indicated OR 
laryngeal edema 
intervention indicated 
Symptomatic mild 
bronchospasm 
Chills 
Symptoms causing no or 
Symptoms causing greater than 
Symptoms causing inability to 
NA 
minimal interference with 
minimal interference with usual 
perform usual social & 
usual social & functional 
social & functional activities 
functional activities 
activities 
Fatigue 
Symptoms causing no or 
Symptoms causing greater than 
Symptoms causing inability to 
Incapacitating fatigue/malaise 
Malaise 
minimal interference with 
minimal interference with usual 
perform usual social & 
symptoms causing inability to 
usual social & functional 
social & functional activities 
functional activities 
perform basic self-care 
activities 
functions 
Fever (nonaxillary) 
37.7°C to 38.6°C 
38.7°C to 39.3°C 
39.4°C to 40.5°C 
> 40.5°C 
99.8°F to 101.5°F 
101.6°F to 102.8°F 
102.9°F to 104.9°F 
> 104.9°F 
Pain - Indicate Body Site 
Pain causing no or 
Pain causing greater than minimal 
Pain causing inability to 
Disabling pain causing 
See also Injection Site 
minimal interference with 
interference with usual social & 
perform usual social & 
inability to perform basic self- 
Pain, Headache, 
usual social & functional 
functional activities 
functional activities 
care functions OR 
Arthralgia, and Myalgia 
activities 
Hospitalization (other than ER 
visit) indicated 
Unintentional Weight 
NA 
5% to 9% loss in body weight from 
10% to 19% loss in body 
≥ 20% loss in body weight 
Loss 
baseline 
weight from baseline 
from baseline OR Aggressive 
intervention indicated [eg, 
tube feeding or total parenteral 
nutrition] 


CRI 15-05 Protocol 13SEP2017 
Page 70 
 
 
 
 
 
INJECTION SITE REACTION 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Injection Site Pain (pain 
Pain/tenderness causing no 
Pain/tenderness limiting use of 
Pain/tenderness causing 
Pain/tenderness causing inability 
without touching) 
or minimal limitation of use 
limb OR Pain/tenderness 
inability to perform usual 
to perform basic self-care 
Or Tenderness (pain when 
of limb 
causing greater than minimal 
social & functional activities function OR Hospitalization 
area is touched) 
interference with usual social 
(other than ER visit) indicated 
& functional activities 
for management of 
pain/tenderness 
Injection Site Reaction 
Erythema OR Induration 
Erythema OR Induration OR 
Ulceration OR Secondary 
Necrosis (involving dermis and 
(Localized), > 15 Years 
of 5 × 5 cm to 9 × 9 cm (or 
Edema > 9 cm any diameter 
infection OR Phlebitis OR 
deeper tissue) 
25−81 × cm2) 
(or > 81 cm2) 
Sterile abscess OR Drainage 
Pediatric ≤ 15 Years 
Erythema OR Induration 
Erythema OR Induration 
Erythema OR Induration 
Necrosis (involving dermis and 
OR Edema present but 
OR Edema > 2.5 cm 
OR Edema involving 
deeper tissue) 
≤ 2.5 cm diameter 
diameter but < 50% surface 
≥ 50% surface area of the 
area of the extremity 
extremity segment (eg, 
segment (eg, upper 
upper arm/thigh) OR 
arm/thigh) 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage 
Pruritus Associated with 
Itching localized to injection 
Itching beyond the injection 
Generalized itching causing 
NA 
Injection 
site AND Relieved 
site but not generalized OR 
inability to perform usual 
See also Skin: Pruritus 
spontaneously or with 
Itching localized to injection 
social & functional activities 
(itching—no skin lesions) 
< 48 h treatment 
site requiring ≥ 48 h treatment 


CRI 15-05 Protocol 13SEP2017 
Page 71 
 
 
ENDOCRINE/METABOLIC 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Lipodystrophy (eg, back 
Detectable by study 
Detectable on physical exam by 
Disfiguring OR Obvious 
NA 
of neck, breasts, 
participant or caregiver 
health care provider 
changes on casual visual 
abdomen) 
(for young children and 
inspection 
disabled adults) 
Diabetes Mellitus 
NA 
New onset without need to initiate 
New onset with initiation of 
Life-threatening consequences 
medication OR Modification of 
indicated med OR Diabetes 
(eg, ketoacidosis, 
current meds to regain glucose 
uncontrolled despite treatment 
hyperosmolar non-ketotic 
control 
modification 
coma) 
Gynecomastia 
Detectable by study 
Detectable on physical exam by 
Disfiguring OR Obvious on 
NA 
participant or caregiver 
health care provider 
casual visual inspection 
(for young children and 
disabled adults) 
Hyperthyroidism 
Asymptomatic 
Symptomatic causing greater than 
Symptoms causing inability to 
Life-threatening consequences 
minimal interference with usual 
perform usual social & 
(eg, thyroid storm) 
social & functional activities OR 
functional activities OR 
Thyroid suppression therapy 
Uncontrolled despite treatment 
indicated 
modification 
Hypothyroidism 
Asymptomatic 
Symptomatic causing greater than 
Symptoms causing inability to 
Life-threatening consequences 
minimal interference with usual 
perform usual social & 
(eg, myxedema coma) 
social & functional activities OR 
functional activities OR 
Thyroid replacement therapy 
Uncontrolled despite treatment 
indicated 
modification 
Lipoatrophy (eg, fat loss 
Detectable by study 
Detectable on physical exam by 
Disfiguring OR Obvious on 
NA 
from the face, extremities, 
participant or caregiver 
health care provider 
casual visual inspection 
buttocks) 
(for young children and 
disabled adults) 
 


CRI 15-05 Protocol 13SEP2017 
Page 72 
 
 
 
GENITOURINARY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Intermenstrual Bleeding 
Spotting observed by participant 
Intermenstrual bleeding not 
Intermenstrual bleeding greater 
Hemorrhage with life- 
(IMB) 
OR Minimal blood observed 
greater in duration or amount 
in duration or amount than usual 
threatening hypotension OR 
during clinical or colposcopic 
than usual menstrual cycle 
menstrual cycle 
Operative intervention 
exam 
indicated 
Urinary Tract 
NA 
Signs or symptoms of urinary 
Signs or symptoms of urinary 
Obstruction causing life- 
obstruction (eg, stone) 
tract obstruction without 
tract obstruction with 
threatening consequences 
hydronephrosis or renal 
hydronephrosis or renal 
dysfunction 
dysfunction 
INFECTION 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Infection (any other 
Localized, no systemic antiμbial 
Systemic antiμbial treatment 
Systemic antiμbial treatment 
Life-threatening 
than HIV infection) 
treatment indicated AND 
indicated OR Symptoms 
indicated AND Symptoms 
consequences (eg, septic 
Symptoms causing no or 
causing greater than minimal 
causing inability to perform 
shock) 
minimal interference with usual 
interference with usual social 
usual social & functional 
social & functional activities 
& functional activities 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated 
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
 
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. 


CRI 15-05 Protocol 13SEP2017 
Page 73 
 
 
 
Appendix 5: 
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Recommendations 
 
 
Pregnancy and Contraception Requirements for Males and Females of Childbearing 
Potential 
 
Non-clinical toxicity studies of Epclusa demonstrated no adverse effect on embryo-fetal development. 
However, there are no clinical studies of Epclusa in pregnant women. Please refer to the latest version of 
the Investigator’s Brochure for additional information. 
 
Definition of Female of Childbearing Potential and Contraceptive Requirements for Female 
Subjects (and their male partners) 
 
Women >54 years of age with cessation for ≥12 months of previously occurring menses, or women of 
any age who have had a hysterectomy, have had both ovaries removed, or have had medically 
documented ovarian failure will be considered to be of non-childbearing potential. 
 
Women who are ≤ 54 years of age (including those with amenorrhea of any duration) who have not had 
a hysterectomy, have not had both ovaries removed, and have not had medically documented ovarian 
failure will be considered to be of childbearing potential. 
 
Women of childbearing potential must have a negative serum pregnancy test at screening and a 
negative urine pregnancy test on the Baseline/Day 1 visit prior to enrollment. They must also agree to 
one of the following from 3 weeks prior to Baseline/Day 1 until 30 days after last dose of study drug: 
 
1) Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted. 
 
Or 
 
2) Consistent and correct use of 1 of the following methods of birth control listed below in 
addition to a male partner who correctly uses a condom from the date of screening until 30 
days after last dose of study drug: 
 
a) intrauterine device (IUD) with a failure rate of < 1% per year 
b) female barrier method: cervical cap or diaphragm with spermicidal agent (if locally 
available) 
c) tubal sterilization 
3) vasectomy in male partner 
a) hormone-containing contraceptive: 
i) implants of levonorgestrel 
ii) injectable progesterone 
iii) oral contraceptives (either combined or progesterone only) 
iv) contraceptive vaginal ring 
v) transdermal contraceptive patch 
 
3.  Contraceptive Requirements for Male Subjects (and their female partners) 
 
All male study participants must agree to consistently and correctly use a condom, while their female 
partner agrees to use 1 of the methods of birth control listed above, from the date of screening until 90 


CRI 15-05 Protocol 13SEP2017 
Page 74 
 
 
days after administration of the last dose of study drug: 
 
Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of study 
drug. 
 
4.  Procedures to be Followed in the Event of Pregnancy 
 
Subjects will be instructed to notify the Investigator if they become pregnant at any time during the 
study, or if they become pregnant within 30 days (90 days for partners of male subjects) of last Epclusa 
dose. Subjects who become pregnant or who suspect that they are pregnant must report the information to 
the Investigator and discontinue study drug immediately. Subjects whose partner has become pregnant or 
suspects she is pregnant must report the information to the Investigator. 
 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in Section 
9.8. 
 
 


CRI 15-05 Protocol 13SEP2017 
Page 75 
 
 
 
 
Appendix 6: 
HCV Treatment Curriculum 
 

ICF_002.pdf: 
 
 Informed Consent for patients: Sponsor-Investigator Initiated CRI #15-05  
Title: 
Bridging Care to HCV Treatment Among Opioid Dependent Patients on 
Buprenorphine/naloxone Maintenance Therapy: A Pilot Study of 
Treating HCV with Epclusa at a Psychiatrist-staffed Outpatient 
Addiction Clinic 
 Approved:  August 3, 2017                                          
NCT03235154 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
1 
 
INFORMED CONSENT 
 
 
TITLE: 
Bridging Care to HCV Treatment Among Opiate Dependent 
Patients on Buprenorphine/naloxone Maintenance Therapy: A 
Pilot Study of Treating HCV with Epclusa at a Psychiatrist-staffed 
Outpatient Addiction Clinic 
 
PROTOCOL NO.: 
15-05 
 
WIRB® Protocol #20170423 
 
PROTOCOL 
VERSION/DATE: 
V6.2 February 23, 2017 
 
FUNDER: 
Gilead 
 
SPONSOR: 
Community Research Initiative of New England 
 
INVESTIGATOR: 
Dr. Amy Colson, MD, MPH 
 
Schrafft’s City Center 
 
529 Main Street, 3rd Floor 
 
Boston, Massachusetts 02129 
 
United States 
 
SITE(S): 
Outpatient Addiction Services 
 
Cambridge Health Alliance 
 
26 Central Street 
 
Somerville, MA 02143 
 
United States 
 
Tel: 617-665-1000 
 
Email: zschuman@challiance.org 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Amy Colson, MD, MPH 
 
617-502-1700 
 
617-502-1799 (24-hours) 
 
SUB- 
INVESTIGATOR(S): 
Zev Schuman-Olivier, MD 
 
 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
2 
 
INTRODUCTION 
 
You are being asked to take part in a clinical research study involving a currently available 
treatment for Hepatitis C virus (HCV).  The treatment, Epclusa, is approved by the Food and 
Drug Administration for treatment of HCV.  It is a fixed-dose combination (FDC) tablet which 
combines two separate medicines called sofosbuvir (SOF) and velpatasvir (VEL) into one tablet 
for the treatment of the Hepatitis C virus (HCV). This consent form gives you information about 
the study. A member of the study staff will read through the consent with you, discuss all the 
information, and will answer any questions that you may have.  Ask your study doctor or study 
nurse to explain any words or information in this consent form you do not clearly understand.  
You should understand the purpose of the study, how taking part may help you, any potential 
risks to you, and what is expected of you during the study.  If you then want to be in the study, 
you will be asked to sign this consent form. Once signed, you will receive the signed and dated 
copy to keep. 
 
You may show this consent form to family, other doctors, or friends. You may want to discuss it 
with them to help you decide if you want to be in this study. If you don’t know another doctor 
but want a second opinion about this study, please ask. The study doctor will recommend 
someone for more information. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the Web 
site will include a summary of the results.  You can search this Web site at any time. 
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
The main purpose of this study is to assess the safety and effectiveness and tolerability of 
Epclusa in HCV-treatment naïve and treatment-experienced (including treatment-intolerant) 
subjects with chronic HCV infection who regularly attend a clinic for Suboxone therapy. 
 
Epclusa is an FDA approved drug that is used to treat chronic Hepatitis C Infection. In clinical 
trials of Epclusa, medication side effects were generally mild. The most common side effects 
seen were tiredness and headache.  Nausea, lack of energy and insomnia were also seen in 
clinical trials of Epclusa in a small fraction of participants (less than 10%). 
 
Epclusa has been shown to be effective in curing Hepatitis C infection.  In clinical trials, cure 
rates ranged from 89% to 98% depending upon patient characteristics and duration of 
treatment. 
 
You are being asked to be in this study because you: 
 
 Are infected with the Hepatitis C virus 
 Meet safety criteria for treatment with Epclusa 
 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
3 
 
Dr. Amy Colson is the person in charge of this study at Community Research Initiative.   She will 
work with nurses and doctors at Cambridge Health Alliance to conduct the study.  Your study 
visits will take place during your regularly scheduled visits to the Suboxone clinic. Epclusa will 
be provided to you at no charge. 
 
This Informed Consent refers to the Community Research Initiative staff as the “study staff” and 
to the doctor that you regularly see for your medical care at the Suboxone clinic as your “study 
doctor.” The doctor who oversees this study is referred to as the “Principal Investigator.” 
 
HOW LONG WILL THIS STUDY LAST? 
 
The study is expected to last for 48 weeks. Twenty individuals with HCV at one clinic in the 
United States will be enrolled in this study. 
 
THE STUDY: 
 
If it is determined that you are eligible for the study, you will be provided treatment with 
Epclusa for the full treatment course of 12 weeks as prescribed by your study doctor. 
 
WHAT ARE THE PROCEDURES OF THIS STUDY? 
 
Screening Visit 
 
The first visit of the study is the screening visit to see if you qualify for the study. At this visit, 
the study staff will go over this consent form with you. If you want to be in the study, you will 
sign this consent. At this visit, after you sign the consent, you will be asked about: 
 
 Your recent medical history including recent or past drug allergies 
 Your current medical health 
 The medications that you take 
 your current alcohol use 
 
In addition, the following may occur: 
 
 Blood samples (between 1 and 2 tablespoons) will be obtained to evaluate: 
o HCV viral load (amount of HCV in your blood) 
o HCV genotype test (to determine the type of HCV infection, if not yet known) 
o Complete blood panel 
o Hepatic function tests ALT, AST (test the function of your liver) 
o Basic metabolic panel and estimated GFR (tests of your kidney function) 
o FibroSure (to estimate the amount of fibrosis of your liver) 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
4 
 
o Hepatitis B virus testing to assess for presence of active infection or immunity to 
the virus 
o Serum pregnancy test if you are a woman who can become pregnant 
 Urine sample for drug screening and presence of Suboxone 
 Vital signs including blood pressure, pulse, height and weight 
 A recording of the rhythm and speed of your heartbeat 
 
These test results will be used to see if you qualify for this study. 
 
Baseline Visit 
 
This visit will occur within 30 days of the screening visit during a regularly scheduled clinic visit.  
At this visit you will do the following: 
 
 Complete three questionnaires about your health and quality of life  
 Supply a urine sample for drug screening and presence of Suboxone 
 Have a urine pregnancy test if you are a woman who can have children 
 
In addition, at this visit the study doctor and study staff will do the following: 
 
 Review all medicines that you are taking 
 Review side effects and new physical findings that you may have 
 Measure your blood pressure, pulse, and weight 
 Perform a physical examination if indicated 
 Provide Epclusa study treatment 
 Provide medication adherence counseling 
 
Every two weeks during your study treatment you will be seen during a regular OAS clinic 
visit: 
 
At each visit during treatment with Epclusa the study staff and doctor will do the following: 
 
 Review all medicines that you are taking 
 Review side effects and new physical findings that you may have 
 Measure your blood pressure, pulse, and weight 
 Review medication adherence and provide adherence counseling 
 Provide study medications 
 Collect study medication containers 
 
At each visit the following will also occur: 
 
 Supply a urine sample for drug screening and presence of Suboxone 
 Have a urine pregnancy test if you are a woman who can have children 
 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
5 
 
At the Week 4 visit only: 
 
 Blood samples (between 1 and 2 tablespoons) will be obtained to evaluate: 
o HCV viral load (amount of HCV in your blood), 
o Hepatitis B virus testing to assess for presence of active infection 
o Hepatic function tests ALT, AST (test the function of your liver) 
 Complete three questionnaires about your health and quality of life 
 
At your final treatment visit only study staff will ask you to do the following: 
 
 Complete three questionnaires about your health and quality of life 
 
Post-Treatment Assessments 
 
After you have completed your Epclusa study treatment, you will be seen at the clinic for study 
visits.  These visits will take place 4 weeks and 12 weeks after your stop Epclusa treatment.  At 
this visit study staff and the study doctor will: 
 
 Review all medicines that you are taking 
 Review side effects and new physical findings that you may have 
 
In addition: 
 
 a blood sample will be drawn to assess HCV viral load (amount of HCV in your blood) 
 
At the post-treatment week 12 visit only: 
 
 Complete three questionnaires about your health and quality of life 
 
Instructions for Taking Study Medication 
 
The study medication is formulated as a tablet and should be stored at room temperature.  
Take one tablet by mouth daily, with or without food. 
 
Tablets will be supplied in bottles with 28 doses in each bottle. When you are given your study 
medication bottle by study staff, you will also be given a bottle cap that has an electronic dose 
recording system embedded in the packaging.  It is very important that you return the entire 
bottle and cap to the study doctor at each visit during treatment.  The study doctor or study 
staff will download your dosing information from the packaging at every visit and review it with 
you. 
 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
6 
 
Subject’s Responsibilities 
 
As a participant in this study, it is your responsibility: 
 
 to come to the study site for all scheduled study visits 
 to take the medications according to the directions given by the study doctor and study 
staff 
 to return your study medication packaging at each study visit 
 to tell study staff about all medications you are taking 
 to tell study staff about any side effects you may have 
 
ARE THERE MEDICATIONS THAT YOU CANNOT TAKE WHILE ON THIS STUDY? 
 
We encourage you to discuss all medications and herbal supplements you plan to take during 
the study, including: 
 
 Any prescription drugs, including vaccines 
 Any over the counter medicines 
 Any herbal preparations 
 
At each visit the study staff will review all medicines you are taking. You should call the study 
staff any time you are given a new medicine prescribed by another doctor. You will be given the 
staff number and a pager number. 
 
WHAT PROCEDURES ARE BEING PERFORMED FOR THE PURPOSES OF THIS STUDY (THAT ARE 
NOT CONSIDERED STANDARD CARE FOR YOUR HCV INFECTION)? 
 
 More frequent medical monitoring 
 Pregnancy tests 
 Responding to questionnaires 
 Electronic recording of dosing by study medication packaging 
 
WHAT ARE THE RISKS AND DISCOMFORTS? 
 
RISKS AND BENEFITS 
 
Epclusa: 
 
There are potential side effects associated with the use of Epclusa including tiredness, 
headache, nausea, lack of energy and insomnia.  In clinical trials, these side effects were 
generally mild and were seen in less than 25% of participants. 
 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
7 
 
Blood Draws 
 
In addition to risks associated with the study drug, drawing blood from a vein may cause local 
pain, bruising, occasional lightheadedness, fainting, and very rarely, infection at the site of the 
blood draw. 
 
Other Risks: 
 
As with any drug, there is a risk of allergic reaction. If you have a very serious allergic reaction, 
you may be at risk of death. Some symptoms of allergic reaction are rash; difficulty breathing; 
wheezing; sudden drop in blood pressure; swelling around the mouth, throat or eyes; a fast 
pulse; and sweating. 
 
Please seek treatment and inform the study doctor and study staff at once if you have any of 
these symptoms, or any other side effects, during the study. 
 
There is a possibility that Epclusa will not treat your HCV.  Epclusa is generally effective but has 
reduced effectiveness when not taken correctly.  It is very important to follow the study doctor 
and study staff’s dosing instructions. 
 
You may have side effects that are not yet known or have not yet been reported. 
 
If you want to be in this study, you may be excluded from participating in other studies at the 
same time. If you are taking part in another study, you should let the study staff know about 
the other study. The study staff person will need to make contact with the other study site to 
make sure that it is all right for you to also participate in this study. The study staff person will 
also need to discuss this with the study medical monitor to make sure that participation in both 
studies is allowed. 
 
Possible Benefits of the Study 
 
There is no guarantee that you will receive personal benefit from participating in this study. 
Your participation in this study may benefit the community, scientists and doctors who work 
with HCV by providing increased knowledge and information about the treatment of your 
disease. 
 
PREGNANCY AND BREAST FEEDING 
 
WHAT IF YOU ARE CONSIDERING HAVING A CHILD? 
 
Women: 
 
The safety of Epclusa has not been studied in pregnant women.  If you are a woman who can 
become pregnant, you can only be in this study if you are not pregnant and use birth control 
that is very reliable for the duration of the study and until at least 8 weeks after the last dose of 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
8 
 
study medication.  A barrier type of birth control is required in addition to the use of an IUD, 
hormonal contraceptive or a second barrier method. Barrier methods include male condoms 
(should be used without spermicide), female condoms, diaphragms, and cervical caps.  This 
would not be required if you are non-heterosexually active, practice sexual abstinence, or have 
a vasectomized partner (confirmed sterile) or have undergone a tubal ligation (tubes tied). 
Pregnancy tests will be done before you start on the study, at each study visit, and at any time 
that pregnancy is suspected.  It is important for you to tell the study doctor at once if you get 
pregnant or think that you might be pregnant while you are in the research study.  If you 
become pregnant while on the study, you will be discontinued from the study.  You may also be 
asked questions about your pregnancy and the baby.  Your study doctor will want follow up 
information on your infant for a minimum of 8 weeks. 
 
Breast-feeding: 
 
Medicine can pass from mother to a nursing child. This may cause harmful side effects to the 
child. The safety of Epclusa for the nursing baby is not known. Women who are breast-feeding 
may not be in this study. 
 
Men: 
 
The effect of the study drugs on sperm is not known. You should not father a child or donate 
sperm while you are on the study and for 90 days after receiving the study drug. If you have sex 
with a woman who can get pregnant, you should use a condom.  When using a condom, it is 
recommended to use a condom without spermicide.  You must inform your study doctor if your 
partner becomes pregnant during the study or within 90 days after the last study drug 
administration. 
 
IF YOU DO NOT PARTICIPATE IN THIS STUDY, WHAT ARE YOUR ALTERNATIVES FOR CARE? 
 
Instead of being in this study, you may be eligible for HCV treatment, including the use of 
Epclusa, as prescribed by a local HCV treatment specialist. 
 
WILL YOU BE INFORMED OF NEW FINDINGS? 
 
Any new information that is learned about the study drug while you are on the study will be 
given to you. This new information might cause you to change your mind about staying in the 
study. You will be asked to sign a new consent form with the new information. This is to show 
that you have been told about this new information. 
 
HOW WILL YOUR CONFIDENTIALITY BE PROTECTED? 
 
You have a right to privacy. All information collected during this study is confidential as far as 
the law allows. The study forms (Case Report Forms) record all the information collected during 
the study. None of these papers will identify you. Your identity will stay confidential. 
 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
9 
 
However, in order to be sure the research is legitimate and legal, auditors and monitors will 
have access to your study records. These people are there to make sure we are doing what we 
say we are doing. Government authorities such as the Food and Drug Administration (FDA) also 
need to know that we do indeed have the subjects we say we do. The Western Institutional 
Review Board (WIRB) may know your name if necessary. That board reviews clinical research 
studies and is there to protect your interests. Community Research Initiative or someone we 
hire will look at all of the information gathered from all of your visits. They will use this 
information to decide whether the study drug was safe for you and the other people in the 
study. 
 
Information about your participation on this study may be looked at in any country in the 
world.  Community Research Initiative may send the information to health authorities all over 
the world. The results of the study might be used in reports and scientific meetings or 
publications. If you leave the study at any time, your information will stay in the study and be 
used for these reports. Your identity will never be used. 
 
Certificate of Confidentiality: 
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the 
National Institutes of Health. The researchers can use this Certificate to legally refuse to 
disclose information that may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings, for example, if there is a court subpoena. The 
researchers will use the Certificate to resist any demands for information that would identify 
you. 
 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States federal or state government agency sponsoring the project and that will be used for 
auditing or program evaluation of agency funded projects or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you or a member 
of your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, medical care provider, or other person obtains your written consent to 
receive research information, then the researchers will not use the Certificate to withhold that 
information. 
 
The Certificate of Confidentiality will not be used to prevent disclosure to state or local 
authorities of child abuse and neglect, or harm to self or others. 
 
WILL THERE BE ANY COSTS FOR PARTICIPATING IN THIS STUDY? 
 
You will not pay for the study visits or procedures required by the study that are not a part of 
standard care for Hepatitis C treatment. You or your insurance company will have to pay for 
costs of procedures not required by the study. You will also pay for any medical costs for care if 
your disease becomes worse. 
 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
10 
 
Epclusa will be provided to you. You or your insurance carrier will have to pay for your other 
medications. 
 
WILL THERE BE COMPENSATION FOR PARTICIPATION IN THIS STUDY? 
 
You will not receive any payment or compensation for your participation in this study. 
 
WILL THE STUDY DOCTOR BE PAID? 
 
Gilead will be providing study drug and funding support to the Principal Investigator at 
Community Research Initiative and your study doctor to conduct this study. The amount of this 
payment is sufficient to cover the doctor’s and/or institution’s expenses to perform the study 
but provides minimal personal financial benefit to your study doctor. 
 
FINANCIAL DISCLOSURE 
 
The Principal Investigator, Dr. Amy Colson, has received payments from Gilead for attending 
Scientific Advisory Board meetings.  Please feel free to ask any questions you may have about 
this matter. 
 
Compensation In Case Of Injury: 
 
If you experience any injury or illness as a direct result of your participation in this research 
study, call Dr. Amy Colson or the study staff at 617-502-1700 or 617-502-1799 (24 hour 
contact). You will be referred to your Primary Care Physician for immediate treatment. The cost 
of that treatment will be billed to your insurance company. Your insurance company may not 
pay. If your insurance company does not pay, or if you do not have an insurance company, you 
will be responsible for all payments.  No funds have been set aside for any other losses such as 
lost wages, disability, or discomfort relating to injury or illness as a result of your participation 
in this study. 
 
By signing this consent form, you will not give up any of your legal rights. 
 
CAN YOU WITHDRAW FROM THE STUDY? 
 
Before you can decide if you want to be in this study, it is important that you know that: 
 
 You do not have to be in this study. 
 You can decide to stop being in this study at any time. 
 Your decision will not result in any penalty or loss of any benefits to which you may be 
entitled. 
 You will be asked to make one last office visit for a final exam and blood work. But, you 
can refuse to do this. 
 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
11 
 
Removal from study: 
 
You may be removed from the study without your consent for any of the following reasons, or 
other administrative reasons: 
 
 If the investigator decides staying on the study would be harmful to you 
 If you require a treatment not allowed on this study 
 If you do not come to the study site for scheduled visits and take your medicine as 
instructed 
 If you become pregnant 
 If you have a serious reaction to the study medication 
 If the study is canceled by Gilead, Community Research Initiative, the FDA, or Western 
Institutional Review Board. 
 If you become imprisoned or involuntarily incarcerated in a medical facility. 
 
NAMES OF CONTACTS FOR QUESTIONS ABOUT THE STUDY: 
 
Dr. Amy Colson 
Staff office: 617-502-1700 
Off hours number: 617-502-1799 
 
You should call Dr. Amy Colson or the study staff and study doctor you have been working 
with for the following reasons: 
 
 If you are worried about how you are feeling 
 If you think you may have been hurt because of the study 
 If you have questions, concerns, or complaints about the study procedures, medication, 
etc. 
 
If you have any questions about your rights as a research subject, or if you have questions, 
concerns, or complaints about the research, you may contact: 
 
Western Institutional Review Board® (WIRB®) 
1019 39th Avenue SE Suite 120 
Puyallup, WA 98374-2115 
Office:  (360) 252-2500 
 
(800) 562-4789 
Fax:  
(360) 252-2498 
Email:  Help@wirb.com 
 
WIRB is a group of people who perform independent review of research. 
 
WIRB will not be able to answer some study-specific questions, such as questions about 
appointment times.  However, you may contact WIRB if the research staff cannot be reached or 
if you wish to talk to someone other than the research staff. 
 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
12 
 
VOLUNTEER’S STATEMENT: 
 
I have been given a chance to ask questions about this research study. These questions have 
been answered to my satisfaction. If I have any more questions about being in this study I may 
contact Dr. Amy Colson, MD, MPH at Community Research Initiative of New England at 617-
502-1700. 
 
I understand that my participation in this research project is voluntary.  I know that I may quit 
the study at any time. I may quit without harming my medical care or losing any benefits I 
might be entitled to. I also understand that the doctor for this study may decide at any time 
that I should no longer be in this study. 
 
If I have any questions about my rights as a research subject in this study, I may contact: 
 
Western Institutional Review Board (WIRB) 
1019 39th Avenue SE, Suite 120 
Puyallup, WA 98374-2115 
Office:  (360) 252-2500 
 
(800) 562-4789 
Fax:  
(360) 252-2498 
Email:  help@wirb.com 
 
I have read and understand the above information. I agree to be in this study. I have been given 
a copy of this signed and dated form for my records. 
 
I understand that I do not give up any of my legal rights by signing this consent form. 
 
 
 
 
 
  
 
Study Participant (signature) 
Date 
Time 
 
 
 
 
Print Participant’s Name 
 
 
 
 
 
  
 
Person who explained this study (signature) 
Date 
Time 
 
 
 
 
Print Name of Person who explained this study 
 


 
APPROVED 
 
AS MODIFIED 
 
Aug 03, 2017 
 
WIRB® 
 
13 
 
The following witness has observed the entire consent process: 
 
 
 
 
 
  
 
Witness Signature (When Appropriate) 
Date 
Time 
 
 
 
 
Witness’s Name (When Appropriate) 

ICF_003.pdf: 
 
 Informed Consent for providers:  Sponsor-Investigator Initiated CRI #15-05  
Title: 
Bridging Care to HCV Treatment Among Opioid Dependent Patients on 
Buprenorphine/naloxone Maintenance Therapy: A Pilot Study of Treating 
HCV with Epclusa at a Psychiatrist-staffed Outpatient Addiction Clinic 
 Approved:  May 5, 2017                                        
NCT03235154 


 
APPROVED 
 
May 05, 2017 
 
WIRB 
 
 
1 
 
PSYCHIATRIST INFORMED CONSENT 
 
 
TITLE: 
Bridging Care to HCV Treatment Among Opiate Dependent 
Patients on Buprenorphine/naloxone Maintenance Therapy: A 
Pilot Study of Treating HCV with Epclusa at a Psychiatrist-staffed 
Outpatient Addiction Clinic 
 
PROTOCOL NO.: 
15-05 
 
WIRB® Protocol #20170423 
 
PROTOCOL 
VERSION/DATE: 
V6.2 February 23, 2017 
 
FUNDER: 
Gilead 
 
SPONSOR: 
Community Research Initiative of New England 
 
INVESTIGATOR: 
Dr. Amy Colson, MD, MPH 
 
Schrafft’s City Center 
 
529 Main Street, 3rd Floor 
 
Boston, Massachusetts 02129 
 
United States 
 
SITE(S): 
Outpatient Addiction Services 
 
Cambridge Health Alliance 
 
26 Central Street 
 
Somerville, MA 02143 
 
United States 
 
Tel: 617-665-1000 
 
Email: zschuman@challiance.org 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Amy Colson, MD, MPH 
 
617-502-1700 
 
617-502-1799 (24-hours) 
 
SUB- 
INVESTIGATOR(S): 
Zev Schuman-Olivier, MD 
 
 


 
APPROVED 
 
May 05, 2017 
 
WIRB 
 
 
2 
 
INTRODUCTION 
 
You are being asked to take part in a clinical research study involving a currently available 
treatment for Hepatitis C virus (HCV).  The treatment, Epclusa, is approved by the Food and 
Drug Administration for treatment of HCV.  It is a fixed-dose combination (FDC) tablet which 
combines two separate medicines called Sofosbuvir (SOF) and Velpatasvir (VEL) into one tablet 
for the treatment of the Hepatitis C virus (HCV). If you participate in this study you will be a 
prescriber of this medication to HCV infected patients receiving buprenorphine/naloxone 
therapy at the Outpatient Addiction Services clinic. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the Web 
site will include a summary of the results.  You can search this Web site at any time. 
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
The main purpose of this study is to assess the safety and effectiveness and tolerability of 
Epclusa in HCV treatment naïve and treatment-experienced (including treatment intolerant) 
subjects with chronic HCV infection who regularly attend a clinic for buprenorphine/naloxone 
therapy.  The study also seeks to design and assess a curriculum and mentorship program to 
support psychiatrists with managing HCV infection. 
 
You are being asked to be in this study because you: 
 
 Are a psychiatrist who has agreed to train for and implement an HCV treatment protocol 
at Outpatient Addiction Services clinic at CHA 
 
HOW LONG WILL THIS STUDY LAST? 
 
The study is expected to last for 48 weeks and to enroll 20 HCV-infected individuals who receive 
buprenorphine/naloxone therapy at the Outpatient Addiction Services clinic at CHA. 
 
Psychiatrists employed at that clinic will prescribe and manage the study treatment, participate 
in the mentorship program and complete questionnaires about their experience managing HCV 
disease for study participants during the study. 
 
THE STUDY: 
 
WHAT ARE THE PROCEDURES OF THIS STUDY? 
 
If you agree to participate in the mentorship and survey assessments, you will be asked to 
review this informed consent and to sign it after all your questions have been answered.  You 
will have access to the consent and a sub investigator or investigator to discuss your questions 
prior to consenting.  If you agree to participate, you will sign the consent with the study team 
prior to any study related activities. 


 
APPROVED 
 
May 05, 2017 
 
WIRB 
 
 
3 
 
Prior to initiating treatment of HCV with eligible subjects, you will attend a scheduled 
mentorship training program conducted by Dr. Amy Colson, an infectious diseases physician 
who is the Principal Investigator of the study.  The curriculum will review all necessary 
information about the management of HCV treatment.  The following topics will be reviewed: 
 
• Pathogenesis of HCV infection 
• Goals of therapy/benefits of curing HCV 
• Pre-treatment assessment, including diagnosis of Cirrhosis 
• Usage of Epclusa 
 
Prior to the scheduled mentorship training program, and after four months of prescribing HCV 
therapy to study participants, you will be asked to complete a brief survey to determine your 
comfort level with providing care for patients with HCV infection. 
 
Regularly schedule weekly telephone support for psychiatrist-prescribers will be provided by Dr. 
Amy Colson throughout the study. 
 
Subject’s Responsibilities 
 
As a participating psychiatrist in this study, it is your responsibility: 
 
 to come to the initial training session 
 to complete surveys as requested by the study team and outlined in the protocol 
 to participate in regularly scheduled weekly support calls with the Principal Investigator 
 
WHAT ARE THE RISKS AND DISCOMFORTS? 
 
RISKS AND BENEFITS 
 
Possible Risks of the Study 
 
All responses to surveys will be kept strictly confidential. However, there is a small theoretical 
risk that survey confidentiality may be compromised. 
 
Possible Benefits of the Study 
 
There is no guarantee that you will receive personal benefit from participating in this study. 
One theoretical perceived benefit may be through participating in the mentorship program 
about HCV treatment you will broaden your knowledge about the topic.  The results of this 
study may benefit future patients receiving HCV treatment. 
 
WHAT ARE MY ALTERNATIVES? 
 
Your alternative is not to participate in this study. 


 
APPROVED 
 
May 05, 2017 
 
WIRB 
 
 
4 
 
WILL YOU BE INFORMED OF NEW FINDINGS? 
 
Any new information that is learned about the study conduct and changes to treatment 
protocols for HCV infection while the study is being conducted will be given to you. This new 
information might cause you to change your mind about staying in the study. You may be asked 
to sign a new consent form with the new information to document show that you have been 
told about this new information. 
 
HOW WILL YOUR CONFIDENTIALITY BE PROTECTED? 
 
You have a right to privacy. All information collected during this study is confidential as far as 
the law allows. The questionnaires you complete will identify you by a provider-subject number 
but NOT BY NAME.  As part of their oversight responsibilities, the research records may be 
reviewed by the U.S. Food and Drug Administration (FDA) and Western Institutional Review 
Board (WIRB).  
 
The results of the study may be presented at scientific meetings or published.  Your identity will 
never be used in these reports. 
 
WILL THERE BE ANY COSTS FOR PARTICIPATING IN THIS STUDY? 
 
There will be no cost to you. 
 
WILL THERE BE COMPENSATION FOR PARTICIPATION IN THIS STUDY? 
 
You will not receive any payment or compensation for your participation in this study. 
 
CAN YOU WITHDRAW FROM THE STUDY? 
 
Before you can decide if you want to be in this study, it is important that you know that: 
 
 You do not have to be in this study. 
 You can decide to stop being in this study at any time. 
 Your decision will not result in any penalty or loss of any benefits to which you may be 
entitled. 
 
Outpatient Addiction Services clinic management does not urge, influence or encourage anyone 
who works at the clinic to take part in a research study.  Your participation in this study is 
completely voluntary.  You may withdraw from the study at any time and for any reason.  Your 
decision not to participate in the study, or a decision on your part to withdraw from the study, 
will have no effect whatsoever on your employment status.  You may refuse to participate or 
you may withdraw from the study at any time without penalty or prejudice. 
 


 
APPROVED 
 
May 05, 2017 
 
WIRB 
 
 
5 
 
Removal from study: 
 
You may be removed from the study without your consent for any of the following reasons, or 
other administrative reasons: 
 
 If you do not participate in the mentorship program as described 
 If the study is canceled by Gilead, CRI, the FDA, or the IRB 
 
NAMES OF CONTACTS FOR QUESTIONS ABOUT THE STUDY: 
 
Dr. Amy Colson 
Staff office: 617-502-1700 
Off hours number: 617-502-1799 
 
You should call Dr. Amy Colson or the study staff and study doctor you have been working 
with for the following reasons: 
 
 If you think you may have a study-related issue 
 If you have questions, concerns, or complaints about the study procedures, medication, 
etc. 
 
If you have any questions about your rights as a research subject, or if you have questions, 
concerns, or complaints about the research, you may contact: 
 
Western Institutional Review Board® (WIRB®) 
1019 39th Avenue SE Suite 120 
Puyallup, WA 98374-2115 
Office:  (360) 252-2500 
 
(800) 562-4789 
Fax:  
(360) 252-2498 
Email:  Help@wirb.com 
 
WIRB is a group of people who perform independent review of research. 
 
WIRB will not be able to answer some study-specific questions, such as questions about 
appointment times.  However, you may contact WIRB if the research staff cannot be reached or 
if you wish to talk to someone other than the research staff. 
 


 
APPROVED 
 
May 05, 2017 
 
WIRB 
 
 
6 
 
VOLUNTEER’S STATEMENT: 
 
I have been given a chance to ask questions about this research study. These questions have 
been answered to my satisfaction. If I have any more questions about being in this study I may 
contact Dr. Amy Colson, MD, MPH at Community Research Initiative of New England at 617-
502-1700. 
 
I understand that my participation in this research project is voluntary.  I know that I may quit 
the study at any time. 
 
If I have any questions about my rights as a research subject in this study, I may contact: 
 
Western Institutional Review Board (WIRB) 
1019 39th Avenue SE, Suite 120 
Puyallup, WA 98374-2115 
Office:  (360) 252-2500 
 
(800) 562-4789 
Fax:  
(360) 252-2498 
Email:  help@wirb.com 
 
I have read and understand the above information. I agree to be in this study. I have been given 
a copy of this signed and dated form for my records. 
 
I understand that I do not give up any of my legal rights by signing this consent form. 
 
 
 
 
 
  
 
Study Participant (signature) 
Date 
Time 
 
 
 
 
Print Participant’s Name 
 
 
 
 
 
  
 
Person who explained this study (signature) 
Date 
Time 
 
 
 
 
Print Name of Person who explained this study