Patient-Centered Models of HCV Care for People Who Inject Drugs
Phase: NA
Conditions: Hepatitis C, Medication Adherence
Sponsor: Prisma Health-Upstate

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Patient-Centered Models of HCV Care for People Who Inject Drugs 
The HERO Study:  Hepatitis C Real Options 
 
 
 
Funding Mechanism:  PCORI 
 
Pharmaceutical Support Provided by:  Gilead 
 
 
Protocol Co-Chairs: Alain Litwin, MD, Kimberly Page, Ph.D., MPH  
 
 
Version Number:  4.0 
 
21 May 2019 
 
 
NCT Number: NCT02824640

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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as 
required by the following:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 
312) 
• International Conference of Harmonisation (ICH) E6; 62 Federal Register 25691 
(1997)  
• Patient-Centered Outcomes Research Initiatives Clinical Terms of Award 
 
All key personnel (all individuals responsible for the design and conduct of this study) 
have completed Human Subjects Protection Training. 
 
 

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SIGNATURE PAGE 
The signatures below constitute the approval of this protocol and appendices, and 
provide the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
 
 
Signed:  
Date: 
 
 
Judith Feinberg, MD 
Co-Investigator 
West Virginia University 
Morgantown, West Virginia 
 
Signed:  
Date: 
 
 
 
 
Nirah Johnson, LCSW 
Co-Investigator 
New York City Department of Health and Mental Hygiene 
New York, NY   
 
Signed:  
Date: 
 
 
Arthur Kim, M.D. 
Co-Investigator 
Massachusetts General Hospital/Harvard Medical School   
Boston, MA 
 
 
Signed:  
Date: 
 
 
Alain Litwin, MD 
Principal Investigator 
Clemson University/Prisma Health-Upstate 
Greenville, SC  
Signed:  
Date: 
 
 
Paula Lum, M.D., M.P.H. 
Co-Investigator 

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University of California San Francisco 
San Francisco, CA 
 
 
 
 
Signed:  
Date: 
 
 
 
 
Shruti Mehta, Ph.D. 
Co-Investigator 
The Johns Hopkins University 
Baltimore, MD 
Signed 
Brianna Norton, DO 
Co-Investigator 
Albert Einstein College of Medicine 
New York, NY 
 
 
 
Date: 
 
 
 
 
 
Signed:  
Date: 
 
 
Kimberly Page, Ph.D., M.P.H. 
Co-Investigator 
University of New Mexico 
Albuquerque, NM 
 
Signed:  
Date: 
 
 
Lynn Taylor, MD 
Co-Investigator 
University of Rhode Island 
CODAC Behavioral Health 
Providence, RI 
 
Signed:  
Date: 
 
 
Judith Tsui, MD., M.P.H. 
Co-Investigator 
University of Washington 
Seattle, WA  
Signed:  
Date: 
 
 
 
John Ward, MD 
Co-Investigator 
Centers for Disease Control and Prevention 
Atlanta, GA 

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TABLE OF CONTENTS 
1 
Key Roles .............................................................................................................. 1 
2 
Background Information and Scientific Rationale .................................................. 5 
2.1 
Background Information ............................................................................... 5 
2.2 
Scientific Rationale ...................................................................................... 9 
2.3 
Potential Risks and Benefits ........................................................................ 13 
3 
Study Objectives ................................................................................................. 16 
3.1 
Primary Objective ...................................................................................... 16 
3.2 
Secondary Objective 1 ................................................................................ 16 
3.3 
Secondary Objective 2 ................................................................................ 16 
4 
Study Design ....................................................................................................... 18 
5 
Study Population ................................................................................................. 19 
5.1 
Inclusion Criteria ........................................................................................ 20 
5.2 
Exclusion Criteria ....................................................................................... 21 
5.3 
Re-Screening ............................................................................................. 21 
5.4 
Randomization ........................................................................................... 21 
5.5 
Withdrawal ................................................................................................ 22 
6 
Investigational Interventions ............................................................................... 23 
6.1 
modified Directly Observed Treatment ......................................................... 23 
6.1.1 OTP Setting .................................................................................................. 23 
6.1.2 Community Health Center Setting .................................................................. 24 
6.2 
Patient Navigation ...................................................................................... 25 
6.3 
Education and Peer Support ......................................................................... 26 
7 
Study Procedures/Evaluations ............................................................................. 27 
7.1 
Clinical Evaluations .................................................................................... 27 
7.2 
Laboratory Evaluations ............................................................................... 27 
7.3 
Non-Clinical Evaluations ............................................................................ 28 
8 
Study Schedule .................................................................................................... 30 
8.1 
Screening and Enrollment ........................................................................... 30 
8.1.1 Screening ..................................................................................................... 30 

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8.1.1.a.  Screening with Chart Reviews.................................................................... 30 
8.1.1.b.  Community-Based Screening ..................................................................... 31 
8.1.2 Visit 0:  Eligibility confirmation, Consent and Enrollment Visit ......................... 31 
8.2 
Visit 1: Baseline Visit ................................................................................. 32 
8.3 
Treatment Initiation .................................................................................... 33 
8.4 
Chart Review Part 2 .................................................................................... 33 
8.5 
Treatment (follow-up) visits: ....................................................................... 34 
8.5.1  Treatment Research Visits ............................................................................. 34 
8.5.1.a  Visit 2: week 4 of treatment, ± 7 days .......................................................... 34 
8.5.1.b  Visit 3: week 8 of treatment, ± 7 days .......................................................... 34 
8.5.1.c  Visit 4: week 12 of treatment, ± 7 days ........................................................ 35 
8.6 
Post-treatment (follow-up) visits .................................................................. 36 
8.6.1 Visit 5: week 24, ±14 days ............................................................................. 36 
8.6.2 Visit 6: week 36, ± 14 days ............................................................................ 37 
8.46.3 Visit 7: week 48, ± 14 days .......................................................................... 37 
8.6.4 Visit 8: week 60, ± 14 days ............................................................................ 38 
8.6.5 Visit 9: week 72, ± 14 days ............................................................................ 38 
8.6.6 Visit 10: week 84, ± 14 days .......................................................................... 39 
8.6.7 Visit 11: week 96, ± 14 days .......................................................................... 39 
8.6.8 Visit 12: week 108, ± 14 days ......................................................................... 39 
8.6.9 Visit 13: week 120, ± 14 days ......................................................................... 40 
8.6.10 Visit 14: week 132, ± 14 days ....................................................................... 41 
8.46.11 Visit 15: week 144, ± 14 days ..................................................................... 41 
8.6.12  Visit 16: week 156, ± 14 days ...................................................................... 41 
8.6.13  Visit 17: week 168, ± 14 days (Exit interview) .............................................. 42 
8.7 
Unscheduled Visits ..................................................................................... 43 
8.8 
Patient Navigator Encounters ....................................................................... 43 
8.7.1 Initial Visit (Required) ................................................................................... 43 
8.7.2  Treatment Readiness Encounter (Required) .................................................... 44 
8.7.3  Treatment Adherence Encounter (3 days post treatment initiation - Required) .... 44 
8.7.4  Treatment Period Encounters (Weeks 1-11) (Recommended) ........................... 44 
8.7.5  After Treatment Encounter (Week 12 of treatment) (Required) ......................... 45 

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8.9 
mDOT Visits ............................................................................................. 45 
9 
Safety Reporting and Safety Assessment Monitoring ............................................ 46 
9.1 
Data and Safety Monitoring Plan. ................................................................. 46 
9.2 
Data monitoring plan .................................................................................. 46 
9.3 
Data Confidentiality ................................................................................... 46 
9.4 
Serious Adverse Events ............................................................................... 46 
10 
Stakeholder Engagement ..................................................................................... 48 
11 
Statistical Considerations .................................................................................... 49 
11.1 
Independent Parallel Analysis ...................................................................... 49 
11.2 
Definition of Study Subjects ........................................................................ 49 
11.3 
Study Hypotheses ....................................................................................... 49 
11.4 
Sample Size Determination ......................................................................... 50 
11.5 
Primary Analytic Principle .......................................................................... 50 
11.6 
Preliminary Data Analysis ........................................................................... 50 
11.7 
Missing data analysis .................................................................................. 51 
11.8 
Heterogeneity of mDOT or PN effects .......................................................... 52 
11.9 
Mediated mDOT or PN effects ..................................................................... 52 
11.10 
Analytic plan for Primary and Secondary outcomes: SVR, Treatment initiation 
rate, Adherence rate, and Treatment completion rate ........................................................ 52 
11.11 
Analytic plan for Resistance and Reinfection Rates ........................................ 55 
11.12 
Analytic plan for Aim 3............................................................................... 56 
11.12.1  Patient Navigator (PN) Stakeholder Qualitative Study. ................................. 56 
11.12.2  The Patient Stakeholder Qualitative Study. .................................................. 56 
11.12.3  Quantitative Analysis ................................................................................ 57 
12 
Data Handling/Record Keeping/Source Documents .............................................. 59 
12.1 
Source Documents and Access to Source Documents ..................................... 59 
12.2 
Data Management Responsibilities ............................................................... 59 
12.3 
Data Capture Methods ................................................................................ 60 
12.4 
Types of Data ............................................................................................ 60 
12.5 
Timing/Reports .......................................................................................... 60 
12.6 
Study Records Retention ............................................................................. 60 
13 
Quality Assurance ............................................................................................... 62 

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Ethics/Protection of Human Subjects ................................................................... 63 
14.1 
Ethical Standard/Declaration of Helsinki ...................................................... 63 
14.2 
Institutional Review Board .......................................................................... 63 
14.3 
Informed Consent Process ........................................................................... 63 
14.4 
Subject Confidentiality ............................................................................... 66 
15 
Protocol Conduct ................................................................................................ 68 
15.1 
Record Confidentiality ................................................................................ 68 
15.2 
Data Collection, Handling, Source Documents .............................................. 68 
15.3 
Protocol Deviations .................................................................................... 69 
15.4 
Recruitment and Retention of Study Subjects ................................................ 69 
15.5 
Study Subject Reimbursement ..................................................................... 70 
16 
Publication Policy ................................................................................................ 71 
17 
References ........................................................................................................... 72 
Appendix One: Patient Navigator Tasks ......................................................................... 80 
Appendix 2: Check Hep C Patient Navigation Program – Workflow for Project HERO .. 82 
Appendix Three:  Study Visit Table ................................................................................ 83 
Appendix Four: Implementation Study .......................................................................... 86 
 
 

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LIST OF ABBREVIATIONS 
Ab 
Antibody 
AASLD 
American Association for the Study of Liver Diseases 
ACTG 
AIDS Clinical Trials Group 
AE 
Adverse Event/Adverse Experience 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Alanine Aminotransferase 
APRI 
AST to Platelet Ratio Index 
ASI 
Addiction Severity Index 
AST 
Aspartate Aminotransferase 
AUDIT 
Alcohol Use Disorders Identification Test 
CHC 
Community Health Center 
CBO 
Community-Based Organization 
CD4 
Cluster of Differentiation 4 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence Interval 
CITI 
Collaborative Institutional Training Initiative 
CFR 
Code of Federal Regulations 
Co-I 
Co-Investigator 
CRC 
Clinical Research Center 
CRF 
Case Report Form 
CT 
Computed Tomography  
DAA 
Direct-acting Antiviral Agent 
DOH 
Department of Health 
DOT 
Directly Observed Therapy 
DSM 
Data and Safety Monitoring 
EASL 
European Association for the Study of the Liver 
eCRF 
Electronic Case Report Form 
eDOT 
Electronic Directly Observed Therapy 
EDTA 
Ethylenediaminetetraacetic Acid 
ETR 
End of Treatment Response 
FDA 
Food and Drug Administration, DHHS 
FDC 
Fixed Dose Combination 
FIB 
Fibrosis 
FQHC 
Federally Qualified Health Center 
FWA 
Federalwide Assurance 
GAD 
Generalized Anxiety Disorder 
GCP 
Good Clinical Practice 
HAART 
Highly Active Anti-Retroviral Therapy 

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HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus 
HERO 
Hepatitis C Real Options 
HgB 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HRC 
Human Rights Campaign 
HU 
Harvard University 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IDSA 
Infectious Diseases Society of America 
IEC 
Independent or Institutional Ethics Committee 
IFN 
Interferon 
IMB 
Information-Motivation-Behavioral 
INHSU 
International Network of Hepatitis in Substance Users 
IOM 
Institute of Medicine 
IRB 
Institutional Review Board 
IU 
International Units 
JHU 
The Johns Hopkins University 
LSAB 
Local Stakeholder Advisory Board 
MARS 
Medication Assisted Recovery Services 
mDOT 
Modified Directly Observed Therapy 
mg 
Milligram 
mL 
Milliliter 
MMC 
Montefiore Medical Center 
MOP 
Manual of Procedures 
MRI 
Magnetic Resonance Imaging 
MSM 
Men who have Sex with Men 
N 
Number (Typically Refers to Subjects) 
NAMA 
National Alliance for Medication Assisted Recovery 
NATAP 
National AIDS Treatment Advocacy Project 
NIH 
National Institutes of Health, DHHS 
NSAB 
National Stakeholder Advisory Board 
NVHR 
National Viral Hepatitis Roundtable 
NYCDOH 
New York City Department of Health 
NYCDOHMH 
New York City Department of Health and Mental Hygiene 
OAT 
Opiate Agonist Treatment 

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OHRP 
Office for Human Research Protections 
OR 
Odds Ratio 
OTP 
Opioid Treatment Program 
PCORI 
Patient-Centered Outcomes Research Institute 
PD 
Protocol Deviation 
PHQ 
Patient Health Questionnaire 
PI 
Principal Investigator 
PN 
Patient Navigator 
POC 
Point of Care 
PWID 
People Who Inject Drugs 
PY 
Person-Years 
RA 
Research Assistant 
RAV 
Resistance-associated Variant 
RCT 
Randomized Control Trial 
REDCap 
Research Electronic Data Capture 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SMS 
Short Message Service 
SOP 
Standard Operating Procedure 
SVR 
Sustained Virologic Response 
TAG 
The Advocacy Group 
TAU 
Treatment as Usual 
UCSF 
University of California San Francisco 
UNM HSC 
University of New Mexico Health Science Center 
URI 
University of Rhode Island 
US 
United States 
UT 
Urine Toxicology 
UW 
University of Washington 
VAS 
Visual Analogue Scale 
VL 
Viral Load 
WHO 
World Health Organization 
WVU 
West Virginia University 
 

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LIST OF TABLES 
Table 1: HCV-infected Patients at OTPs and Community Health Centers .................... 19 
Table 2: Demographic, Clinical, and Psychosocial Characteristics of HCV-infected 
Patients ............................................................................................................ 20 
Table 3: Study Visit Table ............................................................................................. 83 
 
LIST OF FIGURES 
Figure 1:  Schematic of Study Design ........................................................................... xiii 
Figure 2: Barriers to Treatment ....................................................................................... 7 
Figure 3: FQHCs in the US ........................................................................................... 10 
Figure 4: HCV Care Cascade ........................................................................................ 10 
Figure 5: HCV Care Cascade ........................................................................................ 10 
 
 
 
 
 

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Total N=1000±32 
SCREENING  
OTP 
 (N=UP TO 500±16) 
CHC 
 (N=UP TO 500±16) 
ARM B  
PN 
N~250 
ARM A  
MDOT 
N~250 
VISIT 0: CONSENT, ENROLLMENT 
AND RANDOMIZATION  
SCREENING 
ARM B  
PN 
N~250 
ARM A  
MDOT 
N~250 
VISIT 0: CONSENT, ENROLLMENT 
AND RANDOMIZATION 
VISITS 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 
16 AND 17:  POST-TREATMENT 
ARM B  
PN 
N=150±4
ARM A  
MDOT 
N=150±4
RESEARCH VISITS 2, 3, AND 4: 
During Treatment 
VISIT 1: BASELINE 
ARM B  
4+ PN VISITS 
OVER 12 
WEEKS
ARM A  
3-7 MDOT 
VISITS/WEEK 
FOR 12 WEEKS 
INTERVENTION VISITS DURING 
TREATMENT  
VISITS 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 
16 AND 17:  POST-TREATMENT 
ARM B  
PN 
N=150±4
ARM A  
MDOT 
N=150±4
RESEARCH VISITS 2, 3, AND 4: 
During Treatment 
VISIT 1: BASELINE 
ARM B  
4+ PN VISITS 
OVER 12 
WEEKS 
ARM A  
3-7 MDOT 
VISITS/WEEK 
FOR 12 WEEKS 
INTERVENTION VISITS DURING 
TREATMENT  
Figure 1:  Schematic of Study Design 

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PROTOCOL SUMMARY 
 
Title: 
Patient-Centered Models of HCV Care for People Who 
Inject Drugs 
 
Design: 
 
 
Two arm study evaluating modified directly observed 
therapy (mDOT) versus patient navigator (PN) to deliver 
HCV treatment to PWID in two health settings: (1) opioid 
treatment program (OTP), (2) community health center 
(CHC)  
-Sites in eight cities (16 programs) 
 
 
Total number of subjects: Up to 1000 subjects will be 
enrolled and randomized with an expected 600 participants 
initiating treatment. 
 
Participants:  600 subjects on treatment 
Arm A: (1) OTP, N=150; (2) CHC, N=150 
Arm B: (1) OTP, N=150; (2) CHC, N=150 
 
Population: 
 
 
Number of Sites: 
Adults of any gender with current Hepatitis C Virus (HCV) 
infection, people with recent active injection drug use, 18 – 
70 years old. 
 
Eight Sites (Montefiore Medical Center, New York; West 
Virginia University, Morgantown; University of Washington, 
Seattle; University of Rhode Island, Providence; University 
of California San Francisco; The Johns Hopkins University, 
Baltimore; University of New Mexico, Albuquerque) 
 
Study Duration: 
Approximately 6 years 
 
Subject Participation 
Duration: 
Up to 180 weeks:  up to 12 weeks of pre-treatment 
evaluation, 12 weeks of treatment, 12 weeks of follow-up 
to determine Sustained Virologic Response (SVR) 12, and 
144 weeks of follow-up to determine long-term SVR and 
reinfection 
 
Description of Intervention: Participants will be randomized to one of two treatment 

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model arms:  A: mDOT or B: PN, at one of two clinical 
sites:  1) opioid treatment program (OTP) or (2) community 
health center (CHC) setting. 
 
Objectives: 
1. To determine whether SVR-12 rates are higher 
among those randomized to mDOT compared to 
those randomized to PN, among People Who Inject 
Drugs (PWID) treated at opioid treatment program 
(OTP) and community health centers (CHC). 
 
2. We will also examine the following outcomes overall, 
and by randomization arm (mDOT vs. PN): 
(1) HCV treatment initiation  
(2) Adherence 
(3) Treatment completion  
(4) Drug resistance 
(5) HCV reinfection 
 
3. To examine factors associated with key study outcomes 
(treatment initiation, adherence, SVR, drug resistance 
and HCV reinfection) using quantitative and qualitative 
methods. 
 
 
 
Estimated Date of 
Completion: 
2022 
 
 
 

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1 Key Roles 
 
Clemson University/Prisma Health-Upstate 
Alain Litwin, MD, MPH 
Principal Investigator; Protocol Co-Chair  
 
Department of Medicine701 Grove Road 
Greenville, SC 29605 
Cell: 1-845-800-2885 
Fax: 864-455-5008 
Alain.Litwin@prismahealth.org 
Moonseong Heo, PhD 
Co-investigator and Statistician 
 
 
Irene Pericot-Valverde 
Project Director 
 
 
Montefiore Medical Center and Albert Einstein College of Medicine 
Brianna Norton 
Site Investigator 
305 East 161st, Room 7 
Bronx, NY 10451 
Office: 1-718-579-2500 
Fax: 1-718-579-2599 
bnorton@montefiore.org 
 
 
Julia Arnsten, MD, MPH 
Co-Investigator 
 
 
Diane McKee, MD 
Co-Investigator 
 
 
Alison Karasz, PhD 
Co-investigator 
 
 
Paul Meissner, MPH 
Co-Investigator 
 
 
Paula McKinley, PhD 
Co-Investigator and National Project Director 
 
 
Linda Agyemang, MPH 
Local Project Director 
 
 
Kiara Lora 
Research Coordinator 
University of Rhode Island 
Lynn E. Taylor, MD 
Site Investigator 
 
University of Rhode Island 
80 Washington Street 
Providence, RI 02903 

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Office phone 401.277.5001 
CODAC Behavioral Health  
Mobile 401 556 6603 
email LTaylor@uri.edu 
 
 
Aurielle Thomas 
Project Director 
 
 
Harvard Medical School and Massachusetts General Hospital 
Arthur Kim, MD 
Site Investigator 
 
Massachusetts General Hospital 
55 Fruit Street/Cox 5 
Boston, MA  02130 
Office phone 617-724-3230 
Office fax 617-726-5411 
Mobile 617-676-7846 
Email akim1@mgh.harvard.edu 
Jillian Roche, BA 
Project Director 
West Virginia University 
Judith Feinberg, MD 
Site Investigator 
 
Department of Behavioral Medicine & Psychiatry 
and Department of Medicine 
930 Chestnut Ridge Rd 
Morgantown, WV 26505 USA 
Office: +1 (304) 293-5861 
Mobile: +1 (513) 722-5587 
Email: Judith.feinberg@hsc.wvu.edu 
 
 
 
Samuel Wilkinson, 
Project Director 
 
 
University of New Mexico (UNM) 
Kimberly Page, Ph.D., 
M.P.H. 
Site Investigator; Protocol Co-Chair 
Department of Internal Medicine 
University of New Mexico Health Sciences Center 
MSC10 5550 
1 University of New Mexico 
Albuquerque, NM 87131-0001 USA 
Phone: +1 (505) 272-2520 (office) 
Mobile:+1 (415) 350-0625 
Email: Pagek@salud.unm.edu 

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Karla Thornton, M.D., 
M.P.H. 
 
Physician Investigator  
University of New Mexico Health Sciences Center 
Albuquerque, NM 87131-0001 USA 
Phone: +1 (505) 272-6335 (office) 
Mobile: +1  (505) 504-8045 
Email: kthornton@salud.unm.edu  
 
 
Katherine Wagner 
Project Director 
 
 
University of Washington School of Medicine 
Judith Tsui, MD 
Site Investigator 
University of Washington School of Medicine 
Department of Medicine 
325 9th Ave, Box 359780 
Seattle, WA  98104 
Phone : +1 (206) 744-1835 
Fax : +1 (206) 744-9917 
Email : tsuij@uw.edu 
 
 
Kendra Blalock 
Project Director 
 
 
University of California, San Francisco (UCSF) 
Paula Lum, M.D., M.P.H. 
Site Investigator 
 
University of California, San Francisco 
995 Potrero Ave, SFGH, Bldg 80, Ward 84 
San Francisco, CA 94110 USA 
Phone: +1 (415) 476-4082, ext 411 
Pager: +1 (415) 443-3407 
Email: plum@php.ucsf.edu   
 
 
Annie Luetkemeyer, MD 
Significant Contributor 
 
 
Ellen Stein 
Co-investigator 
 
 
The Johns Hopkins University, Baltimore (JHU) 
Shruti Mehta, PhD 
Site Investigator 
Bloomberg School of Public Health 
Department of Epidemiology  

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615 N Wolfe St. E6546  
Baltimore, MD 21205 
Phone: (443) 287-3837 
Email: smehta@jhu.edu 
 
 
Dave Thomas, MD 
Co-Investigator 
 
 
Courtney Borsuk 
Project Director 
 
UNM Division of Epidemiology, Biostatistics and Preventive Medicine 
 
 
 
 
 
Statistician Bert Davis, 
PhD 
Phone: (505) 272-4037 
Email: htdavis@salud.unm.edu 
Biostatistician Cristina 
Murray-Krezan 
Phone: 505-272-3205 
Email: cmurray-krezan@salud.unm.edu 
 
 
New York City Department of Health and Mental Hygiene 
 
Nirah Johnson, LCSW 
Co-Investigator 
 
 
 
 
Institutional Review Boards (IRBs) 
Prisma Health-Upstate: Office of Human Research Protection 
Montefiore Medical Center and Albert Einstein College of Medicine:  Montefiore 
Medical Center IRB of the Einstein Human Research Protection Program 
(HRPP) 
 
Massachusetts General Hospital:  Partners IRB 
The Johns Hopkins University: Johns Hopkins Bloomberg School of Public 
Health IRB 
University of Rhode Island: University of Rhode Island IRB and the Miriam   
Hospital IRB 
West Virginia University:  West Virginia University IRB 
University of California San Francisco:  The Committee on Human Research 
University of New Mexico: UNM HSC Human Research Protections Office 
University of Washington:  University of Washington IRB 

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2 Background Information and Scientific Rationale 
2.1 
Background Information 
HCV epidemic in people who inject drugs (PWID) 
PWID have the highest incidence and prevalence of HCV in the U.S. and globally [1]. In 
the U.S. an estimated 43% of current or former PWID aged 40-65 years have chronic 
HCV [2]. Prevalence of HCV varies by age and duration of injecting, but meta-analyses 
show that in developed countries, including the U.S., mean cumulative incidence was 
over 20%, and prevalence was 72% in PWID with a history of 10 year of injecting [2]. 
The Centers for Disease Control and Prevention (CDC) estimates at least 30,000 new 
HCV infections per year [3], predominantly among PWID, with a 44% increase in the 
number of acute cases from 2010 to 2011 [4]. This increase has been associated with 
an expanding PWID population, especially in non-urban areas across the U.S. [5], and 
has been related in part to increases in prescription opioids, followed by related 
transitions to injection drug use [6, 7]. Addressing methods to optimize access to 
curative HCV treatment in PWID is a priority given their role in the growing HCV 
epidemic in the U.S. HCV causes up to 15,000 deaths annually, and is the leading 
cause of liver transplantation in the U.S. [8-10]. Treatment effectiveness among PWID is 
crucial because PWID remain the leading risk group for HCV infection [11]. PWID have 
the highest prevalence and incidence of HCV in the U.S., yet HCV treatment is rarely 
provided to PWID. In two systematic reviews of interferon-based treatment for PWIDs, 
overall SVR was 56%, and response rates were comparable to large RCTs [12, 13]. 
International guidelines from the American Association for the Study of Liver Diseases 
(AASLD)/ Infectious Diseases Society of America (IDSA), European Association for the 
Study of the Liver (EASL), International Network of Hepatitis in Substance Users 
(INHSU), and the World Health Organization (WHO) all recommend treatment for HCV 
infection among PWID [14-17].  With significant scale up of HCV treatment of PWID, 
overall HCV prevalence could be reduced by up to 75% within 15 years [18]. 
Nevertheless, few data exist on direct-acting antiviral agents (DAAs) treatment 
outcomes in PWID, and therefore PWID are often not eligible to receive DAAs.   
 
HCV treatment uptake among PWIDs is limited by multiple barriers 
Hepatitis C treatment uptake among PWID has been limited by multiple interrelated 
barriers at the level of the patient, the provider and the system (Figure 2) [19, 20]. 
Patient-level barriers included poor knowledge related to HCV and treatment as well as 
the absence of symptoms, which often results in a low perceived need for treatment. 
These issues are compounded by general barriers to health care access (e.g., having 
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immediate attention as well as factors which impede stability including unemployment, 
unstable housing, lack of transportation, incarceration and ongoing substance use [21-
25]. Providers are often unwilling to prescribe HCV treatment to even former PWID 
because of concerns related to 
ongoing substance use, low 
adherence and the potential risk of 
reinfection [20, 25]. 
Some studies have suggested that 
physicians have suboptimal 
knowledge regarding HCV and its 
treatment which can impact which 
patients get tested, referred and 
who initiate treatment [20, 26]. A 
major structural barrier is the cost of 
the medications and the associated 
monitoring. But beyond cost, 
additional structural barriers include 
insufficient locations where HCV 
testing can be performed and where treatment can be delivered [20, 27]. There is also a 
dearth of providers who can treat HCV and patient navigators dedicated to 
spearheading HCV-infected PWID and others through treatment. Finally, HCV care has 
historically been delivered in specialist settings which means it is segregated from other 
services that PWID utilize including primary care, opiate substitution and HIV care.  
 
Efficacy of new HCV regimens for HCV-infected patients 
New direct-acting antiviral agents (DAAs) are efficacious in >95% of treatment-naïve 
patients [14]. The interferon-free DAA fixed dose combination of ledipasvir 90 mg and 
sofosbuvir 400 mg once daily for 12 weeks is associated with SVR rates of >95% in 
genotype-1 infected patients [14], and is associated with fewer side effects than 
previous regimens: fatigue 13% - 18%, headache 11% - 17%, and nausea 6% - 9%.  
The interferon-free DAA fixed-dose regimen of sofosbuvir 400 mg once-daily (nucleotide 
polymerase) and velpatasvir 100 mg once-daily (NS5A inhibitor) has demonstrated high 
efficacy (95-96% SVR12) with a treatment duration of 12 weeks in treatment-naïve 
patients with HCV genotypes 1-6 [28], and was approved for use by the Food and Drug 
Administration (FDA) on June 28, 2016. The availability of a simplified IFN-free DAA-
based once-daily regimen of sofosbuvir/velpatasvir may further enhance the capacity to 
scale-up HCV treatment among PWID. A pan-genotypic regimen can help increase 
access for PWID by eliminating the need for genotypic testing prior to treatment.  
Therefore, fixed-dose sofosbuvir/velpatasvir will now be used for this study. 
Figure 2: Barriers to Treatment 

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PWID excluded from HCV DAA clinical trials 
PWID have been excluded from many clinical trials evaluating the efficacy of DAAs. A 
systematic evaluation of exclusion criteria concerning drug and alcohol use in DAA-
based HCV treatment trials for Human Immunodeficiency Virus (HIV)/HCV co-infected 
persons performed by searching the clinicaltrials.gov website of the U.S. National 
Library of Medicine and National Institutes of Health (NIH) for all available trials through 
May 2013 [29] identified eighteen clinical trials, involving 9 DAAs (protease, polymerase 
and NS5A inhibitors). Nine trials (50%) excluded individuals with either current or prior 
alcohol, “substance,” or “drug” use. In a majority of these trials (78%), exclusion was 
also based upon site investigators’ perceptions of suitability to participate in the trial. 
Developing consistent, evidence-based criteria concerning substance use will permit 
greater, more equitable access to DAA trials for the HCV monoinfected and HIV/HCV 
co-infected populations.  Exclusion of important subgroups such as PWID from clinical 
trials has a direct effect on policy and payer’s willingness to provide medications for 
PWID. The National Association for Medicaid Directors endorsed the University of 
Oregon report entitled, “Sofosbuvir for the treatment of hepatitis C and evaluation of the 
2014 AASLD Treatment Guidelines” which concluded (due to lack of DAA data in 
PWID) that sofosbuvir-based treatment should be excluded from people who have used 
drugs and alcohol over the last 12 months.  
 
Medicaid restrictions of DAAs for PWIDs 
The high price of DAAs and high demand has also led payers to institute restrictions on 
their access, although by law Medicaid programs are entitled to a rebate of at least 23% 
[30, 31]. In the U.S., a disproportionate number of people living with HCV are of low- 
income [32, 33]. Most PWID are eligible for HCV therapy reimbursement through 
Medicaid, the jointly funded federal/state partnership that provides health insurance for 
low-income people meeting the program’s eligibility criteria. Each state has wide 
discretion in administering its own Medicaid program.  A systematic evaluation of State 
Medicaid policies for HCV treatment with sofosbuvir in the United States [34] by 
searching State Medicaid websites between June 23 and December 7, 2014 found that 
overall, 42 states (82%) had publicly available information regarding sofosbuvir 
Medicaid reimbursement criteria. Of these, 88% (n=37) include drug and/or alcohol use 
in their sofosbuvir eligibility criteria, with 50% requiring a period of abstinence. The 
majority of states require that patients be abstinent from drug and alcohol for 6 months 
(n=11), while others require abstinence periods of 1 month (n=2), 3 months (n=5) and 
12 months (n=2). The majority of states (n=27, 64%) require urine drug screening prior 
to treatment to assess drug and/or alcohol use, with only 6 (14%) requiring testing 
specifically for those with previous drug/alcohol abuse.  

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Rather than recommending exclusion of PWID, AASLD/IDSA guidelines list PWID as a 
priority group due to potential treatment as prevention benefit [14]. HCV treatment for 
PWID is cost-effective, particularly when the prevention benefits are considered [35]. 
Nevertheless, PWID in the U.S. are systematically denied access to DAAs.   
 
Direct-acting antiviral HCV agents and resistance 
HCV NS5A resistance-associated variants (RAVs) can emerge following unsuccessful 
treatment with an NS5A-inhibitor containing regimen as they have relatively low barriers             
to resistance [36]. RAVS with reduced drug susceptibility are also observed in 
treatment-naïve patients. Patients who did not achieve SVR in Gilead studies evaluating 
direct-acting antiviral regimens including ledipasvir (but not sofosbuvir) were enrolled in 
a 3-year registry trial. NS5A RAVs were measured at positions 24, 28, 30, 31, 32, 58, 
and 93 because they confer >2.5 reduced susceptibility to ledipasvir in-vitro. At 
baseline, 16% of patients (12/76) of patients treated with ledipasvir had NS5A RAVs. At 
virologic failure, almost all (99%; 72/73) of patients had NS5A RAVs. Moreover, 86% of 
these patients still had NS5A RAVs at follow-up week 96 [37]. NS5A mutations seen in 
monotherapy with velpatasvir include those measured at positions 24, 28, 30, 31, 32, 
58, 92, and 93.  Cross-resistance is observed to all NS5A inhibitors [38]. NS5A inhibitor-
resistant viruses appear to persist for years after treatment failure, and the time needed 
to clear resistant variants is unknown. Therefore, resistant viruses associated with 
decreased response to antiviral treatment may be transmitted to other PWID. 
 
HCV reinfection among PWID 
Reinfection is a potential problem and a barrier to treatment among PWID [23]. Data 
collected to date, principally in PWID who have received interferon-based treatments, 
show reinfection is low: 5.2/100 person years (py) for those who report injection drug 
use after treatment, and less (3.2/100 py) for those who do not report ongoing injection 
drug use [39, 40]. However, recent reports have noted higher rates of reinfection after 
interferon-based treatments in prisoners (8/100 py), HIV/HCV Men who have Sex with 
Men (MSM) (24/100 py), and PWID who relapse to drug use with longer follow-up 
(30/100 py). [41, 42]  
 
Prospective studies assessing HCV reinfection PWID who spontaneously cleared 
infection [43, 44] show that to accurately capture reinfection events, genotyping and 
viral sequencing is necessary to distinguish reinfection from intercalation. Without these 
tests, estimates of reinfection incidence were significantly overestimated. Testing 
interval also has an impact on detection of reinfection. In PWID who clear infection 
spontaneously, testing intervals less frequent than every three months resulted in 
substantial (by up to 66%) underestimation of reinfection rate [45]. A caveat here is that 
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been shown to have a high likelihood of re-clearance of subsequent infections [44, 46, 
47], and immunological responses to reinfection may differ in those with treatment 
induced clearance. Systematic testing (every 3 months after SVR12 in our proposed 
study) to assess the presence of HCV RNA will be essential to accurately determine 
reinfection events. There is little to no data on reinfection rates in the era of DAAs. 
2.2 
 Scientific Rationale 
HCV treatment delivered in primary care settings 
The number of HCV-infected patients who need treatment far exceeds the availability of 
specialists, who are often concentrated in academic medical centers, making access to 
care difficult [48, 49]. When referred to specialty care, 
HCV patients may feel stigmatized by specialist care 
settings that often exclude PWID from treatment [50-
52]. Given the simplicity and efficacy of new HCV 
medications, there is an unparalleled opportunity to 
treat PWID within medical settings that they are already 
accessing, such as Federally Qualified Health Centers 
(FQHCs). Several studies have also shown that PWID 
are effectively treated for HCV in primary care settings 
[53-55]. Primary care clinics, such as FQHCs, are 
abundant throughout the U.S. and serve populations at high risk for HCV; studies show 
an HCV prevalence rate of approximately 8% in FQHCs, almost 5x greater than the 
general population [56, 57]. There are 1200 FQHCs nationwide, delivering care to 
20,000,000 low-income, underserved patients [58]. These individuals, who frequently 
have minimal education, high unemployment, and live in urban areas, also have high 
rates of substance use and dependence [59, 60]. Of 6.4 million PWIDs nationwide [59], 
the majority is not enrolled in substance use disorder treatment, and instead seeks 
medical care in clinics such as FQHCs [61-64].  Increased rates of HCV treatment have 
been found in community-based primary care clinics when primary care-based HCV 
treatment is combined with close collaboration between the HCV medical provider and 
an HCV patient navigator. This favorably impacts the HCV Care Cascade as seen in the 
figures below comparing the cascade in the same community-based clinic with and 
without a primary care based HCV program. [65] 
 
 
 
 
 
 
Figure 3: FQHCs in the US 

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Figure 5: HCV Care Cascade  
without Primary Care 
 
 
Evidence-based interventions to enhance assessment, treatment, and adherence 
in the chronic hepatitis C continuum 
With the availability of DAAs with rates of SVR reaching 95%, evidence-based 
strategies are urgently needed to achieve real-world effectiveness in challenging patient 
populations such as PWID.  Using Institute Of Medicine guidelines, a systematic review 
of evidence-based interventions from PubMED, Medline, Google Scholar, EmBASE, 
and PsychInfo bibliographic databases and citation indices [16] identified evidence-
based interventions to enhance HCV assessment, treatment, and adherence in 4 
categories: 1) diagnosis; 2) linkage to care; 3) pre-therapeutic evaluation or treatment 
initiation; or 4) treatment adherence. Several interventions introduced on-site HCV care 
with patients in previously established opiate agonist treatment programs and showed 
comparable rates of uptake and SVR to non-PWID populations [66-71].  
 
Common to all of these interventions is a multidisciplinary approach that combines 
medical and addiction treatment with intensive social support [13]. Similarly, primary 
care settings represent key opportunities for HCV care linkage interventions, often 
within clinics that have engaged PWID. These studies demonstrated that patients with 
ongoing drug use and psychiatric comorbidity can be effectively linked to care and 
treated within these settings [54, 55, 69, 72-74]. Peer-driven interventions including 
weekly support groups have demonstrated high uptake of HCV treatment and SVR 
rates among PWIDs [75-77]. Additional studies are needed to measure the impact of 
peer-driven interventions [78, 79] in the eras of DAAs.  
 
When PWID are surveyed to assess HCV treatment knowledge and barriers to 
treatment initiation [22], interest [80, 81], and willingness to receive treatment [82], 
treatment-naïve patients were more willing to enter HCV treatment program if they 
perceived themselves at risk for cirrhosis or liver cancer [81] or had more knowledge 
about HCV [82]. A randomized control trial (RCT) of patient navigation intervention 
consisting of motivational interviewing, education, and case management was 
154
122
67
44
17
6
4
0
50
100
150
200
Figure 4: HCV Care Cascade  
with Onsite Primary Care 

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associated with increased HCV clinic visit attendance among patients in methadone 
maintenance [83]. With the simplicity of treatment with newer DAAs (one pill daily), 
treatment has moved towards primary care venues [84].  
 
The 2015 INSHU HCV Clinical Guidelines for PWID [15] recommends that: (I) Models of 
HCV care integrated within addiction treatment and primary care health centers, as well 
as prisons, allow successful pre-therapeutic assessment (Class I, Level B); II) Peer-
driven interventions delivered within opiate substitution treatment settings may lead to 
higher rates of treatment initiation (Class IIa, Level C); and (III) Care coordination in 
conjunction with behavioral interventions can increase likelihood of PWID being 
evaluated and initiating treatment (Class I, Level B). Though on-site multidisciplinary 
models of care have demonstrated good outcomes for PWID, optimal models of care 
must be studied [85].  
 
Directly Observed Therapy 
Similar to the implementation of directly administered antiretroviral therapy, or directly 
observed therapy (DOT) for HIV [86, 87], several interventions involved the provision of 
HCV treatment as DOT [88]. By using a modified DOT approach (mDOT) to observe 
only the morning dose of ribavirin or weekly injections of interferon, HCV treatment was 
successfully delivered in opiate agonist treatment programs [68, 69, 89], prison settings 
[90], and community health centers [75]. Another study provided ribavirin as once-daily 
DOT, demonstrating extremely high rates of SVR among patients stably maintained on 
opioid substitution therapy [91].  
 
RCT of directly observed HAART in methadone-maintained patients 
In an RCT of DOT with Highly Active Anti-Retroviral Therapy (HAART) in HIV-infected 
drug users in methadone clinics seventy-seven participants were randomized to a 24-
week DOT intervention or treatment as usual (TAU), with 86% study retention at 24 
weeks. Participants randomized to DOT (v. TAU) had greater adherence (mean 
adherence: 86% v. 56%, p<0.0001) and VL decreased by 0.52 log10 copies/ml in the 
DOT group while it remained stable in the TAU group (p<0.01).  More DOT than TAU 
participants had undetectable viral load (71% vs. 44%, p=0.03) [86]. Active drug use 
decreased adherence, but the negative impact of drug use on adherence was 
eliminated by DOT [92]. By 3 months after DOT ended, differences in both adherence 
and viral load between DOT and TAU had extinguished [93]. These data demonstrate 
that DOT is associated with improved HIV virological outcomes among methadone-
maintained patients, including active drug users, and that it should be continued long-
term for durable effect. In several other HIV studies, treatment adherence and 
virological outcomes are improved among PWID when DOT is administered at 
methadone clinics and in community settings [94, 95]. 
 

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Study of HCV treatment in methadone-maintained patients 
In 2003, a study within a methadone maintenance treatment program included directly-
administered weekly interferon in addition to screening, assessment of treatment 
eligibility, psychiatric services, and on-site antiviral therapy [96].  Of 73 patients, most 
were Latino (67%) or African-American (12%), nearly half (49%) had used illicit 
substances in the 6 months before initiating treatment, 32% were HIV-infected, and 
current psychiatric illness was common (67%). Most (86%) completed 12 weeks of HCV 
treatment and 45% achieved SVR, including 40% of genotype- 1 patients. Though 30% 
used illicit drugs during HCV treatment, there was no association between illicit drug 
use and virological outcomes. These results demonstrate that PWID with complex 
medical and psychiatric comorbidities can be effectively treated for HCV with co-located 
on-site care.  
However, it is unknown which interventions (on-site care v. DOT injections) contributed 
to the observed outcomes [70, 96, 97]. In 2008 a pilot RCT of modified DOT (mDOT), 
extended the DOT strategy to the oral medication ribavirin. This trial (n=80) was 
designed to test the efficacy of 2 versions of mDOT [89]. The primary objective was to 
determine whether enhanced DOT with both interferon (IFN) plus ribavirin is more 
efficacious than standard DOT with weekly provider-administered IFN and self-
administered ribavirin for improving adherence.  Significant differences in pill count 
adherence between the treatment arms were observed (88% in mDOT arm vs. 77% in 
the treatment as usual, or TAU arm, p=0.02) [98]. In addition, 81% of mDOT subjects 
achieved ≥ 80% adherence v. 53% in the TAU arm (p=0.09). Only 16% discontinued 
treatment, and among genotype-1 infected patients, 55% achieved SVR (half active 
drug users) [94].  
In 2009, treatment for genotype-1 patients in the study was changed to include DAAs 
(telaprevir or boceprevir) in combination with pegylated interferon and ribavirin. Of the 
first 50 patients treated with DAAs (either telaprevir or boceprevir in combination with 
pegylated interferon and ribavirin), 62% achieved SVR despite high rates of recent drug 
use prior to treatment (52%), ongoing drug use during treatment (45%) and psychiatric 
comorbidity (86%) [98]. 
Since January 2014, sofosbuvir-based regimens have been implemented in 115 
methadone-maintained PWID including 51 genotype-1 patients with highly efficacious, 
all-oral regimens of sofosbuvir in combination with simeprevir (n=29) OR fixed-dose 
sofosbuvir in combination with ledipasvir (n=24). To date, almost all patients (98%) are 
either undetectable or have HCV VL<15 International Units (IU)/ml.  Among 31 who 
have completed treatment, 13 have achieved an SVR12, 15 have an end of treatment 
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determination, and 1 had a relapse after ETR. Twenty patients remain on treatment, 
and all are either undetectable (n=13), have HCV Viral Load (VL) <15 IU/ml (n=3) at 
week 4, or have not yet reached week 4 (n=4).  No patients have discontinued 
treatment. 
 
Models of Patient Navigation 
First used with cancer patients, the principal goal of patient navigation is to assist 
patients to move through the medical care system. There are four principal roles of PNs: 
1) coordinating treatment; 2) health education and promotion; 3) assisting patients to 
overcome personal barriers; and 4) providing psychosocial support. In a multi-site U.S. 
study, PNs assisting HIV-positive individuals resulted in higher adherence to medical 
care appointments and a significant increase in those achieving an undetectable viral 
load [99]. HCV models of care integrating PNs within substance use disorder treatment 
and community health centers have been widely implemented in several states, 
including New York [100, 101]. PN models integrating peer support through on-site 
support groups have led to high rates of treatment uptake and SVR in methadone 
maintenance treatment patients including those using drugs, and peers have led to 
improved outcomes in several other chronic diseases [102, 103]. PN models with 
integrated peer support may improve patient-centered outcomes such as self-efficacy, 
shame and stigma. However, the best model of care for treating HCV in PWID is 
unknown, as is which model is most acceptable to patients. Despite availability of highly 
efficacious regimens, PWID face more barriers to treatment than ever, due to continued 
concerns from providers regarding poor adherence and reinfection, and restrictions from 
payers due to lack of data with new DAAs [104]. 
2.3 
Potential Risks and Benefits  
Potential Risks 
The risks of the study include:  
1) Inconvenience of attending research visits, 2) discomfort associated with research 
interviews, 3) venipuncture, 4) discomfort associated with directly observed 
medication administration or with a patient navigator, and 5) confidentiality issues 
associated with research encounters. These risks will be discussed with potential 
participants during the informed consent process. The alternative of not participating 
in the study will be discussed with participants during the informed consent process. 
 
Inconvenience of attending research visits: This study requires that participants 
participate in face-to-face encounters with the research staff at visits 0, 1, 2, 3, 4, 5, 
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Inconvenience of study participants attending research visits will be addressed by 1) 
reimbursement for time spent in research encounters ($20 for each research visit 
and $5 for each returned weekly blister pack), 2) conducting assessments on-site in 
participants’ OTPs, when allowed by the OTP, or 3) conducting assessments at 
community research sites which may be more conveniently located for participants 
that reside nearby.  Additionally, participants will be informed by the research staff 
during the informed consent process that they can choose to withdraw from the 
study at any point. We will also provide rest and refreshment breaks during visits. 
Discomfort associated with research interviews: Surveys will assess health status, 
substance use, psychiatric symptoms, stigma, shame, medication adherence and 
other sensitive subjects. It is possible that survey questions could be uncomfortable 
for participants. Participants will be told that they may choose to stop the interview or 
withdraw from the study if they find the questions troubling. 
Discomfort associated with directly observed therapy or patient navigator: 
Participants may feel uncomfortable with receiving mDOT or with a patient navigator.  
There may be discomfort with the additional level of scrutiny or interaction associated 
with these models of care. 
 
Confidentiality issues in research encounters: The risk of study participation includes 
possible loss of confidentiality.  Risks to privacy and confidentiality exist with all human 
research.  Because this project focuses on people who inject drugs, confidentiality is a 
major concern. The study will be collecting personal information from participants to 
facilitate follow up, and will be asking questions about sensitive data including illicit drug 
use and alcohol use, mental health, and health status. Subjects will be assigned a 
unique study identification number which will be used on case report forms (CRFs), and 
specimens collected for laboratory analyses.  No samples or data will be labeled with 
the subject’s name.  The key to subjects’ names will be accessible only to the study co-
principal investigators, and hard-copies and electronic copies of data will be stored in 
secured locations. 
Venipuncture:  The risk from venipuncture is minimal but may include anxiety, pain, 
bruising, and infection. 
Potential Benefits 
Participants assigned to the mDOT or PN arms of this study may benefit by 
achieving high levels of treatment initiation, adherence and improved HCV 
outcomes. Participants will receive access to medications that are often denied by 
payers and providers to PWID. The patient-centered models of HCV care (mDOT 

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and PN) may also provide a mechanism for rapid identification of potential adverse 
medication effects, and this may result in fewer adverse events, decreased morbidity 
from HCV, and improved psychosocial functioning. Given the low risk presented by 
participation in this study and the high potential for direct benefit of cure if the 
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3 Study Objectives 
 
3.1 
Primary Objective 
 
To determine whether SVR-12 rates are higher among those randomized to mDOT 
compared to those randomized to PN, among PWID treated for HCV at OTPs and 
community health centers. 
 
3.2 
Secondary Objective 1 
 
To examine the following outcomes overall and by randomization arm (mDOT 
compared to PN) among PWID treated at OTPs and community health centers:  
(i) 
Treatment initiation:  whether a higher proportion of participants in the PN 
arm initiate treatment compared to mDOT arm;   
(ii) 
Adherence (≥80% of prescribed medication taken):  whether a higher 
proportion of those in the mDOT arm are adherent compared to PN arm;  
(iii) 
Treatment completion (finishing 100% of prescribed 12-week course):  
whether a higher proportion of participants in the mDOT arm complete 
treatment compared to PN arm;  
(iv) 
Drug resistance: whether the proportion who develop drug resistance is 
higher in the PN arm compared to mDOT arm; 
(v) 
Reinfection: whether (a) rate (incidence), and the (b) proportion who 
become reinfected with HCV is higher in the PN arm compared to mDOT 
arm; 
 
Comparisons will be performed to determine the proportion of subjects in each arm 
who: a) initiate treatment; b) adhere to antiviral treatment; c) complete antiviral 
treatment; d) attain SVR (cure); e) develop drug resistance; f) reinfection.  We will also 
conduct time to event analyses to examine drug resistance and reinfection outcomes.  
Subgroup analyses will be performed to assess differences in outcomes among those 
randomized to PN vs. mDOT in specific sub-populations. 
 
3.3 
Secondary Objective 2 
 
To examine factors associated with key study outcomes (treatment initiation, 
adherence, SVR, drug resistance and HCV reinfection) using quantitative and 
qualitative methods. 
 
Quantitative methods:  We will examine associations between psychosocial factors 
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levels of shame and stigma, with key study outcomes described above. It is 
hypothesized that these psychosocial variables are associated with lower rates of 
adherence and SVR in the PN arm, but not the mDOT arm; and associated with 
lower rates of treatment initiation in the mDOT arm, but not the PN arm.  
 
Qualitative methods: Qualitative methods will be used to conduct an interview study 
focusing on pragmatic concerns and experiences of key stakeholders. Two key 
groups of stakeholders, patients and patient navigators, will be interviewed 
regarding the barriers and facilitators to successful treatment uptake. In the patient 
group, up to 15 patients from each site will be recruited. Recruitment will be of both 
successful and unsuccessful participants along the pathway to care and use 
structured comparisons to understand differences between those who have 
benefited from the intervention and those who have not. In years 1-2 of the project 
period, preliminary results of these analyses will be used for formative evaluation 
purposes, feeding back results to study leaders in order to help improve/adapt 
study features and make the interventions more patient centered. In years 3-6 of 
the project, the data will contribute to the mixed methods summative evaluation to 
understand barriers and facilitators to program success. Protocol and 
implementation details for qualitative methods are detailed in the Implementation 
Study Protocol (Appendix 3).  
 
 
 

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4 Study Design 
 
Overview of study approach 
This is a multi-site national study (8 U.S. cities), where up to 1000 HCV-infected 
PWIDs (injecting illicit substances within 3 months of screening) will be randomized 
to either PN plus weekly or biweekly blister pack dispensation versus mDOT. Among 
patients who go on to initiate HCV treatment (n=600 targeted) with a once-daily 
combination regimen of fixed-dose sofosbuvir/velpatasvir, a comparison will be 
conducted of the proportion of patients in each arm who: (a) optimally adhere 
(>80%), (b) complete treatment, (c) achieve SVR, and (d) develop resistance. The 
primary outcome will be SVR. The 8 sites offer geographic and policy diversity:  New 
York City, Baltimore, Providence, Boston, Morgantown, Seattle, San Francisco, and 
Albuquerque.  
 
Participants will be recruited from diverse venues: OTPs, community health centers, 
syringe exchange programs, community-based organizations, homeless programs, 
and cohorts established by research studies.  The clinical sites will determine 
eligibility based on clinical records, or on-site testing including HCV tests (anti-HCV 
and HCV viremia). Study participants will be screened, consented and enrolled on-
site at OTP and non-OTP settings. There will be differences in linkage, engagement 
and outreach at each site. These procedures will be documented in site specific 
operating manuals.  
 
Patients will be randomized to one of two models of care: patient navigation (PN) vs. 
modified directly observed treatment (mDOT).   Patients enrolled from OTPs who 
are receiving methadone and randomized to mDOT will receive doses of once daily 
medication at the same time as they receive methadone. Patients enrolled from 
community health settings and randomized to mDOT may receive observed doses 
through use of miDOT (emocha Mobile Health, Inc.), a mobile health app on a 
smartphone, or at the CHC.  Subjects randomized to PN will receive a standardized 
PN intervention.  Sites also have the option to offer all subjects optional additional 
support through a peer-led support group. 
 
Participants will be followed for up to 180 weeks: 12 weeks of pre-treatment 
evaluation, 12 weeks of treatment, 12 weeks of follow-up to determine SVR12, and 
144 weeks of follow-up to determine long-term SVR and reinfection. Data sources 
will include clinical lab and imaging results from medical records, blood tests (HCV 
viral load during long-term follow-up and resistance assays), urine toxicology, 
questionnaires, electronic monitors for assessing adherence, and interviews. 

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5 Study Population 
Participants will be recruited from a diverse national patient population from at least 16 
health centers in 8 states- all with on-site HCV care (8 OTPs and 8 community health 
centers – Table 1). Target enrollment is up to 1000 PWID (to target 600 PWID initiating 
treatment) with the following characteristics (Table 2): Caucasian (55%), Latino (21%), 
and African American (20%), male (61%), and mean age of 44 years; 28% will be 
HIV/HCV co-infected. Within the 8 OTPs, there is a potential pool of 4790 mono-
infected and 510 co-infected patients. Within the 8 community health centers, there is a 
potential participant pool of 2809 mono-infected and 1433 co-infected patients. 
Community enrollment has a pool of >4000 HCV-infected clients in the community. 
With over 13,000 HCV-infected patients, target enrollment is 1000 PWID.  Eligibility for 
HCV treatment will be determined by subjects’ on-site medical care providers, as part 
of routine clinical care. 
Table 1: HCV-infected Patients at OTPs and Community Health Centers 
City, State 
OTP 
#HCV 
#HIV/HCV Community Health Center 
#HCV 
#HIV/HCV 
Bronx, NY 
Melrose Wellness 
Center 
1500 
250 
Comprehensive Health Care 
Center 
400 
60 
Providence, RI 
CODAC Behavioral 
Health Services 
750 
25 
Miriam Hospital 
Brown Infectious Diseases 
Center 
50 
400 
Albuquerque, NM 
UNM ASAP 
720 
25 
Truman Health Services 
20 
200 
San Francisco, CA 
Ward 93 Opiate 
Treatment Outpatient 
Program 
325 
70 
PHP Ward 86 and Tom Waddell 
Urban Health Clinic 
100 
213 
Boston, MA 
Bay Cove Human 
Services 
150 
10 
MGH and CCHI 
300 
100 
Baltimore, MD 
Reach Health Services 
300 
60 
Comprehensive Care Practice 
1000 
100 
Seattle, WA 
Evergreen Treatment 
Services 
700 
50 
Harborview Adult Medicine 
884 
250 
Morgantown, WV 
Valley Alliance  
Treatment Services 
345 
20 
Milan Puskar Health Right  
110 
20 
Total 
 
4790 
510 
 
2809 
1433 
 
 
 
 

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Table 2: Demographic, Clinical, and Psychosocial Characteristics of HCV-infected Patients 
State 
NY 
MA 
RI 
WV 
WA 
NM 
CA 
MD 
Total 
Age (mean) 
49.0 
40.5 
55.0 
30.0 
40.0 
41.5 
48.0 
46.5 
43.9 
Gender 
 Male 
 
 62% (78) 
 
 68% (85) 
 
 41% (51) 
 
 55% (69) 
 
 63% (78) 
 
 70% (88) 
 
 82% (102) 
 
 50% (63) 
 
 61% (614) 
Ethnicity  
 Latino 
 
 65% (81) 
 
 13% (16) 
 
 15% (19) 
 
 0% 
(0) 
 
 5% 
(6) 
 
 52% (65) 
 
 17% (21) 
 
 1% 
(1) 
 
 21% (213) 
Race/ethnicity 
 Caucasian  
 African-Am 
 Native-Am  
 Asian 
 Other 
 
 20% (25) 
 25% (31) 
 0% 
(0) 
 0% 
(0) 
 55% (69) 
 
 73% (91) 
 20% (25) 
 1% 
(1) 
 1% 
(1) 
 5% 
(6) 
 
 37% (46) 
 31% (39) 
 11% (14) 
 0% 
(0) 
 21% (26) 
 
 98% (118) 
 2% 
(1) 
 0% 
(0) 
 0% 
(0) 
 2% 
(3) 
 
 62% (78) 
 24% (30) 
 2% 
(3) 
 2% 
(3) 
 10% (13) 
 
 76% (95) 
 3% 
(4) 
 9% (11) 
 1% 
(1) 
 11% (14) 
 
 50% (63) 
 25% (31) 
 1% 
(3) 
 4% 
(5) 
 20% (25) 
 
 25% (31) 
 75% (65) 
 0% 
(0) 
 0% 
(0) 
 0% 
(0) 
 
 55% (546) 
 20% (196) 
 3% (32) 
 1% (13) 
 21% (211) 
Cirrhosis 
 34% (43)  15% (19)  45% (56)  7.5% (9)  15% (19)  33% (41)  14% (18)  5% 
(6)  21% (211) 
HIV-infected 
 20% (25)  13% (16)  50% (62)  2.0% (3 )  5% 
(6)  47% (59)  70% (88)  13% (16)  28% (336) 
Unstably housed  20% (25)  35% (44)  11% (14)  13% (16)  28% (35)  25% (31)  60% (75)  15% (19)  26% (261) 
Psych 
 75% (94)  67% (84)  63% (78)  45% (54)  60% (75)  35% (44)  71% (89)  25% (31)  55% (549) 
 
The participants in the proposed trial will be 1000 patients recruited from 8 cities: 
Bronx (Montefiore Medical Center), Baltimore (John Hopkins University), Providence 
(The University of Rhode Island), Boston (Harvard School of Medicine), Morgantown 
(West Virginia University), San Francisco (UCSF), Albuquerque (University of New 
Mexico), and Seattle (University of Washington).  
5.1 
Inclusion Criteria 
Inclusion criteria that must be met before enrollment: 
 
• Current HCV infection (HCV viremic) 
• HCV Viral load test from any time 
• Must have had the following tests performed in the past 12 months:  AST, ALT, 
platelets 
• Actively injecting drugs (any substance within 3 months of screening) 
• Not previously treated with HCV direct-acting antiviral medications 
• Age 18 – 70 
• Willing to receive HCV treatment with sofosbuvir/velpatasvir 
• Willing to be randomized to either PN vs mDOT 
• If receiving methadone, be attending or be willing to attend OTP a minimum of 
5 times per week  

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• Able to provide informed consent 
• English or Spanish fluency 
5.2 
Exclusion Criteria 
Exclusion criteria will include: 
• Pregnant or breast feeding 
• Hepatocellular carcinoma  
 
5.3 
Re-Screening 
Subjects can be rescreened if they fail screening. Participants can be rescreened only 
one time following first screen failure. 
5.4 
Randomization 
Up to 1000 patients will be recruited, with patients randomized to PN or mDOT in a 
1:1 ratio (500 subjects in each group) in variable block sizes of 2-6 via central, 
computer-generated randomization provided by the UNM Statistical and Data 
Coordinating Center (SDCC). Randomization will occur in blocks to ensure 
comparison groups of approximately equal size. Given that the intervention will not be 
blinded, block size will vary to prevent anticipation of treatment arm assignment.  
 
Two special randomization strategies (stratification and blocking) will be used to avert 
imbalances in prognostic factors or treatment settings, and to ensure comparison 
groups of approximately equal size. Participants will be stratified by 3 factors: city, 
OTP vs. community health center and stage of liver disease (cirrhosis v. no cirrhosis).  
 
In addition, adaptive re-weighting of random allocation in a pseudo urn randomization 
fashion will be made when N~300 has been enrolled to balance the sample size 
between mDOT and PN arms. Specifically, as we hypothesize that number of 
randomized subjects who will initiate treatment will be larger in the PN arm, unbalancing 
between arms is likely to occur during the course of the study. Of note, therefore, a 
randomized subject will not necessary be a clinical treatment subject but will be 
included in the comparison of treatment initiation.    
 
To adjust for this potential unbalance, we will adjust randomization based on observed 
allocation ratio at the middle of trial if the overall allocation difference is greater than 5% 
(i.e., <47.5% vs. 52.5%). 
 

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Storage and dispensing of random allocation codes will be made in a centralized 
fashion. The UNM SDCC will generate and store the codes for all sites and types of 
clinics, and will be embedded into the Research and Electronic Data Capture 
(REDCap) data management system in the backend so that the identification of a 
treatment assignment will be ready and immediate without contacting the coordinating 
center when requested through the REDCap electronic request form by a responsible 
research staff at the sites whenever a new eligible participant is enrolled.  The UNM 
SDCC will also be responsible for conducting re-weighted randomization, if 
necessary, at the middle of the trial.  
 
Randomization will occur at enrollment, however research staff will wait until after the 
baseline assessments have been conducted to reveal the randomization to the 
participant, to avoid bias during baseline data collection. 
5.5 
Withdrawal 
Reasons for Withdrawal 
Subjects may withdraw or be withdrawn for any of the reasons given below.  The reason 
for withdrawal will be recorded on a CRF.  
 
In accordance with the current revision of the Declaration of Helsinki (amended October 
2000, with additional footnotes added 2002 and 2004) and any other applicable 
regulations, a subject has the right to withdraw from the study at any time and for any 
reason and is not obliged to give his or her reasons for doing so.  The Investigator may 
withdraw the subject at any time in the best interests of the subject’s health and well-
being.  In addition, the subject may withdraw/be withdrawn for any of the following 
reasons: 
• Administrative decision by the Investigator. 
• Ineligibility (either arising during the study or retrospective, having been 
overlooked at screening). 
• Significant protocol deviation. 
• Subject non-compliance with study requirements. 

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6 Investigational Interventions 
 
This is multi-site national study (8 U.S. cities), where up to 1000 HCV-infected PWIDs 
(injecting illicit substances within the last 3 months) will be randomized to either PN plus 
blister pack dispensation (weekly or every other week) versus mDOT.  
6.1 
modified Directly Observed Treatment 
6.1.1 OTP Setting 
Observation of HCV medication administration will be linked to methadone visits 
among patients receiving methadone. The schedule of five days per week will be 
considered modified DOT (mDOT). Participants enrolled in the mDOT arm through 
the OTP who are not taking methadone, but another version of opioid agonist 
treatment (OAT), such as buprenorphine, will follow the mDOT protocol for 
community health center participants. 
Method of observation:  Subjects in the mDOT arm will receive: 1) 5 directly 
observed doses per week (from a blister pack) at the same time as they receive 
methadone, and 2) take-home doses packaged in blister packs for self-
administration on other days. In addition, the observing staff will: (i) notify clinicians 
when doses are declined or missed and (ii) refer subjects to clinicians as necessary.   
Administration of Medication:  Medications will be packed in labeled blister packs.  
For participants who are receiving methadone and attending clinic 5 days/week, 
medication will be kept at the clinic where research/clinical staff will observe them 
taking the medications.  Participants will also receive take-home doses packaged in 
blister packs for the days that they are not observed at the methadone clinic.  Blister 
packs will be returned to research staff at the next research visit.   
Each time a subject misses an observed dose, there should be an assessment by 
the observer: the observer will ask whether the patient missed that day's dose, took 
a rescue dose, or took medication from another source. 
 
Rescue Doses: Each participant will receive a container labeled with the contents, 
containing up to two doses of HCV treatment medication.  In the event the participant 
misses the opportunity to take an observed dose at the OTP, they can take one of the 
rescue doses instead.  This container will be either a pill case or a container specified 
by the local site. When the participant presents to the program for the next observed 
dose, the prior missed dose will be given to the participant to replace the rescue dose 
that was taken for any future events. 

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Record keeping:  Each time a subject misses an observed dose, there should be an 
assessment by the observer: the observer will ask whether the patient missed that 
day's dose, took a rescue dose, or took medication from another source. 
Staff that observe the participant taking their medication will log the information on a 
standardized log.  Adherence will be measured with standardized forms each week 
by Study Coordinators and will include pill counts of blister packs. 
 
Participants that choose to leave the OTP during treatment will have the potential to 
remain in the study by being transferred to the Community Health Center. 
 
6.1.2 Community Health Center Setting 
This intervention is considered modified DOT (mDOT) since between 3-7 weekly 
doses will be directly observed.  
 
Method of Observation:  All observed doses will be observed using electronic DOT 
(eDOT), via the mobile health smartphone app miDOT (developed by emocha Mobile 
Health, Inc.).  Participants will be provided with a smartphone that is pre-loaded with a 
data/minutes plan and the miDOT app.  Research staff will train the participant on 
how to use the app.  Using the app, participants will take a video of themselves taking 
their HCV medication, then upload the video to the database maintained by emocha.  
Research staff will review these videos.  On the day of medication pick-up, research 
staff will be available to provide technical assistance with that day’s video. 
 
If a participant loses the study-provided phone or is otherwise unable/unwilling to use 
the miDOT app, participants will receive mDOT three times per week at the CHC by 
clinic/research staff. The remaining doses will be taken by the participant outside of 
the clinic. 
 
Dispensing of Medication:  Participants participating in mDOT will receive their 
medications in weekly blister packs once a week.  Participants will return blister 
packs (with or without any remaining medication) at their next research visit.  If the 
participant is not using the emocha miDOT app, their medication will be packaged in 
weekly blister packs and the participant will receive three observed doses at the 
clinic by clinical or research staff.  The blister pack will remain with staff during the 
week until the participant has received their last observed dose for the week.  The 
participant will then receive the blister pack with remaining doses to take home as 
unobserved doses.  For any unobserved doses during the week prior to their final 
observed dose of the week, the participant will pop out the pill from the blister pack 
and take it home in a labeled pill case.  

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Research or clinic staff will: (i) notify clinicians when doses were declined or not 
observed and (ii) refer subjects to clinicians as necessary.  
 
Rescue Doses:  Each participant will receive a container, labeled with the contents, 
containing up to two doses of HCV treatment medication. In the event the participant 
misses the opportunity to take an observed dose at the OTP, he/she can take one of 
the rescue doses instead. This container will be either a pill case or a container 
specified by the local site. When the participant presents to the program for the next 
observed dose, the prior missed dose will be given to the participant to replace the 
rescue dose that was taken for any future events. 
 
Record keeping:  Research staff will review the miDOT videos, and record the date 
and time that the dose was taken.  For participants not utilizing miDOT, clinic or 
research staff will observe the participant taking their medication and log the 
information on a standardized log.  Adherence will be measured with standardized 
forms each week by Study Coordinators and will include pill counts. 
 
Adherence will be measured and logged with standardized forms each week by 
research staff and will include pill counts of blister packs. 
6.2 
Patient Navigation 
The study will follow a PN model developed by New York City Department of Health 
(DOH) in collaboration with Montefiore Medical Center and the community.  HCV PNs 
have the following functions: 1) coordination of treatment; 2) health education and 
promotion; 3) assisting patients to overcome barriers; and 4) psychosocial support. 
Additional support may be offered through optional weekly peer-led support group 
(see below Section 6.3).  Details of the PN protocol and materials are in the Patient 
Navigator Manual. Implementation of the PN protocol will differ by site based on the 
structure of the PN groups. Sites will document site-specific procedures in their 
operating manuals. 
 
Packing of Pills for Patient Navigation Arm 
For the PN arm pills will be packed in two-week blister packs and dispensed every other 
week.  If participant is having difficulty with adherence on the biweekly schedule, the 
provider will assess changing the dispensing to weekly, and document the reasons for 
changing.  No doses will be observed so even if patient is coming to the clinic weekly 
and picking up medications, all doses will be self-administered. 
 

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6.3 
Education and Peer Support 
 
Optional Peer Support - Weekly Support Groups:  
Peer support groups may be available at all sites for all participants, depending on 
local factors.  Peer support groups will provide support and education covering the 
following topics: natural history, goals of treatment, treatment regimen and side 
effects, adherence (including strategies), drug and alcohol abuse, and transmission / 
reinfection. Support groups will receive HCV support group materials developed by 
Project Inform, Montefiore Medical Center, and HCV Mentor and Support Group; 
each group will be guided by local advisory boards based on local patient 
preferences and barriers. Availability, structure and frequency of peer support and 
education will differ by site. Sites will document available peer support and education 
resources, structure and attendance in a site log. 

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7 Study Procedures/Evaluations 
 
7.1 
Clinical Evaluations 
 
Individual medical records will be reviewed to evaluate HCV-related labs and dates 
performed (HCV viral load, genotype and subtype, FIB-4 (AST, ALT, and Platelets), 
total bilirubin, albumin, prothrombin time, FibroSURE (if available), Fibroscan/liver 
biopsy (if available), abdominal imaging results (ultrasound/MRI) if available, and other 
medical history including the most recent HIV test.  
 
To determine presence of cirrhosis, all subjects will have a FIB-4 biomarker test 
calculated at enrollment (obtained by chart review). If FIB-4>3.25, the patient is 
considered to have advanced cirrhosis.  If available, results of fibroscan, liver biopsy or 
imaging study (ultrasound/CT/MRI c/w cirrhosis) will be used for stratification instead of 
FIB-4. 
 
Psychiatric status will be assessed in all participants using structured instruments, 
including: 1) PHQ-9 to assess for depression and 2) the GAD-7 to assess for anxiety.  
Suicidal ideation will trigger a psychiatric referral.  
7.2 
Laboratory Evaluations 
HCV Viremia: Blood for HCV viral loads will be sent directly to Quest Diagnostics. 
Twenty mL of blood will be collected at visits 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16 and 
17 for HCV viremia testing and archiving.  Specimens will be identified only by study ID 
number or bar-code, and will also be labeled with the name of the research study, the 
date and time of collection, and the specimen number. Each site will send blood 
samples directly to Quest.  Results which will be entered into the study data system.  
Resistance testing:  For subjects who fail to achieve SVR or show evidence of 
reinfection, NS5A/NS5B resistance testing will be performed on the baseline, and either 
treatment failure visit (unscheduled) or Visit 5 specimens. The second time point will be 
determined by when treatment failure is first identified. The specimen for “treatment 
failure visit” will be used if the subject fails treatment during the 12 weeks of treatment, 
and the specimen for “Visit 5” will be used if the subject fails treatment after the 
treatment period.  All specimens for resistance testing will be shipped to Montefiore 
CRC, and banked. Batched runs for resistance testing will be run at Monogram. 
Biorepository specimen:  Blood specimens will be collected at research visits 1, 5, 6, 7, 
8, 9, 10, 11, 12, 13, 14, 15, 16 and 17.  At Visit 1, twenty mL of blood will be drawn and 

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stored locally until sent to the study biorepository.  A biorepository will be established at 
Prima Health-Upstate for archiving stored blood for future studies. At all other visits, 
twenty mL of blood will be drawn and sent to Quest for HCV VL testing and temporary 
archiving before being sent to Prisma Health-Upstate’s Biorepository. 
 
Toxicology:  Urine toxicology tests (American Bio Medica Corporation RapidTox Point of 
Care (POC) test) will be performed at research visits 1, 2, 3, 4, 5, 7, 9, 11, 13, 15, and 
17.  At these research visits, the RA will ask subjects to provide a urine specimen, 
unobserved, in a private bathroom. Collection containers and biohazard bags will be 
available to the study staff from the commercial laboratory. Specimens will be labeled 
with the name of the research study, the date and time of collection, and the specimen 
number; no names or other identifying information will be used.  The specimen number 
will be generated using the subject’s study ID number, the letters UT (to denote urine 
toxicology test), and the visit number. The RA will perform the point of care test (results 
back in 5 minutes).  Urine will be tested for multiple substances: amphetamines, 
barbiturate, benzodiazepine, buprenorphine, cocaine, marijuana, methadone, 
methamphetamine, opiates, and oxycodone. Results will be recorded in REDCap.  
Urine toxicology results are confidential and will only be used for study purposes, not 
recorded in the participant’s clinical record. 
7.3 
Non-Clinical Evaluations 
Participant surveys:  At baseline and every research visit, participants will answer 
surveys administered by the research assistants who will either record the responses 
directly into the REDCap database or onto a paper form, then entered into the REDCap 
database after the research visit is finished. 
 
Medical record:  HCV viral load will be obtained when possible by chart review. 
Information on treatment interruptions and discontinuation will be obtained from medical 
records. 
Adherence by electronic monitors (Med-ic®) and self-report:   
Adherence to medications dispensed in electronic blister packs will be measured by 
electronic compliance monitoring for blistered medications with an attached Med-ic® 
device. Med-ic® is an innovative stick-on paper label for medication blisters that 
provides a disposable method to measure adherence (117). Med-ic® packages yield 
99.6% event accuracy (time of dose removal correctly recorded within +2 minutes). 
This technology will allow tracking of medication usage from weekly blister packs 
prepared by the local pharmacists. Blister packs will be pre-fitted with labels and 
electronic tags.  

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In the PN arm, subjects will receive their HCV medication from the medical staff, 
packaged in 7-14 day blister packs, either weekly or every other week (standard), 
depending upon the determination of the provider after discussion with the participant. 
Used blister packs will be returned at research visits for downloading adherence data.  
In the mDOT arm, subjects (enrolled in the OTP) will take observed doses at the OTP. 
The date and time of the dose will be recorded in the mDOT log. Seven-day blister 
packs containing weekend take-home doses (1-2 doses/week) will be provided on either 
Friday or Saturday. Blister packs will be collected at each research visit.  
Subjects (enrolled in the community health center) will be offered mDOT 7 times a week 
via a smartphone application, miDOT. Alternatively, mDOT will occur 3 times a week at 
the community health center observed by the clinic/research staff.  If the mDOT is 
administered at the community health center, dosing logs will be maintained by staff. If 
receiving miDOT (virtual DOT), subjects will be seen once a week in the clinic and 
receive one observed dose each week – observed by both clinic/research staff and the 
miDOT application. Subjects will be provided with 7-day blister packs for all of their 
doses.  
Pill counts will also be performed by counting remaining doses in blister packs. Self-
reported adherence will be measured using a single-item visual analogue scale (VAS) 
which has been shown to correlate well with both pill counts and virological outcomes in 
HIV-infected patients taking HAART [105, 106]. 

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8 Study Schedule 
 
Participants will be followed for up to 180 weeks: Up to 8 weeks (±4 weeks) of pre-
treatment evaluation, 12 weeks of treatment, 12 weeks of follow-up to determine 
SVR12, and 144 weeks of follow-up post SVR12 to determine long-term SVR and 
reinfection.  
 
8.1 
Screening and Enrollment 
 
8.1.1 Screening 
Potential participants will be identified through two possible means: chart 
reviews of existing patients at the clinics and by community-based outreach and 
screening.  Eligible participants should be enrolled within one month of 
screening.  If enrollment does not occur within one month, eligibility should be 
reassessed. 
 
8.1.1.a.  Screening with Chart Reviews  
Prior to conducting chart reviews of existing patients at the OTP and 
community clinics, sites will obtain a Waiver of HIPAA authorization for 
screening/recruitment purposes. Once this waiver is obtained, charts of 
potential participants will be reviewed to determine if the patient is eligible for 
participation.    
 
• The following will be reviewed through Chart Review Part 1: 
• HCV Antibody (ever) 
• HCV viral load (ever) 
• HCV genotype/subtype (ever) 
• AST/ ALT and platelets in the past 12 months (for FIB-4  
fibrosis estimation),  
• Imaging if available to rule out hepatocellular carcinoma if 
the participant has advance cirrhosis/fibrosis (abdominal 
ultrasound/CT scan with contrast, or MRI with contrast) 
• Confirm that the person has not previously received DAAs 
• Document Study eligibility on CRF  
If subject is deemed eligible via “Chart Review Part 1”, then “Eligibility 
Screener” should be conducted. 
 

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8.1.1.b.  Community-Based Screening 
Participants may also be recruited through community-based outreach and 
screening.  Potential participants will be identified through an eligibility 
screening tool.  If they meet basic eligibility criteria – e.g. HCV positive, 
recent injection drug use – determine if they are currently seeing a provider.   
• If they have an HCV provider: 
• Get a release of information to contact the provider 
• Obtain clinical records from the provider 
• Extract data to assess eligibility (same as listed in 8.1.1.a), 
documenting on Chart Review Part 1. 
• Document Study eligibility on CRF  
 
• If they do not have an HCV provider: 
• Refer to an HCV provider at the community health center or 
OTP 
• Get a release of information 
• Once the clinical record has been started, extract data to 
assess eligibility as listed in 8.1.1.a, documenting on 
Chart Review Part 1. 
• Document Study eligibility on CRF  
 
8.1.2 Visit 0:  Eligibility confirmation, Consent and Enrollment Visit 
A research assistant will meet with the potential participant in a private room in OTP, 
community health center, or other research location to confirm eligibility and obtain 
consent.  Depending upon the time the participant has available and their state, this 
visit may be combined with Baseline Visit. 
 
• Discuss study procedures, risks and benefits of study participation 
• Obtain written signed consent for:  
1) Clinical trial participation;  
2) Study staff to use protected health information from clinic 
records;  
3) Study staff to disclose protected health information in event of 
clinical need  
4) staff to track any hospitalizations or emergency events 

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• Administer the sociodemographic instrument. 
• Participant will be randomized to the DOT or PN arm (stratified, 
blocked) generated by DCC at UNM HSC.  Wait until after baseline 
assessments have been completed before revealing randomization 
status to the participant. 
• If the Baseline Visit is not taking place at this time, schedule the Baseline 
Visit within two weeks of enrollment. 
• Treatment initiation should begin within twelve weeks of enrollment 
 
8.2 
Visit 1: Baseline Visit  
The baseline visit should occur within two weeks of enrollment and prior to 
treatment initiation.  This visit will assess for several different factors including 
HCV clinical factors, potential mediating variables based on the information-
motivation-behavioral (IMB) model, potential moderators, and additional 
psychosocial factors hypothesized to predict adherence, using the following 
research assistant administered instruments, in this order: 
 
• Modified ASI – Baseline (assess drug use) 
• Behavior risk assessment (assesses injection behaviors) 
• AUDIT-C (assess alcohol use) 
• Substance Use Treatment (assess past and present experience with 
treatment) 
• PHQ-9 (assess depression) 
• GAD-7 (assess anxiety) 
• EQ-5D with added pain question (assess quality of life) 
• Stigma scale 
• Shame scale 
• Health efficacy 
• Medical Outcomes Social Support Scale 
 
The baseline visit will also include specimen collection: 
• Urine for POC drug screening  
• Collect 20 mL of whole blood in EDTA tubes for archiving.   
 
Additional services will be provided: 
• Counseling on avoidance of HCV transmission and HIV infection will be 
conducted. 
• Information on drug treatment and needle exchange programs will be 
provided, and other referrals as needed. 

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At this visit, after all baseline instruments have been administered, research staff will 
inform the participant about their randomly assigned treatment delivery arm. 
8.3 
Treatment Initiation 
Treatment initiation will occur after the baseline visit, within 12 weeks of enrollment, 
and as determined by the clinician.  Prior to initiating treatment, the clinician must 
complete the provider checklist. 
 
If treatment initiation does not begin within 12 weeks of enrollment, the participant 
will be withdrawn from the study. 
8.4 
Chart Review Part 2 
Chart Review Part 2 should be completed at 12 weeks after enrollment regardless of 
if the participant initiates treatment. The following information should be collected: 
• Pregnancy status  
• Total bilirubin 
• Albumin 
• Prothrombin time 
• HBV status 
• HAV status 
• Fibrosure, Fibroscan, liver biopsy (if available) 
• Problem list diagnoses: 
 Cirrhosis 
 Psychiatric 
 Medical 
• Imaging if advanced fibrosis/cirrhosis to rule out hepatocellular 
carcinoma (abdominal ultrasound/CT scan with contrast, or MRI with 
contrast) 
• Reason why patient did not initiate treatment (if applicable) 
• HCV Viral load 
• HCV Genotype/subtype 
• FIB-4 score 
• Child-Pugh score 
• ALT and AST levels 
• Platelets 
• HIV status  
• HIV Viral load (if applicable) 
• HIV CD4 count (if applicable) 

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8.5 
Treatment (follow-up) visits:  
During treatment participants will have research visits and either mDOT visits or PN 
visits.  Research visits will be the same for all participants, regardless of assigned 
treatment arm.  Participants will be contacted by research staff regarding their first 
treatment visit by phone or in person and briefed on the visit and what to expect.  
 
8.5.1  Treatment Research Visits 
 
8.5.1.a  Visit 2: week 4 of treatment, ± 7 days 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
 
• Modified ASI – Follow-up (assess drug use) 
• Behavior risk assessment (assesses injection behaviors) 
• Substance Use Treatment (assess past and present experience 
with treatment) 
• Visual Analogue Scale (assess adherence) 
 
Review medical chart and record the following information: 
• HCV viremia 
• Child-Pugh score to assess hepatic decompensation (if available) 
• HIV viral load and CD4 count (if applicable) 
• FIB-4 score (if available) 
 
Collect the following specimens: 
• Urine for POC drug screening 
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.5.1.b  Visit 3: week 8 of treatment, ± 7 days 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
 

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• Modified ASI – follow-up (assess drug use) 
• Substance Use Treatment (assess past and present experience 
with treatment) 
• Visual Analogue Scale (assess adherence) 
 
Review medical chart and record the following information: 
• HCV viremia 
• Child-Pugh score to assess hepatic decompensation (if available) 
• HIV viral load and CD4 count (if applicable) 
• FIB-4 score (if available) 
 
Collect the following specimens: 
• Urine for POC drug screening  
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.5.1.c  Visit 4: week 12 of treatment, ± 7 days 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Modified ASI – follow-up (assesses drug use) 
• Behavior risk assessment (assesses injection behaviors) 
• AUDIT-C (assesses for alcohol use) 
• Substance Use Treatment (assess past and present experience with 
treatment) 
• PHQ-9 (assesses for depression) 
• GAD-7 (assesses for anxiety) 
• EQ-5D with added pain question (assesses quality of life) 
• Health efficacy 
• Medical Outcomes Social Support Scale (assesses social support) 
• Visual Analogue Scale (assess adherence) 
• ONLY FOR THOSE IN PN ARM:  Brief Revised Working Alliance 
Inventory (assesses rapport with PN) 
 
Review medical chart and record the following information: 
• HCV viremia 

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• Child-Pugh score to assess hepatic decompensation (if available) 
• HIV viral load and CD4 count (if applicable) 
• FIB-4 score (if available) 
 
Collect the following specimens: 
• Urine for POC drug screening  
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.6 
Post-treatment (follow-up) visits  
Follow-up visits are scheduled in reference to the treatment start date. 
 
8.6.1 Visit 5: week 24, ±14 days 
 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Modified socio-demographic survey (assess for any changes in 
housing, income) 
• Modified ASI – follow-up (assesses for drug use) 
• Behavioral risk questionnaire (assesses injection behaviors) 
• AUDIT-C (assesses alcohol use) 
• Substance Use Treatment (assess past and present experience 
with treatment) 
• PHQ-9 (assesses for depression) 
• GAD-7 (assesses for anxiety) 
• EQ-5D with added pain question (assesses quality of life) 
 
Review medical chart and record the following information: 
• HCV viremia 
• FIB-4 score (if available) 
 
Collect the following samples: 
• Urine for POC drug screening  
• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 

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Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.6.2 Visit 6: week 36, ± 14 days 
 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Behavioral risk assessment (assesses injection behaviors) 
• Shame scale (assesses shame) 
 
Collect the following samples: 
• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.46.3 Visit 7: week 48, ± 14 days 
 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Behavioral risk assessment (assesses injection behaviors)  
• AUDIT-C (assesses alcohol use) 
• Substance Use Treatment (assess past and present experience 
with treatment) 
• PHQ-9 (assesses for depression) 
• GAD-7 (assesses for anxiety) 
• EQ-5D with added pain question (assesses quality of life) 
• Medical Outcomes Social Support Scale (assesses social support) 
 
Collect the following samples: 
• Urine for POC drug screening 
• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 

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Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.6.4 Visit 8: week 60, ± 14 days 
 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Behavioral risk assessment (assesses injection behaviors)  
 
Collect the following samples: 
• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving. 
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.6.5 Visit 9: week 72, ± 14 days 
 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Modified socio-demographic survey (assess for any changes in 
housing, income) 
• Modified ASI – follow-up (assesses drug use) 
• Behavioral risk questionnaire (assesses injection behaviors) 
• AUDIT-C (assesses alcohol use) 
 
Collect the following samples: 
• Urine for POC drug screening 
• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 

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8.6.6 Visit 10: week 84, ± 14 days 
 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Behavioral risk assessment (assesses injection behaviors)  
 
Collect the following samples: 
• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.6.7 Visit 11: week 96, ± 14 days 
 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Behavioral risk assessment (assesses injection behaviors)  
• AUDIT-C (assesses alcohol use) 
 
Collect the following samples: 
• Urine for POC drug screening 
• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.6.8 Visit 12: week 108, ± 14 days 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Behavioral risk assessment (assesses injection behaviors)  
 
Collect the following samples: 

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• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.6.9 Visit 13: week 120, ± 14 days  
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Modified socio-demographic survey (assess for any changes in 
housing, income) 
• Modified ASI – follow-up (assesses for drug use) 
• Behavioral risk questionnaire (assesses injection behaviors) 
• AUDIT-C (assesses alcohol use) 
• Substance Use Treatment (assess past and present experience 
with treatment) 
• PHQ-9 (assesses for depression) 
• GAD-7 (assesses for anxiety) 
• EQ-5D with added pain question (assesses quality of life) 
• Shame Scale (assesses for shame associated with HCV infection) 
• Medical Outcomes Social Support Scale (assesses for social support) 
 
Collect the following samples: 
• Urine for POC drug screening 
• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
The original HERO protocol involved a total of 13 research visits over a 30-month 
period. On May 2019, participants were offered the opportunity to participate in an 
extended follow-up period involving 4 additional research visits over a 12-month period. 
Participants were invited to participate in the protocol extension period (12 months). 
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participants who agreed to participate and signed the informed consent were enrolled in 
the additional visits. 
 
8.6.10 Visit 14: week 132, ± 14 days 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Behavioral risk assessment (assesses injection behaviors)  
 
Collect the following samples: 
• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
8.46.11 Visit 15: week 144, ± 14 days 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Behavioral risk assessment (assesses injection behaviors)  
• AUDIT-C (assesses alcohol use) 
 
Collect the following samples: 
• Urine for POC drug screening 
• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.6.12  Visit 16: week 156, ± 14 days 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Behavioral risk assessment (assesses injection behaviors)  
 
Collect the following samples: 

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• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
8.6.13  Visit 17: week 168, ± 14 days (Exit interview) 
Research staff will assess for factors of interest by administering the following 
questionnaires: 
• Modified socio-demographic survey (assess for any changes in 
housing, income) 
• Modified ASI – follow-up (assesses for drug use) 
• Behavioral risk questionnaire (assesses injection behaviors) 
• AUDIT-C (assesses alcohol use) 
• Substance Use Treatment (assess past and present experience 
with treatment) 
• PHQ-9 (assesses for depression) 
• GAD-7 (assesses for anxiety) 
• EQ-5D with added pain question (assesses quality of life) 
• Shame Scale (assesses for shame associated with HCV infection) 
• Medical Outcomes Social Support Scale (assesses for social support) 
 
Collect the following samples: 
• Urine for POC drug screening 
• Collect 20 mL of whole blood in EDTA tubes to send to Quest 
Diagnostics for HCV viremia testing and for archiving.   
 
Provide the following services: 
• Counseling on avoidance of HCV transmission and HIV infection. 
• Information on drug treatment and needle exchange programs, and 
other referrals as needed 
 
Research staff will thank the participant for participating in the study. 
 
 

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8.7 
Unscheduled Visits 
Unscheduled visits may occur at any time during the study.  They may occur for the 
following reasons:   
(1) For operational reasons, e.g., a subject may request to reschedule, or to ask 
questions;  
(2) For SAE related reasons.  When interim contacts or visits are completed in response 
to subject reports of SAEs, study staff will assess the reported event and refer the 
subject to appropriate medical care.  All SAEs will be evaluated and reported as 
required (Section 9.4); 
(3) If a subject presents to the study site after having missed a scheduled visit (e.g., in 
response to locator/tracking efforts) on a day that does not fall within a scheduled 
visit window; 
(4) For other reasons at subject request.  All interim contacts and visits will be 
documented in subjects' study records and on applicable data collection forms. 
(5) If a subject fails HCV treatment. This visit will be solely for collection of 20 mL of 
blood to be processed and archived by local labs for resistance testing. 
 
8.8 
Patient Navigator Encounters 
Participants assigned to the PN arm will be scheduled for a minimum of 4 encounters 
with the PN, 3 of which must be conducted in-person and 1 of which can be conducted 
either in-person or remotely (via phone, e-mail or text) .These four minimum encounters 
include: 1) Enrollment, Assessment and Referrals; 2) Treatment Readiness (in-person); 
3) Treatment Adherence Check-in (remotely via text, call or e-mail); and 4) After 
Treatment (in-person). Additional contacts may occur more frequently and via different 
methods (e.g.: phone calls, texts) depending upon the needs of the participant.  PN 
contacts are described in more depth in the PN Protocol.   
 
8.7.1 Initial Visit (Required) 
The initial visit will take place prior to the participant beginning treatment. 
• The PN will use the Health Promotion Guide modules I and II to 
complete the first page of the Patient Navigation Form (Sections: 
Intake, Self-Reported History, Assessment and Referrals) 
• Based on the outcome of the Assessment, the PN and participant will 
develop a Patient Navigation Care Plan together. 
• Referrals for supportive services will be provided 
• Additional visits to complete the assessments, referrals and health 
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8.7.2  Treatment Readiness Encounter (Required) 
In the treatment readiness encounter, the PN and participant will develop a 
treatment plan for the participant, incorporating input from the provider, 
including the provider in the encounter if possible. 
Using Health Promotion Guide Module III: 
• The PN will provide treatment readiness information and counseling 
• The PN and participant will discuss the frequency and method of PN 
encounters to support adherence through the course of treatment. 
Frequency may change during treatment depending on the needs of 
the participant (for example, if the participant has unexpected side 
effects, or trouble remembering to take medications as prescribed, 
adherence support could be increased). 
• The PN and participant will complete the Treatment Planning Form, 
after receiving input from the provider. 
 
8.7.3  Treatment Adherence Encounter (3 days post treatment initiation - 
Required)  
The PN is required to contact the participant three days (2-5 days is 
acceptable) after he/she starts treatment to address any side effects the 
patient may be experiencing, ask if any doses have been missed, and 
intervene to improve adherence.  This encounter can occur in-person or could 
be a remote encounter (phone, email, text) depending upon participant need. 
• Based on the outcome of this check-in, the PN will update the 
Treatment Planning form with any changes to the treatment adherence 
support frequency and method, and then contact the patient as agreed 
upon for the duration of the treatment.  
• The method and frequency of treatment adherence support can be 
adjusted as needed through the course of treatment. 
 
8.7.4  Treatment Period Encounters (Weeks 1-11) (Recommended) 
Weekly adherence check-ins during the course of treatment are 
recommended. These check-ins could occur in-person or remotely via phone 
call, text or email. If weekly contact is not appropriate for the participant, the 
treatment adherence encounters should occur at the frequency agreed upon 
by the provider, PN and participant and documented in the Treatment Plan. 
• The treatment adherence encounters should be documented using the 
Care Coordination Log  

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• The PN will provide referrals to services in which the participant is 
interested. 
 
8.7.5  After Treatment Encounter (Week 12 of treatment) (Required) 
At the final required encounter after treatment, the PN will use the Health 
Promotion Guide Module IV to: 
• Ensure the patient is aware of future clinical monitoring requirements. 
• Provide reinfection prevention information, resources and support. 
• Discharge or transition patient to an appropriate supportive program, 
provide referrals 
• The PN has an option to work with the participant after treatment to 
support reinfection prevention, for up to six months (optional). 
 
8.9 
mDOT Visits 
 
OTP:  Participants assigned to the mDOT arm in the OTP will have a minimum of 5 
observed doses per week by clinic or research staff.    Each observed dose will be 
recorded on the dose log, then entered into the study database.   
 
Community Health Center:  Participants assigned to the mDOT arm in the CHC will 
have one observed dose by clinic or research staff per week when they pick up their 
medication.  Other doses will be observied as described in section 6.1.2.  All observed 
doses will be recorded on the mDOT log (Adherence Calendar) and entered into the 
study database.

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9 Safety Reporting and Safety Assessment Monitoring 
9.1 
Data and Safety Monitoring Plan. 
The PI (Dr. Litwin) will be responsible for monitoring the safety and efficacy of this 
study, executing the Data and Safety Monitoring (DSM) plan, and complying with the 
reporting requirements. The PI will provide a summary of the DSM report to PCORI on 
an annual basis as part of the progress report. The DSM report will include the 
participants’ sociodemographic characteristics, a summary of Severe Adverse Events 
(SAEs), any actions or changes with respect to the protocol, and any quality assurance 
or regulatory issues that occurred during the past year. The DSM report to PCORI will 
also include, when available, the results of any efficacy data analysis conducted. 
9.2 
Data monitoring plan 
Because the intervention is very low risk and is highly integrated within usual clinical 
care, the main element of the monitoring plan will be continuous, close monitoring by 
study staff and investigators, with prompt identification and reporting of adverse events 
(AEs).  
9.3 
Data Confidentiality 
Each participating site will maintain appropriate medical and research records for this 
trial, in compliance with ICH E6, Section 4.9 and regulatory and institutional 
requirements for the protection of confidentiality of subjects.  Forms for use as source 
documents will be derived from the electronic case report forms (eCRFs) and be 
provided by the Statistical and Data Coordinating Center (SDCC).  Source documents 
will only be accessible by study staff and all research records will be kept in a locked 
filed cabinet in the research office of the PI. 
 
Medical records are stored in locked rooms in each clinic, or in password protected 
computer files. The RA with assistance from the Co-I/PI will review the charts. Prior to 
starting the chart review process, research staff will complete online training in patient-
oriented research, including confidentiality, and will receive further training in 
confidentiality and the chart review protocol from the PI. 
9.4 
Serious Adverse Events 
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• Death 
• Life-threatening 
• Hospitalization (initial or prolonged) 
• Disability or permanent damage 
• Congenital Anomaly/Birth Defect 
• Required intervention to prevent permanent impairment or damage 
(devices) 
• Other serious important medical event  
SAEs will be systematically assessed at each of the research visits. Any SAE will be 
reported according to the IRB requirements of the institution that the participant is 
enrolled through.  The initial SAE report will be followed by submission of a 
completed SAE report to Einstein. In the event that a research subject either 
withdraws from the study or the investigator decides to discontinue a patient due to a 
SAE, the patient will be monitored by the investigator via ongoing status assessment 
until: (1) a resolution is reached, i.e., the problem requiring hospitalization has 
resolved or stabilized with no further changes expected, (2) the SAE is determined 
to be clearly unrelated to the study intervention, or (3) the SAE results in death.  
Outcome of SAEs will be periodically reported to PCORI.  A summary of the SAEs 
that occurred during the previous year will be included in the annual progress report.  
Subjects enrolled in this study will be prescribed FDA-approved antiviral medications 
as part of standard clinical care.  The study involves randomization to the mode of 
administration of the antiviral medications. For each SAE, the site investigator will 
determine if the SAE was related to the study. A second opinion will obtained if 
needed from a PI at a different clinical site.  

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10 Stakeholder Engagement 
This project was conceptualized and designed with the active participation of patients, 
researchers and other stakeholders from its inception.  Patient engagement, including 
individuals who have or are currently injecting and have HCV, or have been cured from 
HCV, has been actively fostered in study planning at each local site. Because this 
project brings together patients and providers representing a diverse geography and 
policy, patients and other stakeholders will continue to be actively and formally involved 
in the planning, design and execution of the study at two levels – locally and nationally. 
At the local level, each research site will form a Local Stakeholder Advisory Board 
(LSAB) which consists of a Primary Investigator, 1-3 patients (termed Co-Investigators) 
and local representatives from participating venues such as OTPs, community health 
centers, syringe exchange programs, community-based organizations (CBOs), public 
health boards/departments, HCV providers, and homeless programs.  Site PIs, in 
consultation with OTP and community treatment site leadership have identified patients 
to serve on the local Stakeholder Advisory Board. 
The LSAB will meet on a quarterly basis to allow discussion of study implementation, 
recruitment, participant tracking, intervention delivery, and outcome assessment. The 
board will provide technical assistance and guidance to the research sites. 
 
At the second level, a National Stakeholder Advisory Board (NSAB) will be convened, 
consisting of the local site PI and a local representative as well as representatives from 
national partners such as CDC (lead governmental organization); professional policy, 
educational, and advocacy organizations - TAG, NATAP, HRC, Hepatitis Support and 
Mentor Group, Project Inform, Hepatitis Education Project, NVHR; professional patient 
organizations - NAMA and Medication-Assisted Recovery Services (MARS); 
governmental organizations - NYSDOHMH and NYCDOH; industry – Gilead, Quest, 
Monogram, and Orasure. Other partners will be recruited, such as Medicaid payers 
based on recommendations elicited in the initial convocation of the group. The National 
Stakeholder Advisory Board will meet on a quarterly basis in Year 1 to review the 
project design, ensure the project will answer questions in alignment with stakeholder 
priorities, and provide guidance on dissemination planning from the outset. In years 2-4 
the NSAB will meet on a quarterly basis to monitor progress to date, address difficulties 
with study implementation, recruitment, intervention or outcome assessment, and 
discuss strategies for communicating results to the wider community and all interested 
stakeholder groups. In Year 5 the NSAB will meet quarterly to review results and guide 
dissemination activities. 

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11 Statistical Considerations 
11.1 Independent Parallel Analysis 
To assure reproducibility of statistical analysis results, two independent statisticians, Dr. 
Herbert Davis at UNM and Dr. Moonseong Heo at Einstein, will adhere as closely as 
possible to the analytical plans detailed below. They will analyze the primary outcome, 
the 12-week sustained viral response (SVR), independently in a blinded and parallel 
manner, and compare their results. If their results are substantially different beyond a 
tolerable variation, then the two statisticians will examine each other’s analytic strategy 
and software codes to reach a consensus. Final results will be produced upon 
agreement of the two statisticians. Investigators will not be involved in this process, and 
more importantly, data analysis will not be guided or influenced by the indications of 
results. Each aspect of data analysis such as cleaning, analysis, and output will be 
logged and archived for review. Whenever possible, the two statisticians will follow the 
procedure for other outcome analysis (see 11.3 below) as well. 
11.2 Definition of Study Subjects  
The study subjects for the primary and secondary outcomes are who: 1) meet the 
inclusion and exclusion criteria (sections 5.1 and 5.2); 2) sign the consent form; 3) are 
randomized; and 4) initiate treatments, i.e., intake at least one dose of the medicine. As 
we do not anticipate that all randomized subjects will initiate treatments, a randomized 
subject will not necessarily be a study subject for primary analysis and beyond. 
However, depending on secondary or other study questions such as comparison of 
treatment initiations, all randomized subjects will serve as an analytic sample.      
11.3  Study Hypotheses 
SVR:  Among subjects who initiate HCV treatment, rate of SVR will be higher in the 
mDOT vs. PN arm. We hypothesize that SVR rate will be 80% in PN arm. 
Treatment initiation rate:  A higher proportion of patients in the PN arm will initiate 
treatment compared to the mDOT arm, which is expected to have 60% treatment 
initiation rate.   
 
Adherence rate:  Patients in the mDOT arm will have higher adherence rate, 
compared to the PN arm which is expected to have 80% adherence rate.  

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Treatment completion rate:  Patients in the mDOT arm will have higher treatment 
completion rate, compared to the PN arm, which is expected to have 80% completion 
rate.  
 
Detectable resistance:  Patients in the PN arm will have higher resistance rate, 
compared to the mDOT arm.  We hypothesize that the majority (65%) of patients who 
fail to achieve SVR will develop detectable resistance, yielding an overall 10% 
resistance rate.  
 
Reinfection rate: The hypothesis is that there will be a minimum 5% reinfection rate 
based on meta-analysis of reinfection rates in patients treated with IFN-based 
regimens.   
11.4  Sample Size Determination 
Sample size N=300 per arm, or a total of N=600, was determined based on feasibility 
of recruitment from all sites during the study period.  Power analysis for each 
hypothesis below is conservatively conducted based on a reduced sample size (N= 
270 per arm, or N=540 in total) after considering 10% attrition rates. The target power 
is 80% with a two-sided significance level of 0.05. To this end, minimally detectable 
effect sizes and widths of 95% confidence intervals were computed with those 
parameters and the sample size after attrition.  
11.5 Primary Analytic Principle 
The intention-to-treat principle will be used as the primary analytic principle, which 
pertains more to a real-world situation. That is, once a treatment was randomly 
assigned to a participant, the participant’s treatment identity will not change in the 
analysis even if s/he changes to the other model of care during the trial period or did 
not take the assigned treatment. Other analytic strategies such as per protocol or as-
treated analyses will also be applied to examine robustness of effectiveness of mDOT 
vs. PN. 
11.6  Preliminary Data Analysis 
First, the distributions of all variables will be examined using graphical or descriptive 
statistics to identify any values out of range. When identified, out of range values will 
be found in the original record, compared and corrected if needed. Second, although 
by the stratified randomization design, each arm will equally be distributed across city, 
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success of randomization will be checked as a way of checking key assumptions by 
comparing the PN and mDOT groups on key variables, such as age, gender, ethnicity, 
race, viral load, subtype, psychiatric history, drug use type, and social support. 
Continuous variables will be compared between arms using the t-tests or Mann-
Whitney tests, and categorical variables will be compared using chi-square or Fisher’s 
exact tests. 
 
Variables that are not equally distributed, albeit expected to be rare, will be included in 
multivariate models to control for their potential cofounding effects. When necessary, 
normal assumptions will be checked for continuous variables by applying a formal 
Kolmogorov-Smirnov test, and if violated, Box-Cox transformations will be considered.  
All preliminary statistical analysis and beyond will be conducted using SAS v9.3. 
11.7 Missing data analysis  
In order to not compromise internal or external validity of our study results, every effort 
will be made to minimize missing data that could occur due to missed visits or subject 
attrition.  A maximum 10% subject attrition rate is anticipated during the first 24-week 
intervention period considering a real-world situation that withstands a tight control. 
However, the missing outcome data rates will depend on the outcome definition 
whereas most analyses will use baseline characteristics as covariates that will thus 
have negligible missing data rate.  
 
The primary analysis will be based on available data without missing data imputation; 
however, we will conduct variety of missing data imputation methods for sensitivity 
analyses. Depending on the clinical nature of outcome, worst scenario imputation or, if 
deemed more relevant, mean imputation methods will be considered. In addition, fully 
specific conditional specification multiple imputation methods will also be applied, 
which are applicable to non-ignorable missing data.  
 
Characteristics of patients who are lost to follow-up will be compared to those that 
remain in the study to assess the degree of any selection bias due to attrition, and the 
analysis results of the different types of imputed missing data will be compared to the 
primary analysis results.  In particular, variability of the coefficients of primary 
predictors across the different imputation methods will be assessed to evaluate 
robustness of the findings.  If the changes in the coefficients are greater than 15% from 
those of the primary analysis, we will limit the generalizability, internal and external 
validity of our findings, which we nevertheless do not believe will occur if attrition rates 
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11.8 Heterogeneity of mDOT or PN effects 
The mDOT or PN effects depending on outcome (see Aim 1 hypotheses) will be 
assessed for each subgroup stratified various factors (e.g., clinic setting, demographic, 
or clinical), which are specified below, and will be compared across the subgroup 
strata. Forest plots will be produced to show graphically the differences or contrasts in 
effect sizes across all subgroups. Formal tests will follow via testing significance of 
pertinent interaction terms with the mDOT or PN arm indicator in statistical models. 
11.9  Mediated mDOT or PN effects 
Mediator analysis will be conducted to identify potential mediators between mDOT/PN 
effect and each of the five outcomes. A mediator will be a variable whose value 
changes or occurs between the baseline and the end of the study; for example, 
reduced stigma and shame, extent of peer support, changes in social support, and 
increased self-efficacy. The potential mediating effects will be assessed by differences 
in mDOT or PN effect sizes depending on outcome between with and without a 
potential mediator variable in statistical models. Their significance will be tested 
following the Baron and Kenny mediation test principle. 
11.10 Analytic plan for Primary and Secondary outcomes: SVR, 
Treatment initiation rate, Adherence rate, and Treatment completion rate 
 
Study Hypotheses: 
SVR:  Among subjects who initiate HCV treatment, rate of SVR will be higher 
in the mDOT vs. PN arm. We hypothesize that SVR rate will be 80% in PN 
arm. 
Treatment initiation rate:  A higher proportion of patients in the PN arm will 
initiate treatment compared to the mDOT arm, which is expected to have 
60% treatment initiation rate.   
 
Adherence rate: Patients in the mDOT arm will have higher adherence rate, 
compared to the PN arm which is expected to have 80% adherence rate.  
Treatment completion rate.  Patients in the mDOT arm will have higher 
treatment completion rate, compared to the PN arm, which is expected to 
have 80% completion rate.  
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Multivariable logistic regressions will be applied to test the overall effectiveness of 
mDOT or PN on the five binary outcomes (success vs. failure) with the SVR rate as the 
primary outcome. The arm indicator will be the predictor for each outcome. With respect 
to adherence outcome in particular, repeatedly measured adherence will be analyzed 
(using 6 post-baseline time points and adherence as a continuous measure) applying a 
mixed effects linear model to test if the two arms are significantly different. This model 
accounts for within-subject longitudinal outcome correlation by taking the subject-level 
intercept as random. All models will include potential confounding variables that are 
significantly different between the two arms; the sites will be included as a covariate as 
well. Likewise, mixed effects logistic regression will also be applied to test the 
significance of PN and DOT on repeatedly-measured undetectable HCV VL throughout 
the intervention period, adjusting for substance use in addition to other confounding 
variables. Changes in illicit drug use will be analyzed using urine toxicology data from 
each visit, counting the “person-month” as a unit of analysis, and analyzing the 
percentage of person-months that are positive for use of illicit drugs during the study 
period using a t-test or Mann-Whitney test. 
Power analysis: Minimally detectable effect sizes 
SVR:  Considering the base 80% SVR rate of in PN arm, a minimum of 9% difference 
between the two arms will be detected (i.e., 89% vs. 80%, Odds Ratio (OR)=2.1) in a 
multivariable logistic regression model in which confounding variables will explain 10% 
of variation in the predictor variable. This study posits that a >9% difference in SVR 
between the PN and mDOT groups will be clinically significant based on studies that 
showed that SVR in treatment naive patients was >90% [14]. 
Mixed effects logistic regression models for the undetectable HCV load will be able to 
detect even smaller percent point difference since they will utilize repeated measures 
for each subject no matter how large within-subject outcome correlations will be. 
Treatment initiation rate:  With anticipated 60% treatment initiation rate in the mDOT 
arm, a minimum of 7% difference will be detectable (i.e., 60% vs. 67%, OR=0.74) in any 
outcome in a multivariable logistic regression model in which confounding variables will 
explain 10% of variation in the predictor variable.  Note that sample size for this analysis 
will be N=1000, the total number of randomized participants. 
 
Adherence rate: With expected 80% adherence rate in the PN arm, a minimum of 9% 
difference in adherence rates between the 2 arms will be detectable (i.e., 89% vs. 80%, 
OR=2.1) in a multivariable logistic regression model.  Per the repeatedly measured 
continuous adherence percentage outcome, mixed effects linear models will be able to 
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Deviation (SD)) greater than 0.2 irrespective of magnitudes of within-subject outcome 
correlations overt time. In a previous DOT study, a standardized effect size of mDOT vs. 
TAU was estimated to be 0.6.   
Treatment completion rate.  Under the expected 80% completion rate in the PN arm, 
a minimum of 9% difference in completion rates between the two arms will be 
detectable (i.e., 89% (mDOT) vs. 80% (PN), OR=2.1). 
 
Subgroup Heterogeneity Analyses  
 
To assess heterogeneity of mDOT or PN effects, additional analyses will be conducted 
to evaluate whether the mDOT effect varies by variety of subgroups stratified by the 
following characteristics: OTP (50%) vs. CHC (50%); Males (70%) vs. Females (30%); 
Patients using illicit drugs during treatment (65%) vs. those not using illicit drugs (35%); 
HIV/HCV coinfected (28%) vs. HCV mono-infected (72%); Cirrhosis (21%) vs. non-
cirrhosis (79%); African American / Latino (41%) vs. Caucasian (59%); Marginally 
housed (26%) vs. stably housed (74%); Comorbid mental illness (55%) vs. no mental 
illness (45%); and Peer-support (70%) vs. no peer-support (30%). Initially, subgroups 
will be defined based on the above factors and estimates of treatment effect will be 
obtained separately in each subgroup using the methods described above.  The 
significance of any heterogeneous mDOT or PN effects across these factors will be 
formally tested by testing significance of corresponding interaction terms with the 
mDOT or PN arm indicator.  In addition, we will also conduct within-arm subgroup 
analyses to identify factors that are associated with outcomes within arms.  For 
example, one test would be if increased social support will be associated with higher 
treatment initiation within the PN arm. 
 
Power analysis for subgroup analysis: For the subgroup analysis, the minimally 
detectable effect size will depend on the sample size of subgroups. However, assuming 
that a subgroup has 50% of the total sample, i.e., N=270, and that a base outcome rate 
is 80% (e.g., SVR), then ≥12% difference will be detected using a Chi-square test. The 
minimally detectable standardized effect size for continuous outcome will be 0.3. This 
power analysis also applies to detect binary or continuous factors associated with 
outcome from within-arm subgroups analyses since the sample size of each arm will be 
N=270 after attritions. For the subgroups with smaller sample size, the minimally 
detectable effects sizes, binary or continuous, will be larger. For example, for some of 
our subgroups will be as small as 20% (or, N= 108) of the sample (e.g. HIV/HCV 
coinfected), minimum effect sizes are larger at ≥17% for SVR and 0.5 standardized 
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11.11 Analytic plan for Resistance and Reinfection Rates  
 
Study Hypotheses: 
Detectable resistance: Patients in the PN arm will have higher resistance rate, 
compared to the mDOT arm.  We hypothesize that the majority (65%) of patients who 
fail to achieve SVR will develop detectable resistance, yielding an overall 10% 
resistance rate.  
 
Reinfection rate: The hypothesis is that there will be a minimum 5% reinfection rate 
based on meta-analysis of reinfection rates in patients treated with IFN-based 
regimens.   
 
Statistical Model 
 
The precision of proportion of participants who develop resistance or reinfection will be 
determined with 95% confidence intervals (CIs) calculated using exact binomial 
methods. To identify factors associated with resistance or reinfection, we will conduct 
bivariate analysis using (exact) logistic regressions for both continuous and dummy-
coded categorical variables. A series of bivariate analyses will be followed by a 
multivariable logistic regression that includes all factors significant in the bivariate 
analysis at a two-sided 0.05 significance level. All analyses will be separately 
conduced for each of resistance and reinfection outcomes.  For the examination of 
association between resistance and adherence in particular, a multivariable logistic 
regression will also be applied in which overall adherence will be the primary predictor 
in the presence of other factors identified in the bivariate logistic regression analysis. In 
all multivariable analysis, the mDOT arm indicator will be included for adjusting 
purpose. 
 
Power analysis  
With a total of N=540 after attrition, the expected 95% confidence intervals are (7.7%, 
12.8%) and (3.5% and 7.2%) for the resistance and reinfection rates, respectively, For 
the bivariate analysis, any binary variable with odds-ratio (OR) ≥1.8 (or 7% vs. 14.4%) 
for resistance and OR > 3.3 (or 2.5% vs. 7.8%) for reinfection will be identified with 
>80% power; and any continuous variable with OR>1.6 and OR>2.1 per 1 SD unit 
changes will be detected for resistance and reinfection, respectively. In the multivariable 
analysis, binary variables with OR > 2.5 (7% vs. 16.2%) and OR > 4.0 (2.5% vs. 9.3%) 
and continuous variables with OR 1.8 and OR>2.5 per 1 SD unit change will be 
detected for resistance and reinfection, respectively, with>80% power, expecting that as 
large as 30% of variation of each variable will be explained by the other variables in the 
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adherence rate and resistance, OR ≥1.8 per 1 SD unit change will be detected with > 
80% power. 
11.12  Analytic plan for Aim 3 
11.12.1  Patient Navigator (PN) Stakeholder Qualitative Study.  
Recruitment. 10-15 PNs will be recruited in Year 1 including at least one navigator from 
each site. Data will be utilized as part of a formative evaluation, with the goal of 
identifying emerging barriers to program success and facilitating problem solving [107].  
Data collection. After participating in an informed consent process, navigators from 
each of the project sites will be interviewed by telephone. Study staff have considerable 
experience with telephone interviews [108, 109]. Thirty-minute semi-structured 
interviews will be conducted focusing on navigator experiences and perceptions of the 
intervention, with particular focus on gaining the perspectives of these front line workers 
into barriers to successful patient outcomes.  
Analysis. Interviews will be recorded and transcribed. Data will be analyzed using Miller 
and Crabtree’s “Editing” approach [110]. The Qualitative Team (Drs. Karasz, McKee, 
and RA) will create a preliminary coding scheme, which is then revised in iterative 
fashion as it is applied to new subsets of the data. When the coding scheme is judged 
to be adequate by the team, the entire data set will be coded in NVivo, a qualitative data 
analysis program that facilitates the rapid organization and retrieval of thematically 
related data [109, 111, 112]. Themes related to successes and failures, and sources of 
stress and satisfaction will be summarized. Data summaries will be presented to the 
NSAB to discuss implications, identify emerging problems, and brainstorm solutions. 
 
11.12.2  The Patient Stakeholder Qualitative Study.  
The focus of the Patient Stakeholder Study, conducted in Years 2-5, will be to 
understand barriers to successful outcomes along the pathway to care, including: the 
lack of treatment uptake, poor adherence (< 80%), failure to achieve SVR, development 
of drug resistance, and HCV reinfection. By contrast to the Navigator study, the Patient 
Stakeholder Study incorporates a comparative design. With the goal of identifying 
barriers to successful treatment, structured comparisons will be made between 
successful and unsuccessful patients at each stage along the pathway to care.  
 
Recruitment. At the treatment uptake stage, a sample of 10 patients who successfully 
initiated treatment will be recruited and interviewed, and a similar group of patients who 
did not. Similarly, we will recruit patients who adhered/did not adhere, achieved SVR/did 
not adhere; and who became re-infected/remained HCV free.  

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Data Collection. Patients will be recruited and interviewed by telephone. An interview 
guide will be developed that focuses on potential barriers and facilitators to successful 
treatment participation, including perceptions of the intervention, perceived need for 
treatment, relationships with staff, and experiences with medication. The guide will 
include questions on contextual barriers to successful participation such as economic, 
social, and psychological stressors, as well as facilitators such as social support and 
other resources.  
 
Data Analysis. Data analysis will proceed in two steps. The first step entails the 
standard data analysis approach described above. In a second step, the analysis team 
will make structured comparisons across successful and unsuccessful patients, 
searching for patterns in the data that reveal core differences across groups and 
provide insight into why some patients are able to succeed with treatment and some are 
not.  In Year 2, data from these comparative analyses will be summarized and 
presented to the Stakeholder team, with the goal of improving the capacity of 
intervention team to provide patient-centered care and better meet patient needs. Data 
collected in later years of the project will be used as part of a summative evaluation, to 
understand the successes and failures of the intervention with the goal of increasing 
scientific knowledge and improving the effectiveness of future interventions. 
 
11.12.3  Quantitative Analysis  
The proposed mDOT and PN interventions are guided by Fisher’s IMB model [113-115]. 
The IMB model asserts that information, motivation, and behavioral skills are 
fundamental determinants of adherence [113]. The IMB model further specifies that 
personal and situational characteristics, such as poor psychologic health, substance 
use, unstable housing, or inadequate access to medical care, may moderate these 
relationships and impact adherence [113]. In extreme cases, strong negative effects on 
adherence are expected, and interventions aimed at improving information and 
motivation may not be effective without adjuvant support. Both interventions - mDOT 
and PN - focus on enhancing information, motivation, and behavioral skills, and provide 
adjuvant support to lessen negative impacts of moderating factors. While primarily 
operating on behavioral skills, the mDOT intervention also enhances both information 
and motivation (through support from nurses and outreach workers). The PN 
intervention addresses information (through education), motivation (through PN and 
peer support), and behavioral skills (PN and peer-led skill-building sessions).  
 
IMB model mediator analysis. The analysis will examine if mDOT vs. PN adherence, for 
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adherence will be assessed at baseline, and during the intervention, and will use as the 
observed values of IMB mediators changes in those variables from the baseline to the 
intervention period. The indirect effects of IMB mediators will be tested by assessing 
changes in coefficients of the intervention effect (PN or mDOT) with and without IMB 
component(s) in mixed effects models. Confidence intervals of the mediated effects will 
be calculated by bootstrapping, and mediation assumed if confidence intervals do not 
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12 Data Handling/Record Keeping/Source Documents 
The principal investigator at each site is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
 
Forms for use as source documents will be derived from the electronic case report 
forms (eCRFs) and provided by the SDCC to the sites to record and maintain data for 
each subject enrolled in the study.  All source documents should be completed in a 
neat, legible manner to ensure accurate interpretation of data.  Black or blue ink is 
required to ensure clarity of reproduced copies.  When making a change or correction, 
the original entry should be crossed out with a single line, and the change should be 
initialed and dated.  Do not erase, overwrite, or use correction fluid or tape on the 
original.  Data entry, media/tools and data management platform are described in detail 
in a Data Management Plan. 
 
Data reported in the eCRF should be consistent with the source documents or the 
discrepancies should be documented. 
12.1  Source Documents and Access to Source Documents 
 
Each participating site will maintain appropriate medical and research records for this 
trial, in compliance with ICH E6, Section 4.9 and regulatory and institutional 
requirements for the protection of confidentiality of subjects.  Forms for use as source 
documents will be derived from the eCRFs and be provided by the Statistical and Data 
Coordinating Center (SDCC).  Source documents will only be accessible by study staff 
and all research records will be kept in a locked filed cabinet in the research office of the 
PI. 
 
These medical records are stored in locked rooms in each clinic, or in password 
protected computer files. The RA with assistance from the Co-I/PI will review the charts. 
Prior to starting the chart review process, research staff will complete online training in 
patient-oriented research, including confidentiality, and will receive further training in 
confidentiality and the chart review protocol from the PI. 
12.2  Data Management Responsibilities 
 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site principal investigator.  During the study, the investigator must 
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and laboratory reports must be reviewed by the clinical team and data entry staff, who 
will ensure that they are accurate and complete.  Serious adverse events must be 
reviewed by the site principal investigator or designee.   
 
The Biostatistics group at the UNM Division of Epidemiology, Biostatistics and 
Preventive Medicine will serve as the Statistical and Data Coordinating Center (SDCC) 
for this study, and will be responsible for data management, quality review, analysis, 
and reporting of the study data. 
12.3  Data Capture Methods 
Sources of data will include: blood and urine tests, participant interviews, medical 
charts, direct observation of staff and PNs, and electronic adherence monitors.  
Information from participant interviews will be either directly entered into an electronic 
data capture system, or will be recorded on paper, then entered.  In-person research 
interview data will be recorded on paper or computer-based data collection instruments.  
All HCV VL load, HCV resistance assays, urine tests, and adherence data will be 
measured by electronic monitors.   
12.4  Types of Data 
This study will collect quantitative and qualitative information.  Quantitative data will be 
collected from 1) subject interviews; 2) blood specimens for HCV viral load and 
resistance assays; 3) urine toxicology test at each research visit; 4) electronic monitors 
for assessing adherence; 5) clinic records for methadone or buprenorphine dose, 
clinical tests and medical history.  Qualitative data will be collected from patients and 
staff interviews (qualitative aim). 
12.5  Timing/Reports 
• Each site will enter accrual and study data from source forms into the study 
database maintained by the SDCC within 7 days of collection. 
• The UNM SDCC will provide weekly accrual, and enrollment reports by site and 
overall. Reports will include information on treatment initiation, study exiting and 
loss to follow up.   
• The UNM SDCC will maintain a “Consort” log of trial progress.   
12.6 Study Records Retention 
The UNM SDCC will store and secure all quantitative data. The Research Informatics 
Core of the Montefiore Medical Center will store all qualitative data. A patient-level de-

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identified copy of the final datasets will be available in electronic form for investigators 
willing to sign a data use agreement with provisions for protecting patients from any 
attempts to de-identify the data, as well as that any findings derived from the data would 
be made public within nine months of the end of the final funding year or by earlier 
request, to PCORI and other relevant parties. Documentation will accompany the final 
data sets that enables others in the research community to utilize the data for 
additional/secondary analysis. Data may be shared electronically or via file-transfer 
protocols and will be provided in a SAS or STATA datafile for quantitative data, and 
original transcriptions for qualitative data obtained through interviews and focus groups. 
Syntax files from SAS or STATA used for quantitative analyses will be archived and can 
also be made available. 
The link between the subject and the research study will be destroyed 5 years after the 
end of the study.   

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13 Quality Assurance 
There will be three levels of data quality assurance: 
First, at each site there will be trained research staff (either the project director or 
research associate) who will be responsible for complete and accurate data collection 
and entry of source data into the UNM DCU. The designated research staff at each 
hub will undergo training in all aspects of the clinical protocol, with refresher training 
once per year.  
Secondly, the UNM SDCC will have a central data quality coordinator who will: (1) 
provide training for site-based personnel; (2) perform periodic monitoring and audits of 
the data collected including source (clinical records and laboratory) and entered (site-
based) to ensure consistent and accurate records.  
Third, the UNM SDCC will have a data manager who will be responsible for receiving, 
reviewing and cleaning all of the study data. The data manager will be responsible for 
regular collation of all incoming data from study sites, maintenance of recruitment, 
enrollment and accrual records, generation of weekly accrual reports, and conducting 
basic analyses for reports and papers. S/he will ensure secure data storage of verified 
and documented data, audit trails for data changes, and ensure back-up systems are 
working. 
PROCESS AND FIDELITY ASSESSMENT: All patient navigators and outreach 
workers will be trained by the New York City Department of Health and Mental 
Hygiene (NYC DOHMH), and NYC DOHMH will provide technical assistance to 
project directors and other staff during the study period. To assess fidelity, local 
Project Directors will observe local project staff to ensure that patient navigation 
protocols are appropriately delivered.  Feedback will be provided with retraining and 
reassessment when indicated.  In addition, Montefiore site visit protocols will include 
observation of local staff delivering patient navigation and DOT protocols. 
 

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14 Ethics/Protection of Human Subjects 
14.1  Ethical Standard/Declaration of Helsinki 
The investigator(s) will ensure that this study is conducted in full conformity with 
principles of the Belmont Report:  Ethical Principles and Guidelines for the Protection of 
Human Subjects of Research of the National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 
CFR 46, 21 CFR 50 and 56, and ICH E6; 62 Federal Regulations 25691 (1997), if 
applicable. The investigator’s Institution will hold a current Federal-wide Assurance 
(FWA) issued by the Office for Human Research Protections (OHRP) for federally 
funded research. 
14.2  Institutional Review Board 
Each participating institution will provide for the review and approval of the study 
protocol and the associated informed consent documents, by an appropriate ethics 
review committee or Institutional Review Board (IRB) listed on their Federal Wide 
Assurance.  Any amendments to the protocol or informed consent materials must also 
be approved before they are placed into use unless change is for the safety of the 
subject.  Only those IRB members who are independent of the investigators and the 
sponsor should provide an opinion on study related matters.  Verification of IRB 
approval of the protocol and the written informed consent will be transmitted by the 
investigator or designee prior to the shipment of medication.  No deviations from or 
changes to the protocol will be initiated without prior approval of an appropriate 
amendment unless change is for the safety of the subject. 
14.3  Informed Consent Process 
The written informed consent document will embody the elements of informed consent 
as described in the Declaration of Helsinki and will adhere to the ICH Harmonised 
Tripartite Guideline for Good Clinical Practice.  Informed consent should be 
implemented before any protocol-specified procedures or interventions are carried out.  
Informed consent will be obtained in accordance with 21 CFR 50.25 and 45 CFR 46.  
Information should be presented both orally and in written form. 
 
Prior to the administration of any study measures, research assistants will obtain 
consent for screening using an informed consent form (ICF), which describes the study, 
and reinforces the confidentiality of all survey information. Interested patients who are 
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consent document. The informed consent process will include discussion of the study 
purpose; study interventions, study procedures, research visit schedule and 
reimbursement; risks, benefits, and alternatives to study participation; and confidentiality 
of research records. The following general principles will be emphasized: 
• Participation is voluntary 
• Participants can discontinue participation at any time 
• Emergency contact information will be provided 
• They are required to consent for trial participation 
• We will require authorization for study staff to use protected health 
information, including laboratory test results from OTP and CHC records, and 
HCV provider 
• In the event of psychiatric distress, study staff will require authorization to 
disclose health information to medical staff 
• Treatment related visits will occur through usual systems of delivery of care, and 
thus may be billed to insurance as any other medical visit.  
• There is the possibility that the participant will not receive HCV treatment 
• There is also possibility that additional medications (ribavirin) may be 
recommended/added during treatment, which will not be provided by the study 
• There is the potential for direct benefit if the participant receives HCV treatment, 
as there is a 95% chance that they will be cured based on current clinical trial 
evidence 
• The subject is free to ask questions at any time to allow him or her to understand 
the purpose of the study and the procedures involved 
• Refusal to participate involves no penalty or loss of medical benefits 
 
The aims of the study and all tests to be carried out will be explained.  The subject will 
be given the opportunity to ask about details of the trial, and will then have time to 
consider whether or not to participate.  If they do decide to participate, they will sign and 
date two copies of the ICF, one for them to take away and keep, and one to be kept by 
the investigator.  These forms will also be signed and dated by the study staff person 
obtaining the informed consent. 
 
Study staff must inform subjects that the trial involves research, and explain the purpose 
of the trial, those aspects of the trial that are experimental, any expected benefits, all 
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treatment, the particular treatment or procedure may involve risks to the subject or to 
the embryo or fetus, if the subject is or may become pregnant, that are currently 
unforeseeable), the expected duration of the subject’s participation in the trial, the 
procedures of the research study, including all invasive procedures, and the probability 
for random assignment to treatment groups.  Subjects will be informed that they will be 
notified in a timely manner if information becomes available that may be relevant to their 
willingness to continue participation in the trial.  They must also be informed of 
alternative procedures that may be available, and the important potential benefits and 
risks of these available alternative procedures.  Subjects must receive an explanation 
as to whether any compensation and any medical treatments are available if injury 
occurs, and, if so, what they consist of, or where further information may be obtained.  
Subjects must be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the 
subject for participating in the trial.  They must be informed of whom to contact (e.g., the 
investigator) for answers to any questions relating to the research project.  Information 
will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated.  The subjects must be informed 
that participation is voluntary and that they are free to withdraw from the study for any 
reason at any time without penalty or loss of benefits to which the subject is otherwise 
entitled. 
 
Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to 
participate or continue to participate in the trial.  The extent of the confidentiality of the 
subjects’ records must be defined, and subjects must be informed that applicable data 
protection legislation will be followed.  Subjects must be informed that the auditors(s), 
IRB, and regulatory authority(ies) will be granted direct access to the subject’s original 
medical records for verification of clinical trial procedures and/or data without violating 
the confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations, and that, by signing a written ICF, the subject is authorizing such access.  
Subjects must be informed that records identifying the subject will be kept confidential, 
and, to the extent permitted by the applicable laws and/or regulations, will not be made 
publicly available and, if the results of the trial are published, the subject’s identity will 
remain confidential. 
 
Informed consent forms must be in a language fully comprehensible to the prospective 
subjects.  Informed consent shall be documented by the use of a written ICF approved 
by the IRB and signed and dated by the subject and the person who conducted the 
informed consent discussion.  The signature confirms that the consent is based on 
information that has been provided and all questions have been answered to the 
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investigator for possible inspection by Regulatory Authorities and/or the sponsor and 
Regulatory Compliance persons.  The subject should receive a copy of the signed and 
dated written ICF and any other written information provided to the subjects, and should 
receive copies of any signed and dated ICF updates and any amendments to the written 
information provided to subjects. 
14.4  Subject Confidentiality 
Drug abuse and HCV infection require special sensitivity to issues of confidentiality. 
Patient confidentiality will be carefully protected. Study records will be kept in locked 
files and/or within limited access, code-protected computer files, available only to the 
investigators and study personnel. Patient identifiers will be removed and only initials 
and code numbers will be present on study records and documents.   
Protection of subject identity. Subjects will not be identified by name on any written 
or verbal reports. They will only be identified by a study ID number. Subjects’ names 
and study ID numbers will be kept in a password protected file in the research office 
of the Principal Investigator. Access will only be allowed to the senior project staff. 
The link between the subject and the research study will be destroyed 5 years after 
the end of the study.  All research records will be kept in a secure area and locked in 
a file cabinet in the research office of the PI. 
Protection of confidentiality 
To ensure that confidentiality is maintained, the following procedures will be 
instituted: 
• 
Medical staff will not have access to trial survey data, except under specific 
circumstances.  Specifically, report of active suicidal ideation will trigger 
immediate clinical evaluation by an on-site physician, physician assistant, or 
psychiatrist, based on the psychiatric distress protocol. Consents will be 
obtained from participants for disclosure of research information under 
these circumstances prior to their enrollment in the proposed trial.  
• 
The Research Assistant will complete the Collaborative Institutional 
Training Initiative (CITI) computer-based training program, which includes 
a specific module on issues of privacy and confidentiality. 
• 
A system will be used that prevents linking sensitive material to participants’ 
personal identifiers. All documents with participant identifiers, including 
consent forms, medical records and contact information, will be filed 
together. All documents that do not include identifying information or 
signatures will use participants’ study IDs rather than names and will be filed 

Q4 Protocol_PCORI 
 
Version 4.0 
 
 
21 MAY2019 
 
 
 
67 
 
together. All forms will contain either participants’ names or their study IDs, 
but not both. Data collection forms will include no identifiers other than a 
study ID code. There will only be one electronic document that links 
participants’ names to their study IDs, which will be password protected. 
• 
Study records will be stored on a password protected computer database 
and/or in locked file cabinets. 
• 
A federal Certificate of Confidentiality will be obtained by each site to protect 
participants’ sensitive information. 
• 
Phone messages left for participants to schedule research visits will not 
include personal identifying information or mention HCV or OAT  
• 
Publication or presentation of study results will not identify subjects by name. 

 
68 
 
15  Protocol Conduct 
The protocol will be conducted in compliance with federal regulations and the principles 
of Good Clinical Practice (GCP), including the following processes: 
• Protocol registration, activation, and implementation; 
• Informed consent, screening, and enrollment; 
• Clinical and safety assessments; 
• Safety monitoring and reporting; 
• Data collection and documentation; 
• Study follow-up and close-out; 
• Quality management; 
• Protocol monitoring and compliance; 
• Risk reduction counseling; and 
• Specimen collection, processing, and analysis. 
15.1 Record Confidentiality 
 
The investigators will maintain appropriate medical and research records for this trial, 
in compliance with ICH E6 GCP and regulatory and institutional requirements for the 
protection of confidentiality of subjects.  The study protocol, documentation, data and 
all other information generated will be held in strict confidence.  No information 
concerning the study, or the data will be released to any unauthorized third party, 
without prior written approval of the sponsor.  The principal investigators from each site 
will obtain a Certificate of Confidentiality from NIH to further protect subjects’ privacy. 
15.2  Data Collection, Handling, Source Documents 
Clinical research data will be collected as described in detail in Section 12. 
 
Standard GCP will be followed to ensure accurate, reliable, and consistent data 
collection.  Each participating site will maintain appropriate medical and research 
records for this trial, in compliance with ICH, GCP, regulatory, and institutional 
requirements for the protection of confidentiality of subjects. 

 
69 
 
15.3  Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical 
Practice (GCP), or Manual of Procedures (MOP) requirements.  The noncompliance 
may be on the part of the subject, the investigator, or the study site staff.  As a result of 
deviations, corrective actions are to be developed by the site and implemented 
promptly.   
 
These practices are consistent with Good Clinical Practice: 
4.5  
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1  
Quality Assurance and Quality Control, section 5.1.1 
5.20 
Noncompliance, sections 5.20.1 and 5.20.2d 
 
It is the responsibility of the site to use continuous vigilance to identify and report 
deviations per site IRB guidelines.   
 
All deviations from the protocol must be addressed in study source documents.  A 
completed copy of the Protocol Deviation (PD) Form must be maintained in the 
Regulatory File.  Protocol deviations must be submitted to the local IRB/IEC per their 
guidelines.  The site PI/study staff is responsible for knowing and adhering to their IRB 
requirements. 
15.4  Recruitment and Retention of Study Subjects 
The research staff will recruit potential participants from OTPs and community health 
centers and by referral from other community-based organizations. Recruitment will be 
active (medical providers and community outreach workers will inform HCV-infected 
patients about the study) and passive (clinic counseling staff, word of mouth, and fliers 
in clinic waiting areas).  For active recruitment medical providers and community 
outreach workers will inform HCV-infected patients about the study and assist with 
referral, and for passive recruitment subjects will self-refer.  Self-referred subjects will   
meet with their provider to determine whether starting HCV treatment is appropriate.   
Potential study participants will demographically and clinically reflect those most 
impacted by chronic hepatitis C and will be identified in a number of ways: community 
outreach including posters and written materials at recruitment sites and at other key 
locations in the community; by self-referral; by referral from local patient stakeholders 
such needle exchange programs; by referral from staff at OAT treatment centers, 
participating clinics or other medical or mental health caregivers; and by direct approach 
from a site Research Assistant / Patient Navigator (RA/PN).   

 
70 
 
Retention will be enhanced using multiple methods including but not restricted to: 1) 
conducting interviews with participants at research visits; 2) reminders using text 
messaging (SMS), written reminders and phone calls; and 3) reimbursement for 
research assessments.   
To assist retention, at enrollment and subsequent visits, the following information will 
be collected: 1) participants’ address, phone number, and social security number (if 
available and required by local sites); 2) contact information of family or friends; 3) 
contact information of participants’ community-based organizations; 4) contact 
information of case managers; 5) locations where participants “hang out”; and 6) 
participants' social media presence and willingness to be contacted by person-to-
person messaging on this medium. 
15.5 
 Study Subject Reimbursement 
Participants will receive $20 for each of 17 research visits ($20/visit, 17 research visits, 
$340 total) and an additional $5 for returning one-week electronic blister packs or $10 
for two-week (12 weeks, $5/week, $60 total) for a total of $400 per participant. This 
level of reimbursement is standard for clinical research conducted in our setting, and is 
not considered undue inducement for research participation. 
 
 
 
 
 
 
 
 
 

 
71 
 
16  Publication Policy 
 
The project is designed based on the dissemination priorities and needs for the sites, 
patients and stakeholders involved in its planning and implementation.  During the 
project period, patient partners and other stakeholders will have an active role in 
developing appropriate material and communicating and disseminating information 
about the project and its activities and reporting to their various constituencies about 
progress made towards meeting the goals and objectives of the study. Project staff will 
work with each to ensure that customized material is produced to ensure that 
communication is understandable and usable by each constituency. Patient partners 
will be involved in outreach to the local community through both the participating sites 
in each city and local media as well as through other community connections to PWID 
in neighboring cities to make other patients aware of study opportunities to receive 
treatment for HCV. As progress is made in generating findings, patient and stakeholder 
partners will be invited to author or co-author articles and opinion pieces describing the 
study findings for publication in local press and other media outlets. Other advocacy 
and public health stakeholders will facilitate disseminating study findings based on the 
communities and organizations they represent. This will be accomplished by sharing 
study findings to their membership and to their funders through newsletters, website 
postings, presentations at meetings and conferences, as well as through more formal 
professional publications.  The study has a publication policy and procedure document.   
 
 
 

 
72 
 
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101. R FCaH-M. Evaluating the quality of HCV care and treatment in primary care 
settings. In: AASLD. Washington, DC; 2013. 
102. Bruggmann P, Litwin AH. Models of care for the management of hepatitis C virus 
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Suppl 2:S56-61. 
103. Ramirez AG, Turner BJ. The role of peer patients in chronic disease 
management. Ann Intern Med 2010,153:544-545. 
104. Leof A GM, Thielke A, et al. Sofosbuvir for the treatment of hepatitis C and 
evaluation of the 2014 AASLD treatment guidelines. In. Portland, OR: Center for 
Evidence-based Policy, Oregon Health & Science University. 
105. Chesney MA, Ickovics JR, Chambers DB, Gifford AL, Neidig J, Zwickl B, et al. 
Self-reported adherence to antiretroviral medications among participants in HIV 
clinical trials: the AACTG adherence instruments. Patient Care Committee & 
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Clinical Trials Group (AACTG). AIDS Care 2000,12:255-266. 
106. Kalichman SC, Amaral CM, Swetzes C, Jones M, Macy R, Kalichman MO, et al. 
A simple single-item rating scale to measure medication adherence: further 
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107. Glasgow R. What types of evidence are most needed to advance behavioral 
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80 
 
Appendix One: Patient Navigator Tasks 
Patients who are HCV Antibody-positive (Linkage to Care) 
1) Navigate patients to on-site viral load testing 
2) Follow-up with all patients for post-test counseling 
3) Attempt to contact patients lost to follow-up 
4) Provide basic HCV-related education:  natural history, prevention of 
transmission, evaluation, and treatment 
 
Patients who have chronic hepatitis C (Care Coordination: Case 
Management, Education, Outreach, Collaboration, Logistical Support, and 
Other) 
1) Schedule patients for first HCV evaluation with HCV specialist (within one week) 
2) Schedule patients for follow-up evaluation and treatment meetings 
3) Work closely with HCV primary care champion to ensure patients are engaged 
with HCV care (e.g. weekly HCV clinic and preparation of charts for weekly 
visits) 
4) Promote adherence to all HCV-related appointments 
5) Schedule patients for all off-site liver clinic appointments as appropriate (e.g. 
decompensated cirrhosis; other liver disease; transplant evaluation) 
6) Remind patients one day prior to appointment 
7) Check to see if patients adhered to appointment 
8) Check in with patients after seeing HCV primary care champion: 
a) 
see how patient is doing (build rapport) 
b) 
ask patient to clarify next steps 
c) 
schedule follow-up appointments in real-time (e.g. ultrasound) 
d) 
elicit fears and concerns 
e) 
answer questions 
9) Identify barriers and facilitators to care and provide motivational interviewing 
to assist patients in overcoming barriers. 
10) Motivate patients to continue to move through the HCV cascade of care 
11) Work with any insurance issues and refer to Medicaid office or social 
worker as appropriate 
12) Prior authorizations for all HCV medications, adjuvant medications (e.g. zofran 
for nausea), and other related-procedures (e.g. MRI for liver imaging) 
13) Work with Medicaid managed care plans and mail order pharmacies for 
ordering and delivering HCV­ related medications 
14) Work with pharmacist: dispensing medications, checking in regarding 
patient adherence to medications; counseling with patients; and drug-drug 
interactions 
15) Provide adherence counseling and assist with side effect management   for 
patients on treatment 
16) Pre-treatment readiness assessments to identify potential barriers to treatment 
17) Make all HCV-related appointments and ensure follow-up: 

 
81 
 
a) Ultrasound and other imaging 
b) Liver biopsy if necessary 
c) Other off-site specialists appointments (e.g.dermatology) 
d) Upper endoscopy to screen for varices 
e) Transplant  evaluation 
18) Provide HCV education (evaluation, treatment, adherence, and side effect 
management) including formal brief educational intervention with power-
point slides 
19) Conduct rapid HCV testing at outreach sites and navigate new HCV antibody 
+ patients to clinic for follow-up viral load testing, primary care, and HCV-
related care. 
20) Organize and administer any program incentives (e.g. metro cards) 
21) Collect all PN-related data and input in timely manner within databases 
22) Maintain all PN-related databases 
23) Provide weekly updates to HCV team meeting for problem solving and QI 
24) Attend local HERO team meetings 
25) Report to Project Director 
26) Attend national HERO PN team meetings via conference calls 
27) Work at multiple clinics in various locations throughout the week 
28) Work closely with community to develop and maintain HCV-related networks 
(e.g. syringe exchange program and CBOs) 
29) Work with HCV peers  
30) Obtain outside medical records as needed 
31) Provide administrate support to the Project Inspire team 
32) Send letter and/or  telegram as needed for patients lost to follow-up 
33) Work with Montefiore/NYDOH teams for exchange of data 
34) Other duties as needed 

 
82 
 
Appendix 2: Check Hep C Patient Navigation Program – Workflow for Project HERO 

 
83 
 
Appendix Three:  Study Visit Table 
Table 3: Study Visit Table 
 
 
Pre-Treatment 
Treatment Visits 
Post-Treatment Visits 
Research Visit Activities 
Time (Minutes) 
Pre-Screening 
Enrollment 
Baseline 
Week 4, ± 1wk 
Week 8, ± 1 wk 
Week 12, ± 1 wk 
Week 24, ± 2 wks 
Week 36, ± 2 wks 
Week 48, ± 2 wks 
Week 60, ± 2 wks 
Week 72, ± 2 wks 
Week 84± 2 wks 
Week 96, ± 2 wks 
Week 108, ± 2 wks 
Week 120, ± 2 wks 
Week 132, ± 2 wks 
Week 144, ± 2 wks 
Week 156, ± 2 wks 
Week 168± 2 wks 
Visit Number 
  
  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
TIME (in min) 
  
  
40 
70 
37 
22 
90 
70 
20 
65 
15 
45 
15 
25 
15 
90 
15 
25 
15 
90 
Release of Information 
  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
Informed Consent 
30 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
Randomization 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
Instruments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
Socio-Demographic Survey 
10 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
Short Socio-Demographic Survey 
5 
  
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Behavioral Risk Assessment 
10 
  
  
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Depression (PHQ-9) 
5 
  
  
X 
  
  
X 
X 
  
X 
  
  
  
  
  
X 
  
  
  
X 
Anxiety (GAD-7) 
4 
  
  
X 
  
  
X 
X 
  
X 
  
  
  
  
  
X 
  
  
  
X 
AUDIT-C 
3 
  
  
X 
  
  
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Modified ASI – baseline 
10 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Modified ASI – follow-up 
5 
  
  
  
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Substance Use Treatment 
3 
  
  
X 
X 
X 
X 
X 
  
X 
  
  
  
  
  
X 
  
  
  
X 
EQ-5D 
8 
  
  
X 
  
  
X 
X 
  
X 
  
  
  
  
  
X 
  
  
  
X 
Visual Analogue Scale 
(Adherence) 
2 
  
  
  
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical Outcomes Social Support 
Scale 
5 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
X 
 
 
 
X 

 
84 
 
 
 
Pre-Treatment 
Treatment Visits 
Post-Treatment Visits 
Research Visit Activities 
Time (Minutes) 
Pre-Screening 
Enrollment 
Baseline 
Week 4, ± 1wk 
Week 8, ± 1 wk 
Week 12, ± 1 wk 
Week 24, ± 2 wks 
Week 36, ± 2 wks 
Week 48, ± 2 wks 
Week 60, ± 2 wks 
Week 72, ± 2 wks 
Week 84± 2 wks 
Week 96, ± 2 wks 
Week 108, ± 2 wks 
Week 120, ± 2 wks 
Week 132, ± 2 wks 
Week 144, ± 2 wks 
Week 156, ± 2 wks 
Week 168± 2 wks 
Brief Revised Working Alliance  
(PN arm only) 
5 
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
 
 
 
  
Stigma Scale 
5 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
Shame Scale 
2 
  
  
X 
  
  
  
  
X 
  
  
  
  
  
  
X 
 
 
 
X 
Health Efficacy Scale 
3 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
  
  
 
 
 
 

 
85 
 
 
 
Pre-Treatment 
Treatment Visits 
Post-Treatment Visits 
Research Visit Activities 
Time (Minutes) 
Pre-Screening 
Enrollment 
Baseline 
Week 4, ± 1wk 
Week 8, ± 1 wk 
Week 12, ± 1 wk 
Week 24, ± 2 wks 
Week 36, ± 2 wks 
Week 48, ± 2 wks 
Week 60, ± 2 wks 
Week 72, ± 2 wks 
Week 84± 2 wks 
Week 96, ± 2 wks 
Week 108, ± 2 wks 
Week 120, ± 2 wks 
Week 132, ± 2 wks 
Week 144, ± 2 wks 
Week 156, ± 2 wks 
Week 168± 2 wks 
Labs 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
HCV Antibody 
  
MC 
  
MC 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
HCV viremia 
  
MC 
  
MC 
MC 
MC 
MC 
MC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCV Genotype/subtype 
  
  
  
MC 
MC 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
HIV Test 
  
  
  
MC 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
HIV Viral Load* 
  
  
  
MC 
MC 
MC 
MC 
  
  
  
  
  
  
  
  
  
 
 
 
 
HIV CD4* 
  
  
  
MC 
MC 
MC 
MC 
  
  
  
  
  
  
  
  
  
 
 
 
 
AST/ALT/Platelets/ 
  
MC 
  
MC 
MC 
MC 
MC 
MC 
  
  
  
  
  
  
  
  
 
 
 
 
FIB-4 Calculation 
 
 
 
 
Total Bilirubin 
  
  
  
MC 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
Albumin 
  
  
  
MC 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
Prothrombin time 
  
  
  
MC 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
FibroSure/Fibroscan/Liver biopsy 
  
  
  
MC 
MC** 
MC** 
  
  
  
  
  
  
  
  
  
  
 
 
 
 
Imaging study** 
  
MC 
  
MC 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
Child-Pugh Score (exclude B,C) 
  
  
  
MC 
MC 
MC 
MC 
  
  
  
  
  
  
  
  
  
 
 
 
 
Pregnancy test* 
  
  
  
MC 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
Archiving sample 
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCV GenoSure NS5A/NS5B 
Assay* 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
 
 
 
 
HBV panel 
  
  
  
MC 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
HAV Status 
  
  
  
MC 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
Urine toxicology POC assay 
  
  
  
X 
X 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
 
X 
 
X 
MC = Medical Chart                 * If applicable 
 
**If available 

 
86 
 
Appendix Four: Implementation Study 
 
Implementation Evaluation--Protocol 
 
We are proposing to add an implementation evaluation to the approved study. We 
propose to examine 1) implementation ‘outcomes’—how well the program was 
implemented across the eight study sites; and 2) causal factors affecting 
implementation, i.e. barriers and facilitators. 
 
Implementation outcome data that will be collected in this evaluation include: data on 
program acceptability, feasibility, dose, and fidelity. Acceptability to patients will be 
assessed using a single patient satisfaction question administered at the F12 interview, 
and through a qualitative interview with a convenience sample of approximately 40 (the 
number of interviews depends on data saturation, and may be as many as 60) patients. 
Feasibility will be assessed through examination of recruitment and retention records 
(assessed through study databases); and by an examination of the execution of work 
plans for each of the 8 study sites. Intervention ‘dose’ and fidelity will be assessed by 
examining the degree to which treatment plans are adhered to (collected through 
administrative data); and by visit logs created by patient navigators indicating the 
degree to which the patient received the planned elements of navigation. 
 
Barriers and facilitators to implementation will be assessed through interviews and 
questionnaires collected with key stakeholders in the study, including site leaders, site 
staff, and patients. We will use the following methods.  
 
1. Site leader interviews. We will conduct between 2 and 5 telephone interviews with 
site leaders at each site over the next 5 years. Site PIs will assist the team in identifying 
appropriate clinical leaders. Telephone interviews are expected to last approximately 
15-30 minutes and will be recorded and transcribed. Questions will focus on relevant 
topics such as clinical site research experience, current on site HepC treatment, DOT, 
PN, local resources, larger societal influences, perceptions of study burden and 
feasibility, etc. Site leaders will be approached through their local PIs and interviews will 
be conducted by the Bronx Qualitative Team members. In an initial phone call we will 
explain the purpose of the study. If participants are willing to participate they will engage 
in an informed oral consent by telephone. Specifics of these interviews may be found in 
Table 1.  
 
2. Grumbach Workplace Environment Questionnaire. This brief questionnaire 
addresses the workplace environment in primary care. It was designed to measure staff 
perceptions of teamwork and adaptability to take on practice improvements and 
innovations.  The questionnaire will also include a few questions about attitudes towards 
HepC tx for active PWID. The questionnaire will be administered to relevant staff of the 
clinical sites—including nursing, physicians, support staff, front desk, etc. Participants 
will be approached at the meeting or in their workplaces and requested to fill out these 

 
87 
 
forms anonymously.  The Project Director will collect the questionnaires during site 
visits. A waiver of consent is requested for this questionnaire.  
 
3. Working Alliance Questionnaire. This questionnaire will be administered at the F12 
follow up research visit to all patients in the PN arm of the study. This questionnaire 
assesses the quality of the relationship between the patient and the front line 
treatment provider. This questionnaire will be included in the interview packet. No 
separate consent process will be needed.  
 
4. Staff Interviews. These 10-30 minute qualitative interviews will focus on staff 
experiences with the HERO project, levels of engagement and enthusiasm, and 
perceptions of structural/institutional as well as patient level barriers to program 
implementation. Relevant staff members will be identified through discussions with Site 
Principal Investigators or local Clinical Site leaders. We will conduct these interviews 
with identified staff (number is currently unknown, depends on the site, but may be up to 
6 staff members per site, or 48 overall). In an initial phone call, we will explain the 
purpose of the study. If participants are willing to participate they will engage in an 
informed oral consent by telephone. These interviews will be conducted at various time 
points with different groups of staff. Specifics may be found in the tables. 
 
5. Patient Satisfaction, Treatment Experiences and Barriers Interviews. These 30 
minute qualitative interviews will examine patient experiences, characteristics, and 
perceptions associated with varied treatment outcomes. They will be administered to 
patients in various groups chosen for their contrast on key outcomes: patients who 
successfully adhere to treatment (n<=10) vs. those who do not (n<=10); patients who 
complete treatment (n<=10) vs. those who do not (n<=10); and patients who remain 
virus free (n<=10) vs. those who do not (n<=10) for a total of n<=60. The total number 
depends on data saturation achieved through the analysis: we anticipate that at least 8 
patients in each group or approximately 1 per site will be recruited for a total of at least 
6 per site. A $15 incentive will be offered to participate in the phone interviews. If 
participants are willing to participate they will engage in an informed oral consent by 
telephone. 
 
 

 
88 
 
TABLE I: DATA COLLECTION PLAN FOR BARRIERS/FACILITATORS STUDY 
 Pre-Implementation 
Purpose  
Data Collection Instrument  
Respondent’s 
Responsible 
To understand 
relevant 
experiences and 
characteristics at 
HERO clinical sites 
that may impact 
project roll out 
Site Leader Interviews. 15-30 minute telephone 
interviews. Questions will focus on relevant topics 
such as site research experience, current on site 
HepC treatment, DOT, PN, local resources, 
perceptions of study burden and feasibility, etc...    
Clinical site medical 
directors or other 
stakeholders determined 
through discussion with 
PIs 
 
Bronx 
Implementation 
Team 
 
To understand 
characteristics of 
the work 
environment that 
may impact 
Implementation 
from the point of 
view of clinical and 
admin staff 
Grumbach Workplace Environment 
Questionnaire. This brief questionnaire addresses 
the workplace environment in primary care. It was 
designed to measure staff perceptions of teamwork 
and adaptability to take on practice improvements 
and innovations.   The questionnaire will also 
include a few questions about attitudes towards 
HepC tx for active PWID.   
Relevant clinical and 
administrative staff of 
the sites—including 
nursing, physicians, 
support staff, front desk, 
etc. To be administered 
during  staff meeting or 
in the clinic/health center 
Site RAs 
Early Implementation Period (3-6 months into project period) 
Purpose  
Data Collection Instrument  
Respondent’s 
Responsible 
To understand 
perceptions of 
HERO among clinic 
site staff 
Brief staff interviews. Open ended questions 
focusing on perceived relevance, burden, 
feasibility, and complexity of HERO will be 
conducted with relevant staff identified through 
discussions with PI or site leaders.  
Relevant providers  and 
admin staff 
Bronx Project 
Coordinator @ 
Site Visit 
12 Week Follow Up Patient Interviews 
Purpose  
Data Collection Instrument  
Respondent’s 
Responsible 
To understand the quality 
of HERO staff/patient 
interactions 
Working Alliance Questionnaire 
(Administered at F12 Interview) 
All Patients in the PN 
Arm 
Site F12 Inter-
viewers 
 
 

 
89 
 
Post Implementation –Timeframe TBD 
Purpose  
Data Collection Instrument  
Respondents 
Responsible 
To understand site 
leaders perceptions of 
the program and 
barriers/facilitators 
Site Leader Interviews. A 20 minute telephone 
interview. Questions will focus on site leader’s 
perceptions of the project—barriers, facilitators, 
benefits, burden, surprises. The interview will also 
examine structural/environmental factors such as 
local politics, insurance regulatory environment, 
stigma, and similar issues potentially affecting 
sustainability and replication-- 
Relevant site 
leaders as 
described above 
Bronx 
Implementation 
Team 
To understand frontline 
worker experiences, 
characteristics, and 
perceptions of 
implementation barriers 
and facilitators to DOT 
and PN Interventions  
Frontline Worker Interviews. This 30 minute 
qualitative interview will focus on frontline worker 
experiences with the HERO project, level of 
engagement and enthusiasm, and perceptions of 
structural/institutional as well as patient level 
barriers to program implementation. 
Frontline workers 
as many as 
feasible 
Bronx 
Implementation 
Team 
To understand patient 
level barriers and 
facilitators to successful 
treatment from patient’s 
viewpoint and understand 
experiences with 
treatment 
Patient Treatment Experiences and Barriers to 
treatment interviews.* This 30 minute qualitative 
interview will examine patient experiences, 
characteristics, and perceptions associated with 
varied treatment outcomes 
Purposive 
sampling from 
various outcome 
groups 
Bronx 
Implementation  
Team 

 
90 
 
TABLE II: DATA COLLECTION PLAN FOR ASSESSING IMPLEMENTATION OUTCOMES 
 
Variables 
Data Collection  & Source 
Responsible 
Method of Date Analysis 
Responsible:  
Acceptability of Intervention 
Pt. Satisfaction w TX 
1 TX Satisfaction Question @ 
F12 
Site RA 
Quantitative 
Site RA 
Positive/Negative 
Experiences with TX 
Brief Treatment Experiences 
Interview @ various time points 
Site RA 
Structured, ‘Quantitated’ 
Thematic Analysis w/ 
Qual Data Analysis 
Program 
Bronx Implementation Team 
Feasibility of Intervention 
Recruitment 
Milestones 
Research Database 
Site staff 
Quantitative 
Local/New Mexico 
Retention in 
Intervention 
Research Database 
Site Staff 
Quantitative 
Local/New Mexico 
Execution of Work 
Plans 
Work Plans for Each Arm with 
Milestones and Dates 
Achieved, i 
Bronx Project 
Director 
Qualitative 
Bronx Implementation Team 
Intervention Dose 
Directly Observed TX  
 
 
 
 
# Observed Doses/ 
#Planned Observed 
Doses 
 
Nurse calendar/log or patient 
log--TBD 
Frontline Staff 
Quantitative 
Local/NM 
Patient Navigation 
 
 
 
 
2 in person meetings/  
3 Follow up calls (TBD) 
Case Notes or Other Records—
TBD with DOH Team 
Frontline staff 
Qualitative assessment 
& quant tabulation 
Site Staff Supervisor 
Fidelity of PN Intervention 
To Be Discussed with DOH PN Team  
Care Plan Completed 
Navigation Care Plan  
Frontline staff 
Qualitative assessment, 
tabulation 
PN Records 
Initial Medical Evaluation 
Completed 
Case Notes 
Frontline staff 
Qualitative assessment, 
tabulation 
PN Records 
Referrals Made 
Case Notes 
Frontline staff 
Qualitative assessment, 
tabulation 
PN Records 
Referrals Followed up 
Case Notes 
Frontline staff 
Qualitative assessment, 
tabulation 
PN Records 
Education Sessions #1 & 
2 Provided 
Attendance records/group, 
Case notes/ind. # minutes 
Frontline staff 
Tabulation 
PN Records 

 
91 
 
Consent  
Data Collection Instrument s 
Site leader oral consent 
 
• 
Site Leader Interview 
• 
Site Leader guide post implementation 
Staff Oral Consent 
 
• 
Brief Staff interview 
• 
Frontline Staff Interview Post Implementation 
Patient Oral Consent 
• 
Brief Patient Experience Interview 
• 
Patient Treatment Experiences and Barriers/Facilitators to 
Treatment 
Request waiver of consent—anonymous survey on 
worksite culture 
• 
Grumbach Questionnaire 
Regular study consent form—to be embedded in 12-
Week Follow up Interview  
• 
Working Alliance Questionnaire 

 
92