Phase 1 Pharmacokinetic Trial of Sofosbuvir/Velpatasvir in Pregnant Women With Chronic Hepatitis C Virus Infection
Phase: PHASE1
Conditions: Hepatitis C, Chronic
Sponsor: Catherine Anne Chappell

 
SOF/VEL in Pregnancy, Version 5.0 
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December 2 , 2020 
 
 
Phase 1 Pharmacokinetic Trial of Sofosbuvir/Velpatasvir in Pregnant Women with 
Chronic Hepatitis C Virus Infection 
 
 
 
Protocol version 5.0 
 
 
Funding Agencies: 
Gilead Sciences IN-US-342-5634 
 
National Institutes of Health: K12HD043441 
Building Interdisciplinary Research Careers in Women’s Health in Pittsburgh  
 
National Institutes of Health:  1R21 
Eunice Kennedy Shriver National Institute of Child Health & Human Development  
 
Pennsylvania Department of Health 
 
 
IND #: 146896 
 
IND Sponsor:  
Catherine Chappell, MD, MS 
 
Protocol Chair:  
Catherine Chappell, MD, MS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Phase 1 Pharmacokinetic Trial of Sofosbuvir/Velpatasvir in Pregnant Women 
with Chronic Hepatitis C Virus Infection 
 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .............................................................................. 4 
LIST OF ABBREVIATIONS AND ACRONYMS .......................................................... 5 
PROTOCOL TEAM ROSTER .................................................................................... 6 
PROTOCOL SUMMARY ............................................................................................ 7 
1 
KEY ROLES ............................................................................................... 11 
1.1 
Protocol Identification ................................................................................. 11 
1.2 
Funders, Sponsor and Monitor Identification.............................................. 11 
1.3 
Clinical Laboratories .................................................................................. 12 
2 
INTRODUCTION ....................................................................................... 13 
2.1 
Chronic Hepatitis C Infection in Pregnancy ................................................ 13 
2.2 
Rationale .................................................................................................... 14 
2.3 
SOF/VEL Fixed Dose Combination ............................................................ 17 
2.4 
Clinical Studies .......................................................................................... 18 
2.5 
Rationale for Study Design ........................................................................ 20 
3 
OBJECTIVES ............................................................................................. 21 
3.1 
Primary Objective ....................................................................................... 21 
3.2 
Secondary Objectives ................................................................................ 21 
4 
STUDY DESIGN ........................................................................................ 22 
4.1 
Identification of Study Design ..................................................................... 22 
4.2 
Summary of Major Endpoints ..................................................................... 22 
4.3 
Description of Study Population ................................................................. 23 
4.4 
Time to Complete Accrual .......................................................................... 23 
4.5 
Expected Duration of Participation ............................................................. 23 
5 
STUDY POPULATION ............................................................................... 24 
5.1 
Selection of the Study Population .............................................................. 24 
5.2 
Inclusion Criteria ........................................................................................ 25 
5.3 
Exclusion Criteria ....................................................................................... 25 
6 
STUDY MEDICATION ............................................................................... 27 
6.1 
Regimen..................................................................................................... 27 
6.2 
Administration ............................................................................................ 27 
6.3 
Supply and Accountability .......................................................................... 27 
6.4 
Concomitant Medications ........................................................................... 28 
7 
STUDY PROCEDURES ............................................................................ 29 
7.1 
Pre-screening ............................................................................................. 29 
7.2 
Visit 1- Screening (V1) ............................................................................... 29 
7.3 
Visit 2- Enrollment (V2) .............................................................................. 31 
7.4 
Follow-up Visits .......................................................................................... 31 
7.5 
Follow-up Procedures for Participants Who Permanently Discontinue Study 
Medication.................................................................................................. 36 
7.6 
Pharmacokinetics ....................................................................................... 37 

 
 
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7.7 
Adherence Counseling and Assessment ................................................... 38 
7.8 
In Depth Interviews and Qualitative Analysis ............................................. 38 
7.9 
Clinical Evaluations and Procedures .......................................................... 39 
7.10 
Laboratory Evaluations .............................................................................. 39 
7.11 
Specimen Collection and Processing ......................................................... 40 
7.12 
Biohazard Containment ............................................................................. 40 
8 
ASSESSMENT OF SAFETY ...................................................................... 41 
8.1 
Safety Monitoring ....................................................................................... 41 
8.2 
Clinical Data and Safety Review ................................................................ 41 
8.3 
Adverse Events Definitions and Reporting Requirements ......................... 42 
8.4 
Expedited Adverse Event Reporting Requirements ................................... 44 
8.5 
Regulatory Requirements .......................................................................... 44 
8.6 
Social Harms Reporting ............................................................................. 44 
9 
CLINICAL MANAGEMENT ........................................................................ 44 
9.1 
Grading System ......................................................................................... 45 
9.2 
Dose Modification Instructions ................................................................... 45 
9.3 
General Criteria for Permanent Discontinuation of Study Medication ........ 45 
9.4 
Permanent Discontinuation in Response to Adverse Events ..................... 45 
9.5 
HIV-1 Infection ........................................................................................... 46 
9.6 
Criteria for Early Termination of Study Participation .................................. 46 
10 
STATISTICAL CONSIDERATIONS ........................................................... 46 
10.1 
Overview and Summary of Design ............................................................. 46 
10.2 
Study Endpoints ......................................................................................... 46 
10.3 
Sample Size ............................................................................................... 48 
10.4 
Participant Accrual and Retention .............................................................. 48 
10.5 
Data Analysis ............................................................................................. 48 
11 
DATA HANDLING AND RECORDKEEPING ............................................. 49 
11.1 
Data Management Responsibilities ............................................................ 49 
11.2 
Source Documents and Access to Source Data/Documents ..................... 49 
11.3 
Quality Control and Quality Assurance ...................................................... 50 
12 
CLINICAL SITE MONITORING .................................................................. 50 
13 
HUMAN SUBJECTS PROTECTIONS ....................................................... 50 
13.1 
Institutional Review Boards ........................................................................ 51 
13.2 
Study Coordination .................................................................................... 51 
13.3 
Risk Benefit Statement .............................................................................. 51 
13.4 
Informed Consent Process......................................................................... 54 
13.5 
Participant Confidentiality........................................................................... 55 
13.6 
Special Populations ................................................................................... 55 
13.7 
Compensation ............................................................................................ 56 
13.8 
Communicable Disease Reporting ............................................................. 56 
13.9 
Access to HIV-related Care........................................................................ 56 
13.10 Study Discontinuation ................................................................................ 57 
14 
PUBLICATION POLICY ............................................................................. 57 
15 
APPENDICES ............................................................................................ 57 
APPENDIX I: SCHEDULE OF STUDY VISITS AND EVALUATIONS (Mother) ....... 58 
APPENDIX II: SCHEDULE OF STUDY VISITS AND EVALUATIONS (Infant) ........ 60 

 
 
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Phase 1 Pharmacokinetic Trial of Sofosbuvir/Velpatasvir in Pregnant Women with 
Chronic Hepatitis C Virus Infection 
 
 
Protocol Signature Page 
 
 
I will conduct the study in accordance with the provisions of this protocol and all 
applicable protocol-related documents. I agree to conduct this study in compliance 
with United States (US) Health and Human Service regulations (45 CFR 46); 
applicable U.S. Food and Drug Administration regulations; standards of the 
International Conference on Harmonization Guideline for Good Clinical Practice 
(E6); Institutional Review Board/Ethics Committee determinations; all applicable in-
country, state, and local laws and regulations; and other applicable requirements 15 
(e.g., US National Institutes of Health, Division of AIDS) and institutional policies. 
 
 
 
 
________________________________  
___________________________ 
Catherine Chappell, MD, MS                    
 
 
Date 
Protocol Chair/Principal Investigator 
University of Pittsburgh 
UPMC Magee-Womens Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Phase 1 Pharmacokinetic Trial of Sofosbuvir/Velpatasvir in Pregnant Women 
with Chronic Hepatitis C Virus Infection 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
ALT 
 
 
Alanine transaminase 
AST  
 
Aspartate transaminase 
AUC  
 
Area under the curve 
DBS  
 
Dried blood spot 
DAIDS  
 
Division of AIDS 
DHHS  
 
Department of Health and Human Services 
DNA   
 
deoxyribonucleic acid 
DSMB  
 
Data and Safety Monitoring Board 
EAE   
 
Expedited adverse event 
FDA   
 
Food and Drug Administration 
GCLP  
 
Good Clinical Laboratory Practices 
GCP   
 
Good Clinical Practices 
HBsAg 
 
Hepatitis B surface antigen 
HBV  
 
Hepatitis B Virus 
HCV  
 
Hepatitis C Virus 
HIV  
 
 
Human immunodeficiency virus 
IDI 
 
 
In-depth Interview 
INR 
 
 
International normalized ratio 
IoR  
 
 
Investigator of Record 
IRB   
 
Institutional Review Board 
ISR   
 
Interim Study Review 
VEL 
 
 
Velpatasvir 
SOF/VEL 
 
Sofosbuvir/Velpatasvir  
mL  
 
 
Milliliter 
MWH  
 
Magee-Womens Hospital 
MWRI  
 
Magee-Womens Research Institute 
NIAID  
 
National Institute of Allergy and Infectious Disease 
NIH   
 
National Institutes of Health 
OHRP  
 
Office of Human Research Protections 
PBMC  
 
Peripheral Blood Mononuclear Cell 
PK 
 
 
Pharmacokinetic 
PoR  
 
Pharmacist of Record 
PTID   
 
Participant identification number 
RNA   
 
Ribonucleic acid 
SAE   
 
Serious adverse event 
SOF  
 
Sofosbuvir 
SOP   
 
Standard operating procedure(s) 
SSP   
 
Study-specific Procedures 
UPMC 
 
University of Pittsburgh Medical Center 

 
 
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Phase 1 Pharmacokinetic Trial of Sofosbuvir/Velpatasvir in Pregnant Women 
with Chronic Hepatitis C Virus Infection 
PROTOCOL TEAM ROSTER 
University of Pittsburgh Study Team 
Catherine Chappell, MD, MSc 
UPMC Magee-Womens Hospital  
300 Halket Street 
Pittsburgh, PA 15213 USA 
Phone: 412-641-1809 
Fax: 412-641-1133 
Email: chappellca@upmc.edu 
 
Sharon Hillier, PhD 
Magee-Womens Research Institute  
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8933 
Fax: 412-641-6170 
Email: shillier@mail.magee.edu 
 
Elizabeth Krans, MD, MSc 
UPMC Magee-Womens Hospital  
300 Halket Street 
Pittsburgh, PA 15213 USA 
Phone: 412-641-4222 
Fax: 412-641-1133 
Email: kransee@mail.magee.edu 
 
Debra L. Bogen, MD, FAAP, FABM 
UPMC Children’s Hospital of Pittsburgh 
3414 Fifth Ave, CHOB 320 
Pittsburgh, PA 15213 
Office: (412) 692-6932 
Fax: (412) 692-5807 
Email: bogendl@upmc.edu 
 
University of Colorado 
Jennifer J. Kiser, PharmD, PhD 
Skaggs School of Pharmacy and Pharmaceutical Sciences 
12850 E. Montview Blvd, V20-C238 
Aurora, CO 80045 
Phone: (303) 724-6131 
Fax: (303) 724-6135 
Email: jennifer.kiser@cuanschutz.edu 
 
Gilead Sciences Study Team 
Sarjita Naik, PharmD, MPH 
Senior Medical Scientist, Liver Disease 
Gilead Medical Affairs 
Phone: (412)526-8541 
Email:  Sarjita.naik@gilead.com 
 
 

 
 
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Phase 1 Pharmacokinetic Trial of Velpatasvir/Sofosbuvir in Pregnant Women 
with Chronic Hepatitis C Virus Infection 
PROTOCOL SUMMARY 
 
Short Title: 
Treatment of Chronic Hepatitis C during Pregnancy with 
Sofosbuvir/Velpatasvir 
 
Clinical Phase: 
Phase 1 
 
IND Sponsor: 
Catherine Chappell, MD, MS 
 
Protocol Chair: 
Catherine Chappell, MD, MS 
 
Sample Size: 
10 women and their infants (participants who do not 
complete treatment or report less than 85% adherence will 
be replaced) 
 
Study Population: 
Pregnant women diagnosed with chronic hepatitis C 
infection that are between the ages of 18 and 39 and are 
between 14 + 0 and 22 + 6 weeks of gestation at Screening 
and infants born to the enrolled participants 
 
Study Site: 
UPMC Magee-Womens Hospital, Pittsburgh, PA 
 
Study Design: 
Single-site, single-arm pharmacokinetic study 
 
Study Duration: 
Approximately 28 weeks per maternal participant and one 
year of infant follow up. 
 
Study Medication: 
Fixed-dose combination tablet of Sofosbuvir 400 mg and 
Velpatasvir 100 mg (SOF/VEL) 
 
Study Regimen:  
Participants will take SOF/VEL one tablet once daily starting 
between 23 + 0 and 25 + 6 weeks of gestation for 12 weeks 
total. 
 
PK Sampling:  
Systemic exposure of both VEL and SOF (SOF and inactive 
metabolite GS-331007) and intracellular SOF (GS-461203) 
will be assessed by intensive pharmacokinetic sampling at 3 
time points:  
1) 3 weeks  7 days after first dose (intensive); 
2) 6 weeks  7 days after first dose (sparse);  
 
 
2)  9 weeks  7 days after first dose (intensive). 
 
 

 
 
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Primary Objective: 
• To compare the plasma pharmacokinetic (PK) parameters of SOF/VEL 
administered in pregnancy to available data from nonpregnant women. 
 
Primary Endpoint: 
• Systemic plasma exposures of both VEL and SOF (SOF and GS-331007) will 
be assessed: 
 3 weeks  7 days after first dose (intensive); 
 6 weeks  7 days after first dose (sparse); 
 9 weeks  7 days after first dose (intensive). 
 
Secondary Objectives: 
 
• To compare the intracellular concentrations of SOF (GS-461203) to available 
data from nonpregnant women. 
 
• To compare the protein binding (free-fraction) of VEL in pregnant women vs. 
available data in non-pregnant women. 
 
• To determine the rate of sustained viral response (SVR12), defined by 
undetectable hepatitis C virus twelve weeks after completion of SOF/VEL 
treatment for 12 weeks during pregnancy. 
 
• To evaluate the safety for the mother and for the neonate of hepatitis C 
treatment with SOF/VEL during pregnancy. 
 
 
Secondary Endpoints: 
 
• Intracellular SOF (GS-461203) concentrations will be assessed at:  
 3 weeks  7 days after first dose; 
 6 weeks  7 days after first dose; 
 9 weeks  7 days after first dose. 
 
• Free-fraction of VEL (protein binding) will be assessed at: 
 3 weeks  7 days after first dose; 
 9 weeks  7 days after first dose. 
 
• Sustained Viral Response (SVR12) 
• 
HCV RNA viral load will be assessed at 12 weeks after 
completion of SOF/VEL treatment.  An undetectable viral load 
will be considered a SVR12. 
 

 
 
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• Maternal Safety 
• 
Safety laboratory assessments of blood counts, creatinine, liver 
function, creatinine kinase and lipase will be measured at the 
PK1 and PK2 visits (approximately 3 weeks and 6 weeks after 
treatment initiation). 
• 
Pregnancy and delivery outcomes collected prospectively by 
participant interview and medical record review. 
 
 
• Neonate Safety 
• 
Major malformations, defined as structural abnormalities with 
medical, surgical or cosmetic importance; 
• 
Weight, length, and head circumference at birth, 8 weeks, 6 
months and 12 months; 
• 
HCV RNA viral load at birth (as available), 1 to 3 months, at 6 
months and then again at 12 months only if negative viral loads 
are not documented at 1 to 3 and 6 months; 
• 
Neurodevelopmental assessments at 6 months and 12 months. 
 
Exploratory Objectives: 
 
• 
Describe the perspectives of pregnant women with chronic HCV 
infection screening for a trial of antenatal sofosbuvir/velpatasvir 
(SOF/VEL) therapy 
 
Exploratory Endpoint: 
• 
In depth interviews conducted before enrollment in screened 
participants and after completion of treatment in enrolled 
participants. 
 
 
 

 
 
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Table 1: Study Visit Schedule 
 
 
Maternal Study Visit 
Target windows† 
V1 
Screening 
14+0 to 22+6 weeks gestation (weeks + days) 
V2* 
Enrollment 
23+0 to 25+6 weeks gestation (weeks + days) 
V3 
PK1: Intensive  
3 weeks  7 days after first dose of SOF/VEL 
V3a^ 
PK1a, 24hr sample 
24 hours  2 hours 
V4 
PK2:  Sparse 
6 weeks  7 days after first dose of SOF/VEL 
V5 
PK3:  Intensive 
9 weeks  7 days after first dose of SOF/VEL 
V5a^ 
PK3a, 24hr sample 
24 hours  2 hours 
V6 
End of Treatment 
Within 7 days of SOF/VEL completion 
Del** 
Delivery 
 
V7/iV1 
Post treatment  
12 weeks ± 4 days after completion of therapy 
 
Infant Study Visit 
Infant Age 
Del** 
Delivery 
Newborn 
V7/iV1 
Infant Visit 1 
8 weeks ± 6 weeks† 
iV2 
Infant Visit 2 
6 months ± 2 weeks† 
iV3 
Infant Visit 3 
12 months ± 2 weeks† 
†These are target windows.  If the participant cannot be seen within these windows then it 
will not be considered a protocol deviation.  
*Start SOF/VEL and continue for 12 weeks 
**The Delivery Visit will occur during admission for participants delivering at Magee-Womens 
Hospital.  Participants who deliver at an outside location will be contacted by phone as close 
to delivery as possible to complete the applicable Delivery Visit study procedures (i.e. 
questionnaire, update locator information, update medical history).  All participants, regardless 
of delivery location will undergo a chart review to obtain delivery outcomes/variables, as long 
as medical records can be obtained/reviewed.  
^Study visit is scheduled 24 hours from dosing at previous visit (V3 and V5); the 24 hour study 
visit and associated procedures must occur prior to dosing that day (V3a and V5a) 
 
 
 

 
 
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1 
KEY ROLES 
 
1.1 Protocol Identification 
 
Protocol Title:  
Phase 1 Pharmacokinetic Trial of 
Sofosbuvir/Velpatasvir in Pregnant Women 
with Chronic Hepatitis C Virus Infection   
 
Short Title: 
 
Treatment of Chronic Hepatitis C during Pregnancy 
with Sofosbuvir/Velpatasvir 
 
 
 
1.2 Funders, Sponsor and Monitor Identification 
 
Funding Agencies:  
 
NIH Building Interdisciplinary Research Careers in Women’s Health in Pittsburgh 
 
Gilead Sciences 
 
National Institutes of Health Eunice Kennedy Shriver National Institute of Child 
Health & Human Development 
 
 
Pennsylvania Department of Health 
 
 
IND Sponsor: Catherine Chappell, MD MSc 
 
 
 
 
  
 
Pharmaceutical Collaborator: Gilead Sciences 
 
 
 
 
 
 

 
 
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1.3 Laboratories 
 
Clinical Laboratory: 
UPMC Presbyterian Shadyside CPPUH 
 
UPMC Clinical Laboratory Building 
 
3477 Euler Way 
 
Pittsburgh, PA  15213 USA 
 
Pharmacokinetic Processing: 
Magee-Womens Research Institute  
 
Laboratory of Dr. Sharon Hillier 
 
204 Craft Ave, 5th floor 
 
Pittsburgh, PA 15213 
 
Pharmacokinetic Assays: 
University of Colorado 
 
 
Antiviral Pharmacology Laboratory 
 
 
12850 E Montview Blvd, V20-C238 
 
 
Aurora, CO  80045  
 
 
 
HCV Resistance Testing:  
Quest Diagnostics Incorporated 
1901 Sulphur Spring Rd. 
 
 
 
 
 
Baltimore MD 21227 
 
 

 
 
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2 
INTRODUCTION 
 
2.1 Chronic Hepatitis C Infection in Pregnancy  
 
A rising prevalence of hepatitis C virus (HCV) infection has been one of the most 
significant consequences of the opioid epidemic. Injection drug use among 
reproductive-aged persons is now the leading cause of new HCV infections1 and has 
resulted in a dramatic rise in prevalence of HCV among pregnant women2.  From 
2006 to 2012 the rate of HCV among young people increased by 364% in states 
hardest hit by the opioid epidemic such as Kentucky, Tennessee, Pennsylvania and 
West Virginia3.  Chronic HCV leads to liver disease and cirrhosis4 and is the leading 
cause of mortality from a nationally notifiable infection (NNI) in the US, surpassing all 
60 other NNIs combined5. Infants born to women with HCV have a 4-7% risk of 
perinatal HCV infection6, and are at increased risk for congenital anomalies, low 
birth weight, and neonatal intensive unit (NICU) care2,7,8. HCV-exposed infants also 
have a greater risk of adverse neurologic outcomes, including cephalohematoma, 
fetal distress, feeding difficulties, intraventricular hemorrhage, and neonatal seizure9 
although these finds could be confounded by comorbid substance use. Therefore, it 
is biologically plausible that treatment of HCV during pregnancy could improve both 
pregnancy and neonatal outcomes in addition to prevention of perinatal HCV 
transmission.  
 
HCV cure provides significant health benefits outside of pregnancy. The goal 
of HCV treatment is to render HCV undetectable in the serum, liver tissue and 
mononuclear cells10-12.  Sustained virologic response (SVR12) is defined as the 
absence of detectable HCV RNA in the serum at least 12 weeks after ending 
therapy.  SVR12 has been shown to be a durable predictor of HCV cure when HCV 
RNA is collected for five years or more13,14.  Patients cured of HCV experience 
significant health benefits including decreased liver inflammation, slowed and 
reversed progression of liver fibrosis and cirrhosis15.  Additionally, SVR is associated 
with a 70% reduction in the risk of hepatocellular carcinoma and a 90% reduction in 
the risk of liver-related mortality and liver transplantation16.   Furthermore, treatment 
of persons who use injection drugs can prevent community transmission of HCV, so 
called “treatment as prevention17.” For these reasons, the Infectious Disease Society 
of America (IDSA) treatment guidelines recommend that all HCV-infected persons 
be treated18. Despite these recommendations, pregnant women are excluded 
because the safety and efficacy of treatment during pregnancy has not been 
established.  
 
Pregnant women are a priority population in HCV elimination efforts. In 2016, 
the World Health Organization (WHO) adopted the goal to eliminate hepatitis as a 
major public threat by 2030 by reducing hepatitis incidence from 6-10 to 0.9 million 
cases, and to reduce annual hepatitis deaths from 1.4 to 0.5 million19.  In the 
national response to the WHO goal, the Department of Health and Human Services 

 
 
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National Viral Action Plan 2017-2020 specifically includes pregnant women as a 
priority population due to the risk of perinatal HCV transmission20.  Although 
avoidance of certain obstetric procedures, such as amniotomy and invasive fetal 
monitoring, may decrease perinatal HCV transmission, evidence is lacking21,22. 
Thus, effective HCV treatment during pregnancy could be the most effective 
intervention to prevent perinatal transmission.  
 
 
2.2 Rationale 
 
Pregnancy is a critical window of opportunity for HCV screening and 
treatment. Pregnancy may be the ideal time to provide HCV treatment due to 
enhanced maternal investment in neonatal health outcomes. A meta-analysis of 
adherence to antiretroviral therapy during and after pregnancy showed a statistically 
significant difference in adherence during pregnancy (75.5%) compared to the 
postpartum period (53.0%) 23. In a retrospective cohort study of 369 pregnant 
women who were HCV seropositive at our institution from 2009 to 2012, 285 (77%) 
were referred to hepatology for postpartum treatment, but only 71 (25%) attended 
the consultation and only 6 (1.6%) were treated in the first year postpartum24. 
Furthermore, in an ongoing study of postpartum HCV treatment with SOF/VEL 
paired with medication-assisted treatment (MAT) at our institution, 6 (50%) of 12 
enrolled participants were lost to follow-up prior to treatment completion25. Thus, 
pregnancy may be the ideal period for enhanced HCV treatment adherence and 
engagement.  
 
Addressing the knowledge gap: pharmacokinetic and safety studies of new 
antivirals in pregnancy. Significant physiologic changes occur during pregnancy 
that effect drug absorption, distribution, metabolism and excretion, resulting in PK 
changes which may have clinical consequences26. For example, increased renal 
clearance of drugs could result in suboptimal concentrations with standard dosing for 
renally cleared drugs, leading to antiviral resistance or decreased efficacy27. To 
illustrate this, some antiretroviral medications, such as atazanavir and lopinavir, 
require dose changes during pregnancy to achieve therapeutic drug concentrations 
in the late second or third trimesters27. Plasma protein concentrations including 
alpha-1 acid glycoprotein and albumin decrease in pregnancy, potentially influencing 
free drug concentrations; therefore, to comprehensively evaluate the impact of these 
physiologic changes in pregnancy for highly protein bound drugs, assessment of 
both total and free drug concentrations is critical.  
 
Preliminary data: Our Phase 1 trial of ledipasvir/sofosbuvir (LDV/SOF) 
treatment in pregnancy has promising preliminary results. Between June 2017 
and October 2018, 9 pregnant women between 23-24 weeks’ gestation with chronic 
genotype 1 HCV infection were treated with LDV 90mg- SOF 400mg daily for 12-
weeks. Three intensive PK visits were performed at 25-26, 29-30, and 33-34 weeks’ 
gestation. Plasma was collected pre-dose, 0.5, 1, 2, 3, 4, 5, 8 and 12 hours post-
dose to measure LDV, SOF and GS-331007 (the inactive metabolite of SOF) by 

 
 
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validated HPLC-MS/MS methods28. Of 29 women screened, 20 were excluded due 
to genotype 2 or 3 infection (n=10), ongoing illicit drug use (n=4), declining 
participation (n=3), intention to deliver off-site (n=2), and an APRI score of >1 (n=1). 
All 9 women enrolled were white, with a median age of 31 years. Our published data 
documented that 93% of pregnant women having HCV at our institution are white29.  
Eight women were HCV infected due to intravenous drug use (4 receiving opioid 
pharmacotherapy) and one was perinatally infected. All nine (100%) participants 
were cured and there were no adverse events greater than grade 2 related to 
LDV/SOF30. There were no significant differences found between the PK parameters 
at each gestational age timepoint.   
 
Although there are significant physiologic differences between pregnant and non-
pregnant women, there are minimal differences between the second and third 
trimesters of pregnancy31. For example, the glomerular filtration rate is increased 
37% in the second trimester and 40% in the third trimester32. Therefore, PK 
parameters were averaged across the three visits and compared between 
participants and non-pregnant women from regulatory trials of LDV/SOF. The 
geometric mean ratios and corresponding 90% confidence intervals are shown in 
Table 1. Similar LDV and SOF, but lower GS-331007 exposures were observed 
between pregnant and non-pregnant women. All nine participants (100%) were 
cured. There were no adverse events related to LDV/SOF greater than grade 2. 
One-year follow-up of infants is on-going, and all remain HCV negative. 
 
 
Table 1: Sofosbuvir, GS-331007, and Ledipasvir Exposure in HCV-Infected Pregnant 
women Compared to Non-Pregnant Women 
PK Parameter 
Mean (%CV) 
HCV-infected 
Pregnant 
Women 
 (N=8)** 
HCV-infected 
Non-Pregnant 
Women 
(N=43)*** 
%GMR (90%CI) 
SOF 
AUCtau 
(hr*ng/mL) 
1840 (15.2) 
2210 (49.9) 
92.0 (78.8, 107) 
Cmax (ng/mL) 
1290 (29.3) 
1640 (47.8) 
89.0 (68.6, 115) 
GS-
331007 
AUCtau 
(hr*ng/mL) 
8930 (12.1) 
14800 (29.6) 
62.3 (56.4, 
68.7) 
Cmax (ng/mL) 
706 (15.0) 
1130 (25.9) 
63.7 (57.3, 
70.8) 
LDV 
AUCtau 
(hr*ng/mL) 
10500 (34.4) 
12100 (46.0) 
90.3 (69.6, 117) 
Cmax (ng/mL) 
580 (36.2) 
644 (41.9) 
91.8 (71.2, 118) 
Ctau (ng/mL) 
343 (37.6) 
433 (54.9) 
84.9 (64.0, 113) 

 
 
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*All data are presented to 3 significant digits. Abbreviations: AUCtau, area under the 
concentration-time curve of the dosing interval; Cmax, maximum measured concentration, 
Ctau, concentration at the end of the dosing interval; CI, confidence interval; CV, coefficient 
of variation; GMR, geometric mean ratio. 
**Average of individual participant PK parameters from all 3 PK visits were used. 1 
participant was excluded from the analysis for suspected dosing errors prior to PK visits. 
*** Non-pregnant women from LDV/SOF Phase 2/3 studies with intensive PK assessments. 
 
In this first study of HCV treatment during pregnancy, LDV/SOF was safe and 
effective with similar LDV and SOF PK exposure in pregnancy. Lower inactive 
metabolite (GS-331007) exposure is likely due to increased glomerular filtration rate 
during pregnancy. The results from the completed study support the safety of 
LDV/SOF which provides additional safety data supporting the use of SOF/VEL in 
the proposed study. Further, this pilot study demonstrated that it is feasible to enroll 
and treat HCV infected pregnant women, but a pan genotypic regimen is needed. 
Because the PK did not differ by gestation, the proposed study will limit intensive PK 
sampling to a single gestational age as to not overly burden the participants, but 
sparse sampling will occur at other time points during treatment. Although no 
differences in SOF levels were detected when comparing pregnant women to 
historical nonpregnant controls, the inactive metabolite of SOF (GS-331007) was 
reduced over 30% suggesting that additional data are needed to confirm that no 
change in the active metabolite of SOF occurs. Compared with LDV, VEL is more 
highly reliant on the cytochrome P450 enzyme 3A (CYP3A).  CYP3A is upregulated 
in pregnancy, so there is a potential for a greater effect of pregnancy on VEL. 
 
VEL bioavailability is estimated to be 30-50% based on animal studies and is not 
influenced by food intake. Notably, VEL requires an acidic environment for 
absorption.  VEL is >99.5% protein bound, is hepatically metabolized by cytochrome 
P450 enzymes (CYP3A4, CYP2B6, and CYP2C8). VEL is primarily eliminated via 
biliary excretion, resulting in a plasma half-life of 15 hours33,34. The bioavailability of 
SOF is >80% and a high fat meal increases SOF exposure by 67-91%. SOF is 61-
65% plasma protein bound, 14% is hepatically metabolized by phosphorylation, and 
80% is renally excreted. As a prodrug, SOF half-life is 0.4 hours, while GS-331007 is 
27 hours.  SOF is administered as a phosphoramidate prodrug of the uridine 
nucleotide analogue GS-331007 monophosphate35. SOF is hydrolyzed by cathepsin 
A and/or carboxyesterase 1 and then phosphorylated by cellular kinases to the 
triphosphate moiety (GS-461203)35,36. GS-461203 is the active form of SOF. GS-
461203 then is dephosphorylated to GS-331007, which is the inactive SOF 
metabolite that is most readily measured in the plasma.  
 

 
 
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The physiologic changes of pregnancy and the possible PK effects on SOF and VEL 
are shown in Table 1.    
Given that the magnitude of each physiologic change is hard to predict, the overall 
systemic VEL and SOF exposure cannot be assumed. Further, the plasma 
concentrations of SOF and GS-331007 may not reflect the intracellular 
concentrations of the active SOF metabolite (GS-461230).  To address this 
knowledge gap, we will conduct a thorough PK evaluation of VEL and SOF, 
including protein binding and the measurement of the intracellular GS-461230 
concentrations to offer insights into the physiologic processes altering the PK of 
these drugs in pregnancy and to determine whether dose adjustment is needed. 
 
 
2.3 SOF/VEL Fixed Dose Combination 
 
2.3.1 Description 
 
Sofosbuvir is described chemically as (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5- (2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- 
yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of 
C22H29FN3O9P and a molecular weight of 529.45. Sofosbuvir is a white to off-white 
crystalline solid with a solubility of ≥2 mg/mL across the pH range of 2–7.7 at 37C 
and is slightly soluble in water34. 
Velpatasvir is described chemically as Methyl {(1R)-2-[(2S,4S)-2-(5-{2- [(2S,5S)-1-
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]- 1,11-
dihydro[2]benzopyrano[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4- 
(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate. It has a molecular 
formula of C49H54N8O8 and a molecular weight of 883.0.  
Each tablet contains 100 mg Velpatasvir and 400 mg sofosbuvir. The tablets include 
the following inactive ingredients: copovidone, croscarmellose sodium, magnesium 
stearate, and microcrystalline cellulose. The tablets are film-coated with a coating 
material containing the following inactive ingredients: iron oxide red, polyethylene 
glycol, polyvinyl alcohol, talc, and titanium dioxide.  
2.3.2 Mechanism of Action 
 

 
 
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Velpatasvir inhibits the HCV NS5A protein and sofosbuvir inhibits HCV NS5B RNA-
dependent RNA polymerase, which are essential for viral replication. Sofosbuvir is a 
nucleotide prodrug that is metabolized to the pharmacologically active metabolite GS-
461203, which is incorporated into HCV RNA by NS5B polymerase where it acts as a 
chain terminator.  
 
Velpatasvir has potent pangenotypic antiviral activity against HCV genotypes 1a, 1b, 
2a, 2b, 3a, 4a, 4d, 5a, 6a, and 6e with EC50 values of 0.014, 0.016, 0.016, 0.006, 
0.004, 0.009, 0.004, 0.054, 0.009, and 0.130 respectively.  Sofosbuvir similarly 
demonstrated pangenotypic antiviral activity, with EC50 values against HCV 
genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a, of 40, 110, 50, 15, 50, 40, 15, and 14 
nmol/L, respectively in HCV replicon assays.  SOF/VEL has potent activity against 
HCV genotype 1, 2, 3, 4, 5, and 634.  
 
2.4 Clinical Studies 
 
2.4.1 Clinical Studies of Sofosbuvir/Velpatasvir for the Treatment of HCV 
 
Approximately 1035 participants without cirrhosis or with compensated cirrhosis have 
been enrolled in several multicenter, Phase 3 trials to assess the efficacy of treatment 
with SOF/VEL for 12 weeks in patients with genotypes 1, 2, 3, 4, 5, and 6 chronic 
hepatitis C virus infection, ASTRAL-1, ASTRAL-2 and ASTRAL-3 (Table 2).  ASTRAL-
1 was a randomized, double-blind, placebo-controlled trial that evaluated 
12 weeks of treatment with EPCLUSA compared with 12 weeks of placebo in 
participants with genotype 1, 2, 4, 5, or 6 HCV infection without cirrhosis or with 
compensated cirrhosis37.  ASTRAL-2 was a randomized, open-label trial that 
evaluated 12 weeks of treatment with EPCLUSA compared with 12 weeks of 
treatment with SOF with ribavirin in subjects with genotype 2 HCV infection38.  
ASTRAL-3 was a randomized, open-label trial that evaluated 12 weeks of treatment 
with EPCLUSA compared with 24 weeks of treatment with SOF with ribavirin in 
subjects with genotype 3 HCV infection38.  Approximately 40% (over 400) of the 
participants in these trials were women. There were no on-treatment virologic failures 
reported, however 13 (1%) participants experience virologic failure after treatment or 
relapse, most commonly among participants with genotype 3 infection.  Another 12 
(5%) participants failed to achieve SVR due to non-adherence, due to adverse 
reaction (n=2) or another reason for treatment interruption (Table 2).   
 
Table 2:  Virologic outcome of a 12-week course of SOF/VEL for the treatment of HCV 
infection in participants without cirrhosis or with compensated cirrhosis from ASTRAL-
1, ASTRAL-2, and ASTRAL-3 
Geno-
type 
N Total 
N 
SVR12 
Rate of 
SVR12  
On-Treatment 
Virologic Failure 
After-Treatment 
Virologic Failure 
Other 
1 
328 
323 
98% 
0 
2 (1%) 
3 (1%) 
2 
238 
237 
100% 
0 
0 
1(<1%) 
3 
277 
264 
95% 
0 
11(4%) 
2 (1%) 

 
 
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4 
116 
116 
100% 
0 
0 
0 
5 
35 
34 
97% 
0 
0 
1 (1%) 
6 
41 
41 
100% 
0 
0 
0 
 
 
 
Safety  
 
The safety and tolerability of SOF/VEL has been evaluated within the setting of Phase 
3 clinical trials.  Overall, SOF/VEL was well tolerated by patients with chronic HCV 
infection (N=1035) with only 2 participants permanently discontining  treatment due to 
adverse events was 0.2%.  The most common adverse reactions (adverse events 
assessed as causally related by the investigator and at least 10%) were headache 
and fatigue.  Adverse reactions, all grades, observed in greater than or equal to 5% 
of participants receiving 12 weeks of treatment with SOF/VEL in ASTRAL-1 include 
headache (22%), fatigue (15%), nausea (9%), asthenia (5%), and insomnia (5%). Of 
subjects receiving 12 weeks of treatment with SOF/VEL  79% had an adverse reaction 
of mild severity (Grade 1). With the exception of asthenia, each of these adverse 
reactions occurred at a similar frequency or more frequently in participants treated 
with placebo compared to participants treated with SOF/VEL (asthenia: 3% versus 5% 
for the placebo and SOF/VEL groups, respectively).  The adverse reactions observed 
in participants treated with SOF/VEL in ASTRAL-2 and ASTRAL-3 were consistent 
with those observed in ASTRAL-1. Irritability was also observed in greater than or 
equal to 5% of participants treated with SOF/VEL in ASTRAL-3.  In the ASTRAL-1 
study, rash occurred in 2% of participants treated with SOF/VEL and in 1% of 
participants taking placebo. No serious adverse reactions of rash occurred and all 
rashes were mild or moderate in severity.  In the ASTRAL-1 study, depressed mood 
occurred in 1% of participants treated with SOF/VEL and was not reported by any 
placebo participants. No serious adverse reactions of depressed mood occurred and 
all events were mild or moderate in severity34.   
Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected 
patients who were undergoing or had completed treatment with HCV direct acting 
antivirals, and who were not receiving HBV antiviral therapy. Some cases have 
resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported 
in patients who are HBsAg positive and also in patients with serologic evidence of 
resolved HBV infection (i.e., HBsAg negative and anti-HBc positive).  We will 
exclude participants that are anti-HBc positive for this reason.   Additionally, 
postmarketing cases of symptomatic bradycardia and cases requiring pacemaker 
intervention have been reported when amiodarone is coadministered with a 
sofosbuvir-containing regimen. Additionally a fatal cardiac arrest occurred in a 
patient taking amiodarone that was co-administered with sofosbuvir.  For this 
reason, we will exclude participants who are taking amiodarone34.   
Laboratory abnormalities:  

 
 
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Lipase Elevations: In ASTRAL-1, isolated, asymptomatic lipase elevations of greater 
than 3 times the upper limit of normal were observed in 3% and 1% of participants 
treated with SOF/VEL and placebo for 12 weeks, respectively; and in 6% and 3% of 
participants treated with SOF/VEL in ASTRAL-2 and ASTRAL-3, respectively34.  
Creatine Kinase: In ASTRAL-1, isolated, asymptomatic creatine kinase elevations 
greater than or equal to 10 times the upper limit of normal were reported in 1% and 
0% of participants treated with SOF/VEL and placebo for 12 weeks, respectively; 
and in 2% and 1% of participants treated with SOF/VEL in ASTRAL-2 and ASTRAL-
3, respectively. 
2.4.2 Animal Studies of Sofosbuvir and Velpatasvir During Pregnancy 
 
There are no adequate studies of SOF/VEL in pregnant women.  In animal 
reproduction studies, no evidence of adverse developmental outcomes was observed 
with the components sofosbuvir or velpatasvir at exposures greater than those in 
humans at the recommended human dose. During organogenesis in the mouse, rat, 
and rabbit, systemic exposures (AUC) to velpatasvir were approximately 31 (mice), 6 
(rats), and 0.4 (rabbits) times the exposure in humans at the recommended human 
dose, while exposures to the predominant circulating metabolite of sofosbuvir (GS-
331007) were approximately 4 (rats) and 10 (rabbits) times the exposure in humans 
at the recommended human dose34.  
 
Velpatasvir: Velpatasvir was administered orally to pregnant mice (up to 
1000 mg/kg/day), rats (up to 200 mg/kg/day) and rabbits (up to 300 mg/kg/day) on 
gestation days 6 to 15, 6 to 17, and 7 to 20, respectively, and also to rats (oral doses 
up to 200 mg/kg) on gestation day 6 to lactation/post-partum day 20. No significant 
effects on embryo-fetal (mice, rats, and rabbits) or pre/postnatal (rats) development 
were observed at the highest doses tested. The systemic exposures (AUC) of 
velpatasvir during gestation were approximately 31 (mice), 6 (rats), and 0.4 (rabbits) 
times the exposure in humans at the recommended human dose. 
 
Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) 
and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively, 
and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post- 
partum day 20. No significant effects on embryo-fetal (rats and rabbits) or 
pre/postnatal (rats) development were observed at the highest doses tested. The 
systemic exposures (AUC) of the predominant circulating metabolite of sofosbuvir 
(GS-331007) during gestation were approximately 4 (rats) and 10 (rabbits) times the 
exposure in humans at the RHD. 
 
2.5 Rationale for Study Design 
 
There is currently no experience with SOF/VEL in pregnant women, although based 
on the animal model data submitted to the FDA there were no effects on fetal 
development observed in mice, rats and rabbits with doses higher than those given 

 
 
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for treatment of hepatitis C in humans.  Also, there is reassuring data from our prior 
study of treatment with LDV/SOF.  Unfortunately, LDV/SOF is not approved for 
treatment of HCV genotypes 2 and 3 and therefore a pan-genotypic regimen in 
pregnancy is needed. Before larger scale treatment studies can be undertaken, it will 
be necessary to assess whether the pharmacokinetics of the drugs are similar in 
pregnant and nonpregnant women, and whether treatment response is similar to that 
observed in nonpregnant women, given the higher viral loads observed during 
pregnancy. This study is designed to address those knowledge gaps. We propose a 
single-arm, single-center, open label Phase 1 study of a 12-week course of SOF/VEL 
in 10 HCV-infected pregnant women.  Treatment will be initiated during the second 
trimester, reducing the risk of SOF/VEL exposure during organogenesis and ensuring 
treatment completion by delivery, minimizing the risk of perinatal transmission.   
Additionally, this will allow adequate time for treatment course completion by delivery.   
 
The study will be completed in 10 or 11 visits (7 maternal visits, delivery visit and 3 
infant visits) which should easily align with prenatal and postpartum visits (Table 1). 
We plan to screen patients between 14+0 and 22+6 weeks of gestation confirmed by 
ultrasound by the time of their Enrollment visit who are known to have chronic HCV 
infection.  A HCV RNA level to confirm the patient is actively infected with HCV as well 
as an HCV genotype (when not already available within 3 months of screening visit) 
will be obtained.  A full laboratory evaluation of liver function including CBC, PT/INR, 
hepatic panel, creatinine, creatinine kinase and lipase will be obtained, to evaluate for 
renal failure and decompensated cirrhosis.  A Hepatitis B Virus (HBV) panel will be 
performed to test all patients for evidence of current or prior HBV infection before 
initiation of HCV treatment.  Medical history and demographic information will also be 
collected at screening.  If the following inclusion and exclusion criteria are met, then 
the patient will be enrolled into the study between 23+0 and 25+6 weeks’ gestation 
and initiated on a 12 week course of SOF/VEL. 
3 
OBJECTIVES  
 
3.1 Primary Objective 
 
1. To compare the plasma pharmacokinetic (PK) parameters of SOF/VEL 
administered during pregnancy to those of nonpregnant women. 
 
3.2 Secondary Objectives 
 
1. To compare the intracellular concentrations of SOF (GS-461203) during 
pregnancy to available data from nonpregnant women.  
 
 
2. To compare the protein binding (free fraction) of VEL in pregnant women to 
available data from nonpregnant women. 

 
 
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3. To determine the rate of sustained viral response (SVR12), defined by 
undetectable hepatitis C virus twelve weeks after completion of SOF/VEL 
treatment for 12 weeks during pregnancy. 
 
4. To evaluate the safety for the mother and for the neonate of hepatitis C 
treatment with SOF/VEL during pregnancy. 
 
3.3 Exploratory Objective 
 
1.  To describe the perspectives of pregnant women with chronic HCV infection 
screening for a trial of antenatal sofosbuvir/velpatasvir (SOF/VEL) therapy 
4 
STUDY DESIGN 
 
4.1 Identification of Study Design 
 
This is a single-site, open label, single-arm Phase 1 trial.  
 
4.2 Summary of Major Endpoints 
 
Primary Endpoint: 
 
• Systemic PK 
- 
Systemic exposure of both VEL and SOF will be assessed at three time 
points:  
1) 3 weeks after treatment initiation (intensive sampling); 
2) 6 weeks after treatment initiation (sparse sampling); 
3) 9 weeks after treatment initiation (intensive sampling). 
 
Secondary Endpoints:  
 
• Secondary PK endpoints: 
 
Intracellular concentrations of GS-461203 from dried blood spots 
and peripheral blood mononuclear cells (PBMCs) will be 
assessed at: 
• 3 weeks  7 days after first dose; 
• 6 weeks  7 days after first dose; 
• 9 weeks  7 days after first dose. 
 
 
Free-fraction of VEL (protein-binding) will be assessed at: 
• 3 weeks  7 days after first dose; 
• 9 weeks  7 days after first dose. 
 
• Sustained Viral Response (SVR12) 

 
 
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• 
HCV RNA viral load will be assessed at 12 weeks after 
SOF/VEL treatment completion. An undetectable viral load will 
be considered a SVR12. 
 
• Maternal Safety 
• 
Safety laboratory assessments of blood counts, creatinine, liver 
function, creatinine kinase and lipase will be measured at the 
PK1 and PK2 visit (3 and 6 weeks after initiation of SOF/VEL).  
• 
Pregnancy and delivery outcomes collected prospectively by 
participant interview and medical record review. 
 
• Neonate Safety 
• 
Major malformations, defined as structural abnormalities with 
medical, surgical or cosmetic importance 
• 
Weight, length, and head circumference at birth, 8 weeks, six 
months and 12 months  
• 
HCV RNA will be assessed at birth (as available), 1-3 months 
and 6 months, and then again at 12 months only if detectable 
viral loads are documented in either of the two previous viral 
load assessments 
• 
Neonatal development assessed at 6 months and 12 months 
 
Exploratory Endpoint: 
 
• 
In depth interviews conducted before enrollment in screened 
participants and after completion of treatment in enrolled 
participants 
 
 
4.3 Description of Study Population 
 
The study population will include 10 pregnant women between the ages of 18-39 years 
old (inclusive) at Screening who are chronically infected with Hepatitis C virus, 
genotype 1, 2, 3, 4, 5 or 6 (or any combination of genotypes), as described in Sections 
5.2 and 5.3 and infants born to the enrolled participants 
 
4.4 Time to Complete Accrual 
 
The approximate time to complete study enrollment is expected to be 12 months.  
 
4.5 Expected Duration of Participation 
 
The expected duration for maternal participants is approximately 24 weeks, not 
including the screening window.  Infants will be followed for at least a full year after 
birth; therefore mother-child pairs will be enrolled for approximately one year and 4 

 
 
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months. Maternal study data will be collected from the participant and/or her medical 
records through the Post Treatment Visit (V7).  Maternal participants who have AEs 
at the Post Treatment Visit (V7) that are clinically significant or related to study 
product/participation and have not resolved or stabilized will be followed beyond V7 
until a clinically acceptable resolution of the AE(s) is confirmed and documented. 
Similarly, infant study data will be collected through the 12 month follow-up visit (iV3).  
Infants who have AEs at the iV3 visit that are clinically significant or related to study 
product/participation and have not resolved or stabilized will be followed beyond iV3 
until a clinically acceptable resolution/stabilization of the AE(s) is confirmed and 
documented.  
 
5 
STUDY POPULATION 
 
5.1 Selection of the Study Population 
 
The inclusion and exclusion criteria in Sections 5.2 and 5.3 will be utilized to ensure 
the appropriate selection of study participants. 
 
5.1.1 Recruitment 
 
There are over 10,000 deliveries at Magee-Womens Hospital (MWH) per year and it 
is estimated that approximately 1% of women who deliver are actively infected with 
HCV.  HCV-infected pregnant women will be recruited from MWH and antenatal 
clinics, opiate substitution therapy clinics and recovery programs in Pittsburgh and 
surrounding areas.    
 
Recruitment will be primarily targeted from the MWH Pregnancy Recovery Center, 
which was established in 2014 to provide concurrent treatment for opiate 
dependence (buprenorphine) with prenatal care, which has an estimated retention 
rate of 90% for weekly opiate substitution and prenatal visits.  There are 
approximately 120 opiate addicted pregnant women who received prenatal care at 
the Pregnancy Recovery Center per year.  The prevalence of HCV infection in this 
Center is approximately 60%.  Recruitment will also be targeted at the Magee-
Womens Hospital ambulatory clinic and associated clinics that deliver at Magee-
Womens Hospital.  In order to engage HCV-infected women in recovery, but not yet 
engaged in prenatal care, we may also recruit patients from local opiate substitution 
therapy clinics and recovery programs that treat pregnant women.   
 
Recruitment may also include women who are not receiving care at Magee-Womens 
Hospital through referrals from health care providers.  These women must be willing 
to travel to Pittsburgh to complete the study visits but may deliver at an outside 
hospital as information from delivery may be reviewed after obtaining a signed 
medical record release.   
 

 
 
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Recruitment materials will be approved by the University of Pittsburgh Institutional 
Review Board prior to use. 
 
5.1.2 Retention 
 
The importance of retention will be stressed to the participant at each visit as part of 
protocol adherence counseling.  Once a participant is enrolled, the study staff will 
make every effort to retain the participants in follow-up to minimize possible bias 
associated with loss-to-follow-up. Any participant that discontinues the study before 
the PK3 visit is completed or reports missing more than 1 dose per week averaged 
over the duration of the study will be replaced by recruiting another participant into the 
study.  We anticipate needing to replace no more than one participant.  
 
5.2 Inclusion Criteria 
 
Women must meet all of the following criteria to be eligible for inclusion in the study. 
Any exclusionary laboratory values can be repeated at a later date within the 
Screening window.  If the repeated laboratory values meet inclusion criteria then the 
participant can be enrolled. If there is concern that the participant’s health status has 
changed between the screening visit and the enrollment visit or if there is a clinical 
concern by the study investigators, the screening laboratories can be repeated prior 
to enrollment.   
 
1) 
Age 18 through 39 years (inclusive) at Screening 
 
2) 
Able and willing to provide written informed consent and take part in the 
study procedures 
 
3) 
Able and willing to provide adequate locator information 
 
4) 
Chronic HCV (for at least 6 months prior to screening)by participant report  
 
5) 
Detectable HCV RNA viral load at Screening 
 
6) 
Desired pregnancy at 23 + 0 to 25 + 6 weeks’ gestation at Enrollment with 
gestational dating confirmed by ultrasound 
 
7) 
Singleton gestation with no known fetal abnormalities  
 
8) 
Documented negative Hepatitis B testing for current infection (negative 
HBsAg test) or previous infection (negative anti-HB Core) performed at the 
screening visit 
 
9) 
Negative HIV testing at the screening visit 
 

 
 
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10) Per participant report at Screening and Enrollment, agrees not to participate 
in other research studies involving  investigational drugs or medical devices 
for the duration of study participation 
 
 
 
5.3 Exclusion Criteria 
 
Women who meet any of the following criteria will be excluded from the study: 
 
1) 
Participant report of any of the following at Screening or Enrollment: 
a. Previous treatment for Hepatitis C virus with sofosbuvir or a NS5A 
inhibitor  
b. Use of any medications contraindicated with concurrent use of 
velpatasvir or sofosbuvir according to the most current EPCLUSA 
package insert34 
c. Plans to relocate away from the study site area in the next 1 year and 
4 months and unable/unwilling to return for study visits 
d. Current sexual partner is known to be infected with HIV or Hepatitis B 
virus 
e. History of cirrhosis documented or reported by previous liver biopsy or 
liver imaging tests 
 
2) 
Reports participating in any other research study involving investigational 
drugs or medical devices within 60 days or less prior to Enrollment 
 
3) 
Clinically significant and habitual non-therapeutic drug abuse, not including 
marijuana, as determined by Protocol Chair 
 
4) At Screening or Enrollment, as determined by the Protocol Chair, any 
significant uncontrolled active or chronic cardiovascular, renal, liver (such as 
evidence of decompensated cirrhosis by ascites, encephalopathy, or variceal 
hemorrhage), hematologic, neurologic, gastrointestinal, psychiatric, 
endocrine, respiratory, immunologic disorder or infectious disease (other than 
Hepatitis C) 
 
5) 
Has a high risk of preterm birth defined as a history of spontaneous preterm 
birth at less than 34 weeks of gestation or a shortened cervical length of 
less than 20 millimeters   
 
6) 
Has any of the following laboratory abnormalities at Screening: 
a. Aspartate aminotransferase (AST) or alanine transaminase (ALT) 
greater than 10 times the upper limited of normal 
b. Hemoglobin less than 9 g/dL  
c. Platelet count less than 90,000 per mm3 
d. International normalized ratio (INR) > 1.5  

 
 
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e. Creatinine greater than 1.4  
 
 
7) 
Has any other condition that, in the opinion of the IoR/designee, would 
preclude informed consent, make study participation unsafe, complicate 
interpretation of study outcome data, or otherwise interfere with achieving 
study objectives. 
 
6 
STUDY MEDICATION 
 
6.1 Regimen 
 
Each participant will take a 12 week course of SOF/VEL one tablet by mouth, once 
daily.   
 
6.2 Administration 
 
Study medication will be dispensed at Enrollment, PK1, PK2, and PK3 visits in the 
quantities sufficient to have one dose per day until the next scheduled visit with 3 extra 
doses.  Tablets will be packaged by the Investigational Pharmacist/Pharmacist of 
Record (PoR)/designee in the pharmacy at Magee-Womens Hospital.   Participants 
will be encouraged to use an IRB approved, secure mechanism to capture a 
photo/video of study medication administration   to assist with keeping track of when 
participants took their doses.  This process will document the date and time of study 
medication administration and can be submitted electronically anytime throughout 
study participation or can be reviewed at a study visit.  Participants will also be given 
a paper log to record the time of their dose and will be asked to return the log at the 
next study visit.  The timing of each dose will be reviewed by the research team at 
each visit.  Any discrepancies will be noted.  
 
Each participant will be given instructions on timing of the dose, what to do if a dose 
is missed and how to store the medication.  If a dose is missed, the participant should 
take the dose as soon as it is remembered, but only one dose per day.  Participants 
will be instructed to take the medication each day at the same time, preferably early 
in the morning.  SOF/VEL can be taken with or without food.  Additionally, participants 
will be given adherence tips, such as setting an alarm on their phone, linking 
medication time to another daily activity, etc. Participants will be instructed to bring 
any unused medication to the next visit and to specifically remember to bring the 
morning dose to the PK1 and PK3 Visits rather than take it at home.  Participants will 
be instructed to call the study staff immediately if they run out of medication or if they 
lose the study medication.  In this case, all possible efforts will be made to get the 
participant study medication as soon as possible. 
 

 
 
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6.3 Supply and Accountability 
 
6.3.1 Supply 
 
Gilead Sciences will supply the study medication that is manufactured under Good 
Manufacturing Practices as FDA approved bulk product.  The product will be shipped 
to UPMC Magee Womens Hospital Pharmacy’s PoR.  Study medication will be 
repackaged and labeled prior to dispensation according to protocol guidelines. 
 
6.3.2 Storage and Dispensing 
SOF/VEL should be stored at room temperature below 30°C within the main pharmacy 
at Magee-Womens Hospital34. The PoR/designee will maintain documentation of 
temperature in the area where the study medication is stored. Study medications will 
be dispensed from the pharmacy in a small bottle containing a quantity sufficient until 
the next study visit with a bottle of three additional doses in the case of a lost dose or 
missed study visit.  Study medications will be dispensed from the pharmacy only upon 
receipt of a written prescription and/or a signed study drug order form from an 
authorized prescriber.  The study medication will be dispensed to the study staff, then 
subsequently provided directly to the study participant in the research clinic.  
 
6.3.3 Accountability 
 
The PoR/designee will maintain complete accountability records of all study SOF/VEL 
received and dispensed. All available unused study medications will be returned to 
Gilead Sciences or destroyed as instructed by Gilead after the study is complete.  
 
6.3.4 Retrieval of Study Medication 
 
The participants will be instructed to return any unused medication at each visit. If the 
participant fails to return unused medication at a scheduled visit, reasonable attempts 
will be made and documented to obtain the unused medication from the participant 
(i.e. at an unscheduled visit). Unused medication will be accounted for by the clinician, 
documented in the participant’s research record and then returned to the PoR and 
accounted for per pharmacy policy.  
 
6.4 Concomitant Medications  
 
Enrolled study participants may use non-prohibited concomitant medications during 
study participation. All concomitant medications reported throughout the course of the 
study will be recorded on case report forms designated for that purpose. All 
prescription medications, over-the-counter preparations, vitamins, nutritional 
supplements, and herbal preparations will be recorded on forms for concomitant 
medications. Participants who are using medications that are contraindicated for 
concomitant use with velpatasvir and sofosbuvir as described in the package insert 
will be excluded from participation.39 Each reported concomitant medication will be 
reviewed to ensure the participant is not using prohibited medications (i.e. St. John’s 

 
 
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wort, carbamazepine) as referenced in the EPCLUSA package insert. At each visit, 
participants will be asked if they have initiated any new medications or changed any 
reported medications.  If the participant reports using acid suppressing medications, 
specific dosing instructions will be reviewed regarding correct timing of acid 
suppressing medication use according to the EPCLUSA package insert.   
7 
STUDY PROCEDURES 
 
An overview of the study visit and evaluations schedule is presented in Appendix 1. 
Any clinical or laboratory information collected as a part of the participant’s routine 
clinical care occurring on the same day as the study visit does not need to be repeated 
and can be collected from the participant’s medical record.   
 
In the unlikely event of interruptions in study procedures (i.e. from severe weather or 
pandemics like COVID-19), study staff will refer to a written HIP2 Mitigation Plan for 
direction in handling study visits and procedures.  The Mitigation Plan outlines tiers or 
severities of interruptions and provides guidance for continuation of research 
activities, namely ensuring participants can complete 12 weeks of study medication. 
The Mitigation Plan will be submitted to the IRB so they are aware of the plan for 
unexpected disruptions in this study.   
 
7.1 Pre-screening 
 
Study staff will pre-screen records to identify potential participants by evaluating 
minimum criteria (i.e. age, gestation age, Hepatitis C status).  Healthcare providers 
will be told about the study and will be asked to provide an IRB approved ad/written 
material to potential participants or will assess interest.  If the participant agrees, 
research staff can provide additional information by reviewing an IRB approved 
screening script, which will include a brief overview of the study and minimum eligibility 
questions.  Women who are interested and qualify based on the screening script may 
schedule a Screening Visit.  Process information (e.g., number of potential participants 
contacted, number presumptively eligible) may be recorded and stored at the study 
site in the absence of written informed consent from potential participants, provided 
the information is collected in such a manner that it cannot be linked to participant 
identifiers. Procedures and documentation will comply with the University of Pittsburgh 
IRB requirements. IRB approved materials (i.e. ads, flyers videos, and social media 
posts) may also be used (i.e. hung throughout the hospital; displayed on electronic 
boards; emailed to providers or appropriate support or community groups). 
 
7.2 Visit 1- Screening (V1) 
 
Screening can take place anytime within the screening gestational age window (14+0 
to 22+6 weeks with gestational age being determined by available clinical information 
at the screening visit with confirmation of gestational age by ultrasound prior to 
enrollment). The gestational age must be confirmed by an ultrasound prior to 
enrollment.  If an ultrasound has not been performed yet, then an ultrasound is 

 
 
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performed as part of routine obstetric care at 20 weeks’ gestation and prior to 
enrollment. The study team will assist the participant in scheduling an ultrasound as 
part routine obstetric care prior to enrollment if the participant does not have one 
already.  Multiple visits may be conducted to complete all required screening 
procedures, if necessary. Written informed consent will be obtained before any 
screening procedures are initiated. Participants will be encouraged to speak with their 
primary care provider to determine whether to initiate hepatitis C treatment during 
pregnancy before deciding whether to participate in the study.  Participants who do 
not meet the eligibility criteria during the screening process will be discontinued once 
ineligibility is determined. Any exclusionary laboratory values can be repeated at a 
later date within the screening window.  If the repeated laboratory values meet 
inclusion criteria then the participant can be enrolled. If there is concern that the 
participant’s health status has changed between the screening and the enrollment visit 
or if there is concern by the study investigators, the screening laboratories can be 
repeated prior to enrollment. 
 
Table 3: Screening Visit (V1) 
Visit 1- Screening Visit 
Component 
Procedures 
Administrative and Regulatory 
 
• 
Review and obtain written informed consent 
• 
ICF Comprehension Assessment 
• 
Assign participant ID (PTID) 
• 
Sign appropriate medical record releases (i.e. to obtain records from 
prenatal care; outside records as necessary) 
• 
Collect locator information 
• 
Collect demographic information 
• 
Visit Questionnaire 
• 
In-depth Interview (IDI)** 
• 
Assess eligibility  
• 
Provide reimbursement for study visit 
• 
Schedule next visit 
Clinical 
• 
Collect medical history & review and print medical/prenatal records 
including documentation of chronic Hepatitis C 
• 
Review and obtain documentation of previous liver biopsy or liver 
imaging, if applicable   
• 
Collect concomitant medications 
• 
Pre/post-test HIV counseling, as applicable 
• 
Perform full physical examination 
• 
Assess fetal heart tones  
• 
Confirm gestational dating (by available clinical information but must 
be confirmed by ultrasound prior to enrollment)  
Laboratory 
• 
Collect blood 
• 
Complete blood count (CBC) with differential and platelets 
• 
Creatinine  
• 
HIV-1 serology 
• 
Hepatitis B Virus testing (HBsAg, anti-HBc, Anti-HBs) 
• 
Coagulation (PT/INR) 
• 
HCV RNA viral load 
• 
HCV genotype*  
• 
Hepatic function panel (AST, ALT, albumin, total and direct 
bilirubin, and alkaline phosphatase) 
• 
Lipase 
• 
Creatinine kinase 

 
 
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* HCV genotype testing will be performed as needed.  If a result from routine care testing is available from within the past 3 
months prior to the screening visit then additional genotype testing does not need to be performed.   
**May be performed at the screening visit or any time prior to enrollment 
7.3 Visit 2- Enrollment (V2) 
 
The following procedures will occur at the Enrollment visit (V2). During the 
enrollment visit the participant will be given instructions on taking the study 
medication. 
 
Table 4: Enrollment (V2) 
Enrollment Visit- Visit 2 (V2) 
Component 
Procedures 
Administrative and Regulatory 
 
• 
Confirm eligibility 
• 
Review/update locator information 
• 
Visit Questionnaire  
• 
Provide reimbursement for study visit 
• 
Schedule next visit 
Behavioral 
• 
Provide counseling  
• 
Protocol adherence 
• 
Study medication use/adherence 
Clinical 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Document pre-existing conditions 
• 
Perform full physical examination 
• 
Assess fetal heart tones 
• 
Provide Screening test results and perform post-test HIV counseling, 
as applicable 
Medications 
• 
Participants will receive study medication (supply enough until next 
visit plus a bottle with 3 extra doses) 
• 
Participants will receive instructions for daily use and for PK visits 
• 
Participants will receive medication adherence log and/or be instructed 
on use of photo/video capture of daily dosing 
Laboratory 
• 
Collect blood 
- 
HCV RNA viral load 
7.4 Follow-up Visits  
7.4.1 Visit 3 to 5 (PK 1, PK2 and PK3) 
 
The PK1, PK2, and PK3 visits will occur 3, 6 and 9 weeks (+/- 7 days), respectively, 
after initiating SOF/VEL.  The PK visits will be scheduled as early as possible within 
visit window to allow for visits that require rescheduling. 
 
Participants will be asked to return the day after V3 and V5 for a 24 hour + 2 hour 
PK visit.  These visits will be labeled as V3a and V5a.  The participant will be 
counseled not to take their dose of study medication until after V3a and V5a 
procedures.  In the event that the participant is unable to be seen in the window 
period (24 hours + 2 hours), the visit and study procedures will still be completed as 
long as the participant has not taken their dose for the day.  Assistance with 
transportation or overnight accommodations will be offered as necessary to attempt 
to increase compliance with these visits/window periods.  

 
 
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Table 5: Follow-up Visits (PK1, PK2, and PK3) 
Follow-up Visits 3-5 (PK1, PK2, PK3) 
Component 
Procedures 
Administrative and Regulatory 
 
• 
Review/update locator information 
• 
Visit questionnaire  
• 
Provide reimbursement for study visit 
• 
Record/update AEs 
• 
Schedule next visit as applicable  
Behavioral 
• 
Adherence assessment  
• 
Provide modified counseling  
• 
Protocol adherence 
• 
Instructing participants to contact study staff when in labor/being 
admitted to labor and delivery  
• 
Study medication use/adherence 
Clinical 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Perform modified physical examination 
• 
Assess fetal heart tones 
• 
Provide available test results (if applicable) 
• 
Administer timed dose of study medication (PK1 and PK3 only) 
• 
Provide study medication with sufficient supply until next visit with 3 
additional doses 
• 
Participants will receive medication adherence log and/or be 
instructed on use of photo/video capture of daily dosing 
Laboratory 
• 
Collect blood (plasma, DBS and PBMCs) 
• 
Intensive PK sampling (PK1, PK3) 
• 
Protein binding assay (PK1, PK3) 
• 
Sparse PK plasma sampling (PK2) 
PRIOR TO VISIT DOSING, if applicable: 
• 
CBC with differential and platelets  (PK1, PK2) 
• 
Hepatic function panel (AST, ALT, albumin, total and direct 
bilirubin, alkaline phosphatase)  (PK1, PK2) 
• 
PT/INR (PK1, PK2) 
• 
Creatinine (PK1, PK2) 
• 
Lipase (PK1, PK2) 
• 
Creatinine kinase (PK1, PK2) 
• 
HCV RNA viral load  
• 
HCV Resistance Testing* 
*as indicated per protocol section 9.3 
 
Table 5a: 24 hour PK visit (PK1a and PK3a) 
Follow-up Visits 3a and 5a (PK1a and PK3a) 
Component 
Procedures 
Administrative and Regulatory 
 
• 
Visit questionnaire  
• 
Provide reimbursement for study visit 
• 
Record/update AEs 
Laboratory 
• 
Collect blood  
• 
Sparse PK sampling  
 
 
 
VEL and SOF PK Evaluation 
 
For the PK1 and PK3 visits (intensive PK), participants will be instructed not to take 
their daily dose at home but rather to bring their dose of SOF/VEL to the visit for a 
timed administration.  Alternately, a dose will be dispensed by the PoR/designee for 

 
 
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the PK visits.  Participants will be instructed about dietary restrictions for these visits 
as outlined in section 7.6.  Participants will have their first PK plasma drawn before 
the time of the dose of SOF/VEL.  The dose at each PK visit will be timed and blood 
samples will be collected at each PK visit as follows (relative to the timed dose):  
pre-dose, 0.5, 1, 2, 3, 4, 5, 8, and 12.  An intravenous catheter may be placed  and 
used to obtained samples throughout the PK visits.  A saline solution will be used at 
a slow drip to attempt to keep the vein patent.  In the event that the catheter fails, 
participants may have another IV inserted or individual venipuncture(s) to attempt to 
collect all PK samples.  If still in place, the catheter will be removed after the 12 hour 
time point. If a PK sample(s) cannot be obtained, then the participant will remain 
evaluable, if at least one sample is obtained at each PK visit.  Participants will return 
the following day for the 24 hour PK time point, which will be obtained by a single 
venipuncture.  The participant will be instructed to take their daily dose following the 
single blood sample collection.  For further details, see section 7.6 
Pharmacokinetics.   
 
For the sparse PK visit (PK2), the time when the previous dose of SOF/VEL was 
taken will be recorded and a single PK sample will be collected.  This draw can 
occur at any time during the PK2 visit window and at any time during the day.   
 
7.4.2 End of Treatment Visit (V6) 
The following procedures will occur at the End of Treatment visit.  This visit will be 
scheduled within 7 days of completion of the 12 week course of study medication.  
The purpose of this visit will be to collect any remaining study medication and to 
collect and follow up on any adverse events.  Participants will also be reminded to 
call the research staff when they present to the hospital for delivery. 
 
Table 6:  End of Treatment Visit 
End of Treatment Visit  
Component 
Procedures 
Administrative and Regulatory 
 
• 
Review/update locator information 
• 
Visit Questionnaire 
• 
In-depth Interview (IDI)** 
• 
Provide reimbursement 
• 
Record/update AEs  
Behavioral 
• 
Protocol adherence counseling, including delivery visit instructions 
• 
Collect remaining study medication 
• 
Collect medication administration log 
Clinical 
 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Perform modified physical examination 
• 
Provide available test results if available  
• 
Assess fetal heart tones (if applicable) 
Laboratory 
• 
HCV RNA viral load 
• 
HCV resistance testing* 
*as clinically indicated 
**May be performed at this visit or prior to post-treatment visit (V7) 
 

 
 
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7.4.3 Delivery Visit (in person visit or chart review) 
Participants will be instructed to contact the study staff when they are in 
labor/admitted to labor and delivery, regardless of delivery location.  The Delivery 
Visit will occur during admission for participants delivering at Magee-Womens 
Hospital and will include maternal and cord blood samples.  The date of the Delivery 
Visit for participants who deliver at Magee will be the date the study staff makes the 
first contact with the participant during her delivery admission, regardless if 
procedures occur over more than one day.  Participants who deliver at an outside 
location will be contacted by phone as close to delivery as possible to complete the 
applicable Delivery Visit study procedures (i.e. questionnaire, update locator 
information, update medical history).  The Delivery Visit date for these participants 
will be the date of the completed phone call.  All participants, regardless of delivery 
location will undergo a medical record review, if medical records are available to 
obtain delivery outcomes/variables. A copy of the delivery records will be placed in 
the participant’s research chart. In the event that the participant delivers prematurely 
at UPMC Magee-Womens Hospital  and is still taking study medication, then 
procedures from previously scheduled visits (V2-V6) may be performed, excluding 
intensive PK sampling.  Rather than intensive PK sampling, a single maternal blood 
sample will be taken as close to the time of delivery as possible and cord blood will 
be collected for SOF/VEL PK analysis. 
 
Table 7: Delivery Visit  
Delivery Visit 
Component 
Procedures 
Administrative and Regulatory 
 
• 
Review/update locator information 
• 
Visit Questionnaire 
• 
Provide reimbursement, as applicable 
• 
Record/update AEs  
• 
Schedule next visit  
Behavioral 
• 
Protocol adherence counseling 
• 
Study medication use/adherence (if still on study medication) 
Clinical (Maternal) 
 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Provide available test results if available  
• 
Perform modified physical examination (or obtain from medical record) 
• 
Dispense study medication, as applicable to complete 12 week course 
(if still on study medication)* 
Clinical (Infant) 
• 
Review medical history including pre-existing conditions 
• 
Review concomitant medications 
• 
Full physical examination (may be collected via chart review) 
Medical Record Review for 
Delivery Outcomes^ 
• 
Type of pregnancy outcome 
• 
Gestational age at pregnancy outcome 
• 
Type of delivery (e.g., vaginal, vaginal forceps-assisted, 
vaginal vacuum-assisted, cesarean section) 
• 
Delivery medications 
• 
Complications related to pregnancy outcome 
 
Delivery complications (e.g., intrapartum and/or postpartum 
hemorrhage, non-reassuring fetal status, chorioamnionitis) 
 
Other complications not related to a delivery 

 
 
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Baseline Infant Information^** 
• 
Sex 
• 
Weight 
• 
Length 
• 
Head circumference 
• 
Apgar scores 
Laboratory*** 
• 
Maternal HCV RNA viral load 
• 
Cord blood collection for HCV RNA viral load 
• 
Cord blood collection for PK analysis (if still on study medication) 
• 
Maternal plasma sample for PK analysis (if still on study medication) 
• 
HCV Resistance Testing (if indicated) 
*Unless participant intends to breastfeed, in which case study medication will be discontinued. 
**All Baseline Infant Information may be extracted from the infant medical record as available. 
***Laboratory tests performed as applicable for participants who deliver at Magee-Womens Hospital. 
^This information may be obtained by chart review abstraction and/or through extraction by R3. 
 
7.4.4 Post Treatment (V7) Visit 
The following procedures will occur at the Post Treatment visit (V7), which should be 
scheduled 12 weeks ± 4 days from the last dose of study medication.  The V7 visit 
can occur simultaneously with the 8 week Follow-up Visit for the infant (iV1).  This is 
the last scheduled clinic visit for the maternal participant.  
 
Table 8: Post Treatment (V7) 
Visit 7 (V7) Post Treatment Visit 
Component 
Procedures 
Administrative and Regulatory 
 
• 
Review/update locator information 
• 
Visit questionnaire  
• 
Provide reimbursement 
• 
Record/update AEs  
Behavioral 
• 
Protocol adherence counseling 
Clinical 
 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Perform modified physical examination  
• 
Provide available test results from delivery, as applicable  
Laboratory 
 
• 
Collect blood 
• 
CBC with platelets and differential  
• 
Hepatic function panel (AST, ALT, albumin, total and direct 
bilirubin, alkaline phosphatase)  
• 
PT/INR  
• 
Creatinine  
• 
Lipase 
• 
Creatinine kinase 
• 
HCV RNA viral load 
• 
HCV resistance testing * 
*If HCV RNA is detectable, the participant would be asked to return to have HCV resistance testing done, and 
HCV resistance testing should be done if the participant is still on study medication at time of delivery and study 
medication was discontinued at the delivery visit because the participant was planning to breastfeed. 
 

 
 
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7.4.5 Infant Follow-Up Visits (iV1, iV2, iV3) 
After delivery, infants will be seen at the following time points:  
iV1:  8 weeks ± 6 weeks 
iV2:  6 months ± 2 weeks 
iV3:  12 months ± 2 weeks 
 
The following procedures will occur at the Infant Follow-Up Visits (iV1, iV2, iV3).  If 
blood sampling is not possible, then the results can be collected from the infant’s 
medical record if available.  Results of physical and developmental exams will be 
shared with the mother, and if necessary with the infant’s routine healthcare 
provider.  Referrals will be made as necessary. 
 
Table 9: Infant Follow-Up Visits (iV1, iV2, iV3) 
Visit iV1, iV2, iV3 Infant Follow-Up Visits 
Component 
Procedures 
Administrative and Regulatory 
 
• 
Review/update locator information 
• 
Review infant demographics (iV1) 
• 
Sign release(s) for medical records for infant 
• 
Provide reimbursement 
• 
Schedule next visit (iV1, iV2) 
• 
Record/update AE’s 
• 
Document pre-existing conditions (iV1) 
Clinical 
 
• 
Review/update medical history*** 
• 
Review/update concomitant medications*** 
• 
Growth 
assessment 
including 
weight, 
length, 
and 
head 
circumference*** 
• 
Perform age appropriate physical examination   
• 
Developmental Exam^ (iV2 and iV3 only); discuss results with mother, 
routine healthcare provider if needed and provide referrals (i.e. early 
intervention) if necessary 
• 
Provide available test results as applicable (i.e. HCV RNA test) 
Laboratory 
 
• 
Collect infant blood 
• 
HCV RNA (iV1, iV2, and as applicable at iV3)* 
• 
HCV resistance testing (if HCV RNA is detectable)** 
^To include  an age appropriate developmental exam, Bayley Scales of Infant and Toddler Development, and a 
general developmental screening tool completed by parents, Ages and Stages Questionnaire (ASQ).  These 
evaluations will be done/reviewed by a qualified individual.  
*If HCV RNA is detectable at iV1 or iV2, the infant would also have an HCV RNA performed at iV3.  If HCV RNA 
is non-detectable/negative at both iV1 and iV2, no additional samples are needed.  If infant sample is unable to 
be collected at iV1 and/or iV2, a sample may be collected at iV3.  
**If HCV RNA is detectable at iV1 or iV2, the infant would need to return to have HCV resistance testing. 
***May be collected from the medical record as applicable    
 
 
7.5 Follow-up Procedures for Participants Who Permanently Discontinue 
Study Medication 
 
Participants will be permanently discontinued for significant laboratory abnormalities 
or adverse events as outlined in section 9.3 and 9.4 or if they choose to discontinue 
the study medication. If participants miss greater than one dose per week (averaged 
over the duration of the study) they may be discontinued at the discretion of the 
Protocol Chair/Principal Investigator.  Participants who are permanently discontinued 
from the study will be instructed to return the study medication and study medication 

 
 
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log.  All protocol-specified study procedures may continue for safety except the 
following: 
• Provision of study medication 
• Provision of medication use adherence counseling  
 
The following procedures will be performed at the visit in which study medication use 
is permanently discontinued: 
• Collection of blood for PK analysis (single time point) 
• HCV resistance testing 
• Viral load as needed (i.e. participant withdraws, investigator opinion) 
• Medical history review  
• Concomitant medication review 
• Brief physical examination including vital signs, if indicated. 
 
 
The participant will be asked to continue in the study and complete all remaining 
scheduled maternal and infant visits per protocol for safety.  
 
7.5.1 Interim Visits 
 
Interim visits may be performed at any time during the study. Study procedures may 
be repeated at interim visits as deemed clinically indicated.  All interim contacts and 
visits will be documented in participants' study records and on applicable CRFs.  
 
7.6 Pharmacokinetics  
 
All enrolled participants will undergo intensive serum PK specimen collection 
procedures at the PK1 and PK3 visits. These collections will occur at study visits as 
described in Table 9.  
 
Table 9:  SOF and VEL PK Sampling 
Time since 
SOF/VEL* 
Plasma 
Sample 
Timed 
Meal 
SOF/VEL 
PK sample 
(mL) 
Protein 
Binding (mL) 
PBMC/DBS 
sample (mL) 
Total blood 
(mL) 
predose 
+ 
 
4 
0 
4 
8 
DOSING 
 
+ 
 
 
 
 
30 mins 
+ 
 
4 
0 
0 
4 
1 hour 
+ 
 
4 
0 
0 
4 
2 hours 
+ 
 
4 
6 
0 
10 
3 hours 
+ 
 
4 
0 
0 
4 
4 hours 
+ 
 
4 
0 
0 
4 
5 hours 
+ 
 
4 
0 
0 
4 
8 hours 
+ 
 
4 
0 
0 
4 
12 hours 
+ 
 
4 
0 
0 
4 
24 hours 
+ 
 
4 
0 
0 
4 

 
 
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*Time listed is the target time for PK sample. If a sample is collected prior to next scheduled PK sample it will not 
be considered a protocol deviation.  Only missed samples will be considered protocol deviations. 
 
Participants will be instructed to bring their daily dose of SOF/VEL to the visits 
requiring intensive PK sampling (PK1 and PK3 visits) for timed administration.  If they 
do not bring their dose, then a dose of study medication can be dispensed from the 
pharmacy/PoR/designee.  Intravenous catheters may be placed during intensive PK 
visits.  A pre-dose sample will be collected.  Study drug will be administered as close 
as possible to the participant’s normal dose time if possible and within 5 minutes of 
completing and within 30 minutes of initiating a standardized moderate-fat-calorie 
breakfast (~600 calories and 25 to 30% fat) following an overnight fast (no food or 
liquids, except water, for at least 8 hours). Participants will be restricted from food 
intake until after collection of the 4 hour blood draw and restricted from water 
consumption 1 hour before and 2 hours after dosing, except for approximately 240 mL 
of water given with study drug and standardized meal.  Whole blood will be collected 
into appropriate sized Vacutainer® Plus plastic sterile tube(s) with K2EDTA (spray 
dried) additive.  Immediately after collection, the collection tube will be inverted 8 to 
10 times to allow mixing with the anticoagulant . Further processing instructions can 
be found in the Specimen Collection and Procedures Manual.   
 
For the PK2 visit (sparse PK visit), a single 8mL blood sample (PK and PBMCs) will 
be drawn noting the time of the collection and the time at which the participant took 
their previous SOF/VEL dose.  
 
7.7 Adherence Counseling and Assessment 
 
Adherence counseling to the study protocol will be performed at each study visit.   
Additionally, investigators may use text messaging (daily or weekly), follow-up phone 
calls, email, and/or meeting study participants at their regular clinic visits in order to 
improve adherence to the study medication and procedures.  All options will be 
included in the informed consent document and will be tailored to the participant’s 
needs.  At the follow-up visits (PK1, PK2, PK3 and End of Treatment Visit), all 
remaining medication will be counted, recorded and returned to the pharmacy.  Study 
participants will be given a medication administration log and also may be instructed 
on the use of photo/video capture of study medication administration using an IRB 
approved and secure mechanism  to assist in study medication adherence.  
Participants will take a photo/video of themselves when taking their study medication 
daily through an IRB approved mechanism and send the photo/video via text to the ID 
research designated study smart phone or the photos/videos may also be reviewed 
during study visits.  The provided paper log will have instructions on how and when to 
take the medication.  Research staff will recommend that participants take the study 
medication consistently at a time convenient for their schedule, preferably in the 
morning.  If a participant forgets to take a dose, she should take the missed dose as 
soon as she remembers but should not take more than one tablet of SOF/VEL per 
day.  Directions on how to store the medication as well as what to do if the medication 
is lost or stolen will be given to the participant and included on the medication 
administration log as applicable.  Participants will be asked to bring the medication 

 
 
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administration log to the next study visit for review.  Medication administration logs will 
be collected at the next visit and a new log (as applicable) will be given with each 
bottle/refill of study medication.  The completed logs will be compared to the 
photos/videos, as available.  Adherence counseling will be performed at the following 
visits: enrollment, PK1, PK2, and PK3 (and at delivery if the participant has not 
completed the 12 weeks of study medication and is not breastfeeding).   
 
 
7.8 Clinical Evaluations and Procedures 
 
Physical exams will include the following assessments:  
 
• General appearance 
• Weight  
• Vital signs 
 Temperature 
 Pulse  
 Blood pressure 
 Respirations 
• Height^ 
• Abdomen*  
• Head, Eye, Ear, Nose and Throat (HEENT) Examination* 
• Lymph nodes*  
• Neck*  
• Heart* 
• Lungs*  
• Extremities* 
• Skin*  
• Neurological* 
 
^obtained at Screening Visit only 
*may be omitted after the Enrollment Visit 
 
Additional clinical assessments may be performed at the discretion of the examining 
clinician in response to symptoms or illnesses present at the time of the exam. 
 
 
7.9 Laboratory Evaluations 
 
Local Laboratory (UPMC Clinical Laboratory) 

 
 
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• Blood 
o HIV serology  
o Hepatitis B Virus testing 
▪ HBsAg  
▪ Anti-HBc 
▪ Anti-HBs 
o PT/INR 
o Lipase 
o Creatine kinase 
o HCV RNA viral load: Maternal and Infant  
o Hepatitis C genotype (as required at screening) 
o CBC with differential and platelets 
o Creatinine  
o Hepatic function panel 
▪ AST 
▪ ALT  
▪ Albumin 
▪ Total and direct bilirubin 
▪ Alkaline phosphatase 
 
Outside Laboratory 
• Blood 
o Blood PK for SOF and VEL(University of Colorado) 
o Dried Blood Spots and Peripheral Blood Mononuclear Cells for 
intracellular concentrations of the active SOF metabolite (GS-461230) 
(University of Colorado) 
o Protein Binding Assay (University of Colorado) 
o HCV Resistance Testing (Quest Lab) 
 
7.10              In Depth Interviews 
 
 
At the screening visit and the end of treatment visit a trained interviewer from the Qual 
EASE team (CHRC Data Center, University of Pittsburgh) will conduct an in- depth 
interview about Hepatitis C infection, risks of perinatal transmission, concerns about 
treatment during pregnancy and drug research during pregnancy.  The interviewer will 
use the HIP Script to conduct the interview.  All interviews will be recorded and 
transcribed verbatim.  The original recordings will be destroyed after transcription.  
The interview may be conducted at the visit or prior to the next visit via phone or a 
secure video conferencing system.  
 
7.11 Specimen Collection and Processing 
 
The study site will adhere to the standards of good clinical laboratory practice and 
standard operating procedures for proper collection, processing, labeling, transport, 
and storage of specimens. Specimens for SOF/VEL PK analysis and protein binding 

 
 
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will be transported from the Clinical Research site to the Magee-Womens Research 
Institute Microbiology Laboratory for storage until they are shipped to the appropriate 
laboratory for processing and analysis.  The samples will be shipped when arranged 
with the respective laboratories listed for PK analysis and protein binding. 
 
7.12 Biohazard Containment 
 
As the transmission of hepatitis C and other blood-borne pathogens can occur through 
contact with contaminated needles, blood, and blood medications, appropriate blood 
and secretion precautions will be employed by all personnel during blood draws and 
transport, shipping and handling of all specimens for this study as recommended by 
the CDC and National Institutes of Health (NIH). All biological specimens will be 
shipped using packaging mandated by Code of Federal Regulations (CFR) 42 Part 
72. All dangerous goods materials, including diagnostic specimens and infectious 
substances, must be shipped according to instructions detailed in the International Air 
Transport Association (IATA) Dangerous Goods Regulations. Biohazardous waste will 
be contained according to institutional, transportation/carrier, and all other applicable 
regulations.   
8 
ASSESSMENT OF SAFETY 
 
8.1 Safety Monitoring 
 
Study investigators are responsible for continuous close safety monitoring of all study 
participants, and for notifying Gilead Sciences if unexpected and/or serious events 
occur. Two independent physician safety monitors, who are not otherwise involved in 
the study will review the safety data once per month or more frequently as needed 
throughout the period of study implementation, discuss study medication 
management, and address any potential safety concerns.  
 
8.2 Clinical Data and Safety Review 
 
The clinical research investigators are responsible for the initial evaluation and 
reporting of safety information at the participant level to the Protocol Chair.  The 
Protocol Chair is responsible for alerting Gilead Sciences if unexpected concerns 
arise. Additional reviews may be conducted at each of these levels as dictated by the 
occurrence of certain events. 
 
The Reproductive Infectious Disease Data Management team will review incoming 
safety data on an ongoing basis. Events identified as questionable, inconsistent, or 
unexplained will be queried for verification. The clinical investigator and two 
independent safety monitors (one obstetrician and one pediatrician) will communicate 
approximately every month, as applicable to review clinical data reports. The content, 
format and frequency of the clinical data reports will be agreed upon by the 
independent safety monitors and the study investigators in advance of study 
implementation. In addition to the routine safety data reviews, the independent safety 

 
 
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monitors and the study investigators will convene on an ad hoc basis to make 
decisions regarding the handling of any significant safety concerns. If necessary, 
external experts representing expertise in the fields of pregnancy, newborn medicine, 
infectious diseases, hepatology and medical ethics may be invited to join the safety 
review. A recommendation to pause or stop the trial may be made at this time or at 
any such time that the safety review team agrees that an unacceptable type and/or 
frequency of AEs has been observed. 
 
To assist in consistent and efficient concomitant medication recording for inpatient 
admissions (delivery and serious adverse event), the UPMC Health Record Research 
Request (R3) service may be used to extract concomitant medications administered 
during any inpatient admission for maternal and infant study participants. If utilized, 
the extracted data will be provided to the study team in a format agreed upon by R3 
and data management.  Additional data may be extracted by R3 and/or the MOMI 
database to assist in data capture (i.e. APGARS, obstetric age, pregnancy outcomes). 
 
 
8.3 Adverse Events Definitions and Reporting Requirements 
 
8.3.1 Adverse Events  
 
An AE is defined as any untoward medical occurrence in a clinical research participant 
administered an investigational medication and which does not necessarily have a 
causal relationship with the investigational medication. As such, an AE can be an 
unfavorable or unintended sign (including an abnormal laboratory finding, for 
example), symptom or disease temporally associated with the use of an 
investigational medication, whether or not considered related to the medication. The 
term “investigational medication” for this study refers to the study medication. 
 
Study participants will be provided instructions for contacting the study site to report 
any untoward medical occurrences they may experience throughout their participation 
in the study.  Participants receiving prenatal care and/or delivering at Magee-Womens 
Hospital will be instructed to come to Magee-Womens Hospital if they experience any 
adverse events requiring evaluation. Participants will be seen by a physician 
investigator/study clinician. If the participant is not receiving care at Magee-Womens 
Hospital, then they will be instructed to seek medical care with their local primary care 
physician/obstetrical team.  Participants may have an unscheduled visit with the 
physician investigator/study clinicians as necessary or desired.  In cases of potentially 
life-threatening events, participants will be instructed to seek immediate emergency 
care. With appropriate permission of the participant, whenever possible, records from 
all non-study medical providers related to untoward medical occurrences will be 
obtained and required data elements will be abstracted and recorded on study CRFs. 
All participants reporting an untoward medical occurrence will be followed clinically as 
deemed appropriate by a physician investigator until the occurrence resolves (returns 
to baseline) or stabilizes. 
 

 
 
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Study site staff will document AEs reported by or observed in enrolled study 
participants by severity and presumed relationship to investigational medication, 
including gradable laboratory findings. Medication from hospital admissions may be 
extracted from the medical record using the UPMC Health Record Research Request 
(R3) service and/or MOMI database to ensure consistency and accuracy of reporting.  
 
Some of the study participants will have opioid use disorder (OUD) and may be 
prescribed either methadone or buprenorphine as treatment. Infants who are exposed 
to these medications often experience neonatal opioid withdrawal syndrome (NOWS). 
Given that this is an expected outcome for this treatment, we will not report this as an 
AE. All opioid exposed infants in the UPMC hospital system have at minimum a 5-day 
observation period and those who require pharmacologic treatment for NOWS can 
remain in the hospital for up to a month (mean 14 days). A study pediatrician, will 
review all NOWS related hospitalization records to ensure that there are no hospital 
events that are outside the scope of standard NOWS findings, for example 
pneumonia, sepsis, and hypoglycemia. 
 
Additionally, certain adverse events are expected as a consequence of labor and 
delivery.  Prior to delivery, expected pregnancy findings, such as lower extremity 
edema, physiologic discharge of pregnancy, and pain from contractions as determined 
by a study clinician will not be considered adverse events. During the postpartum 
period, expected pregnancy findings such as lower extremity edema, abdominal pain 
from uterine cramping, incisional pain from a cesarean section, perineal pain after 
vaginal delivery, and vaginal bleeding as determined by a study clinician will not be 
considered  adverse events. Expected symptoms may be further defined and reported 
accordingly in a protocol specific standard operating procedure (SOP) or guidance 
document.   
 
AE severity will be graded per the most current DAIDS Table for Grading Adult and 
Pediatric Adverse Events.   
 
8.3.2 Serious Adverse Events  
 
An SAE will be defined as an AE that:  
 
• Results in death 
• Is life-threatening  
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
except those that are expected such as hospitalization for neonatal opioid 
withdrawal syndrome.  
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly/birth defect 
• Is an important medical event that may not result in death, be immediately life-
threatening, or require hospitalization but may jeopardize the participant or 
require intervention to prevent one of the outcomes listed in the definition 
above. 

 
 
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8.3.3 Adverse Event Relationship to Study Medication 
 
Relatedness is an assessment made by the physician investigator of whether or not 
the event is related to the study agent.  
• Related: There is a reasonable possibility that the AE may be related to the 
study agent(s) 
• Not Related: There is not a reasonable possibility that the AE is related to the 
study agent(s) 
 
8.4 Expedited Adverse Event Reporting Requirements  
 
8.4.1 Reporting Requirements for this Study 
 
All adverse events will be reported to Gilead Sciences on a monthly basis.  All serious 
adverse events that are considered unexpected and related to the study medication 
will be reported to the University of Pittsburgh Institutional Review Board, the FDA and 
Gilead Sciences according to their reporting guidelines.   
 
8.4.2   Grading Severity of Events 
 
The most current Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table) is available on the RSC website at 
http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
 
8.5 Regulatory Requirements 
 
Information on all applicable AEs will be included in reports to the FDA and other 
applicable government and regulatory authorities. The Protocol Chair will submit AE 
information in accordance with the requirements of the University of Pittsburgh IRB. 
 
8.6 Social Harms Reporting 
 
Although every effort will be made to protect participant privacy and confidentiality, it 
is possible that participants’ involvement in the study could become known to others 
and that social harms may result. Social harms that are judged by the study 
investigators to be serious or unexpected will be reported to Gilead Sciences and to 
the University of Pittsburgh IRB.   
 
 

 
 
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9 
CLINICAL MANAGEMENT 
 
Guidelines for clinical management and permanent discontinuation of study 
medication are outlined in this section. In general, the physician investigators will only 
discontinue study medication in consultation with the independent physician safety 
monitor(s) if they feel that the risk of study medication continuation outweighs the 
benefits of study medication continuation. The physician investigator(s) will document 
all permanent discontinuations on applicable CRFs. 
 
9.1 Grading System 
 
AE severity grading is described in Section 8.3.1. 
 
9.2 Dose Modification Instructions 
 
No dose modifications will be permitted in this study. 
 
9.3 General Criteria for Permanent Discontinuation of Study Medication 
 
A participant will be permanently discontinued from medication use by the physician 
investigator(s) for any of the following reasons, according the HCV treatment 
guidelines23:  
 
• 5-fold or greater increase in ALT or AST at the PK1 or PK2 visit compared to 
baseline result (Screening visit), confirmed by immediate repeat testing 
• Any increase of ALT or AST of less than 5-fold from baseline (Screening visit) 
at the PK1 or PK2 visit that is accompanied by any weakness, nausea, 
vomiting, or jaundice 
• 3-fold or greater increase in ALT or AST accompanied by bilirubin >2x the 
upper limit of normal, confirmed on immediate repeat testing 
• Increase HCV RNA viral load by greater than 10-fold at PK2 visit (6-8 weeks 
after starting treatment) 
• Participant is unable or unwilling to comply with required study procedures 
• If the participant delivers prematurely (and is still on study medication) and 
desires to breastfeed  
• Participant might be put at undue risk to their safety and well-being by 
continuing medication use, according to the judgment of the study 
investigator(s). The study investigators will consult with the independent safety 
physician prior to all study medication discontinuation instituted for this reason.  
 
Any time a participant is permanently discontinued from study medication (prior to 
completion of the 12 week course of study medication), HCV resistance testing will be 
performed.  
 

 
 
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9.4 Permanent Discontinuation in Response to Adverse Events 
 
Grade 1 or 2 
In general, a participant who develops a Grade 1 or 2 AE as defined by the DAIDS 
Table for Grading Adult and Pediatric Adverse Events, Version 1.0, December 2004 
(Clarification dated August 2009) regardless of relationship to study medication will 
continue study medication use.  
 
Grade 3 
For participants who develop a Grade 3 AE as defined by the DAIDS Table for Grading 
Adult and Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated 
August 2009) that is judged by the study investigators to be unrelated to study 
medication, the study medication will continue.  The study medication must be 
permanently discontinued for participants who develop a Grade 3 AE judged by a 
physician investigator to be related to the study medication. 
 
Grade 4 
If a participant develops a Grade 4 AE as defined by the DAIDS Table for Grading 
Adult and Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated 
August 2009) and the AE is determined to be related to study medication, then study 
medication must be permanently discontinued. 
 
Any time a participant is permanently discontinued from study medication (prior to 
completion of the 12 week course of study medication), HCV resistance testing will be 
performed. 
 
9.5 HIV-1 Infection 
 
Participants who are positive for HIV (known or positive at Screening) will not be 
eligible to participate.  If HIV seroconversion occurs during the time of study 
medication use, the study medication will continue.     
 
9.6 Criteria for Early Termination of Study Participation  
 
Participants may voluntarily withdraw from the study for any reason at any time. The 
study investigators also may withdraw participants from the study to protect their 
safety and/or if they are unwilling or unable to comply with required study procedures. 
Participants also may be withdrawn if Gilead Sciences, government or regulatory 
authorities, including the FDA and Office for Human Research Protections (OHRP), 
or site IRBs/ECs terminate the study prior to its planned end date. Detailed reason for 
the withdrawal of a participant will be documented in the research record.  Every 
reasonable effort will be made to continue to follow the participant as scheduled for 
safety.     

 
 
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10 
STATISTICAL CONSIDERATIONS 
 
10.1 Overview and Summary of Design 
This is a Phase 1, single-arm, open label study of treatment for chronic HCV 
infection during pregnancy in 10 HCV-infected pregnant women with a 12-week 
course of SOF/VEL. 
 
10.2 Study Endpoints 
 
Pregnant women meeting all of the criteria in section 5.2 and 5.3 will be enrolled into 
the study and followed prospectively through 12 weeks after the last dose of study 
medication.  Infants will be enrolled upon delivery and followed prospectively through 
approximately one year of age. 
10.2.1 
Primary Endpoints: Maternal 
The primary endpoints of the study are primary plasma PK parameters (specifically 
AUCtau, Cmax, and Cmin) of VEL, SOF, and GS-331007 assessed at 3 weeks (+/- 7 
days of medication initiation.    
 
10.2.2            Secondary Endpoints: Maternal 
 
The secondary endpoints of the study are: 
1) Secondary plasma PK endpoints of VEL, SOF and GS-331007: 
a. Free-fraction of VEL, SOF and GS-331007 
2) Secondary PK endpoints for intracellular SOF (GS-461203) 
a. Pre-dose GS-461203 concentrations from dried blood spots and 
peripheral blood mononuclear cells 
3) Maternal sustained virologic response after 12 weeks of therapy (SVR12) 
4) Adverse events including clinical and laboratory changes 
5) Pregnancy outcomes including the following: 
a. delivery prior to 37 completed weeks of gestation 
b. stillbirth or intrauterine fetal demise  
c. intrapartum hemorrhage 
d. postpartum hemorrhage 
e. non-reassuring fetal status 
f. chorioamnionitis 
g. hypertensive disorders of pregnancy 
h. gestational diabetes 
i. intrauterine growth restriction 
10.2.3 
Exploratory Endpoints 
 
The exploratory endpoint of the study is: 

 
 
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1.) In depth interviews conducted before enrollment in screened participants and 
after completion of treatment in enrolled participants. 
 
Secondary Endpoints: Infant  
Consistent with the secondary study objectives, the following secondary endpoint 
will be assessed for infants: 
 Major malformations, defined as structural abnormalities with surgical, 
medical, or cosmetic importance. 
 Weight, length, and head circumference at birth, 8 weeks, six months and 12 
months. 
 Neurodevelopmental assessments at 6 months and 12 months as measured 
by Bayley Scales of Infant and Toddler Development and Ages and Stages 
Questionnaire (ASQ). 
 Perinatal HCV transmission assessed by presence of HCV RNA at 8 weeks, 
six months or 12 months. 
 
10.3 Sample Size 
To evaluate the primary objective, we estimate a desired sample size of 10 
participants.  In order to maintain our sample size, any participant who discontinues 
treatment during the 12-week treatment period will be replaced.  Based on SOF/VEL 
prescribing information, we will have 87% power to detect a 50% decrease in VEL 
AUC and >99% power to detect a 2-fold increase. For power calculations we chose 
this degree of change in VEL AUC because the therapeutic range of SOF/VEL is 
quite wide and decreases in VEL AUC of up to 50% and increases of up to 2-fold are 
still associated with efficacy and have acceptable safety/tolerability, respectively. 
The FDA does not recommend co-administration of VEL with EFV because it 
decreases the VEL AUC by >50% [34].  Additionally, this sample size provides an 
estimated power of 0.82 to detect a 25% change in the AUC of the SOF, given the 
reported interpatient variability of 35.6% among female patients Power 
determinations were performed in SAS v. 9.4 (SAS, Cary, NC). 
 
Any participant that discontinues the study before the PK3 visit is completed or if a 
participant reports missing more than 1 dose per week averaged over the duration of 
the study then they will be replaced by recruiting another participant into the study.   
 
10.4 Participant Accrual and Retention 
 
Pregnant and chronically HCV-infected women who meet the criteria outlined in 
Section 5 and are interested in participating, will be enrolled into this study. Once a 
participant is enrolled, the study staff will make every reasonable effort to retain her 
for the entire study period. Any participant lost to follow-up prior to Visit 7 will be 
replaced.  
  

 
 
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10.5 Data Analysis 
10.5.1 Analysis of SOF and VEL concentrations 
Between-group comparisons will evaluate changes in SOF and VEL PK parameters 
between the historical controls (nonpregnant women without severe renal disease or 
cirrhosis) compared to the 10 pregnant women. Area under the time concentration 
cure over a dosing interval (AUCtau), maximum concentration (Cmax), and minimum 
concentration (Cmin) will be calculated, as applicable.  The PK parameters (including 
the free-fraction of VEL and intracellular SOF concentrations) of the pregnant 
women will be compared to the historical control group by calculating the geometric 
mean ratios and 90%CIs. Drug concentrations will be summarized descriptively 
(mean, median, minimum, maximum, standard deviation) by study visit.    
 
10.5.2 Analysis of SVR12 
 
Outside of pregnancy, 99% of patients treated with SOF/VEL for 12 weeks obtained 
an SVR12.  In this pilot study, we estimate that at least 9 out of the 10 chronically 
HCV-infected pregnant women will have a SVR12 after treatment.  Participants who 
do not complete the treatment course or report low adherence will be excluded from 
the analysis. 
 
10.5.3 Analysis of Safety Endpoints 
 
Rates of abnormal safety laboratory assessments will be compared to those 
reported in the literature on historic controls and rates of adverse pregnancy 
outcomes will be compared to historic HCV-infected pregnant women who have 
delivered at our institution.  Statistical significance will be determined by chi-square 
test. 
 
Qualitative Analysis 
 
Following transcription of the IDIs, the Qual EASE team will develop a qualitative 
codebook using an editing approach to ensure that all relevant topics and themes 
are represented. Two trained qualitative coders from Qual EASE will then be trained 
in the codebook. A primary coder will code all interviews in the pre- and post- 
treatment interview groups, and a secondary coder will code half of the interviews in 
the pre- and post-treatment interview groups. Coding will be completed using Atlas.ti 
software, which will help to determine the frequency and prevalence of the topics 
and themes which were discussed. Cohen’s Kappa scores will be calculated to 
determine intercoder reliability.   
 
 
10.5.4 Data and Safety Monitoring Plan 
 
No Data and Safety Monitoring Board oversight is planned for this study, however a 
Study Steering Committee comprised by the Protocol Chair, a second physician 

 
 
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investigator from the University of Pittsburgh, a laboratory scientist from the 
University of Pittsburgh, the Data Management lead statistician and a representative 
from Gilead Sciences Clinical Research will provide oversight. Reviews of study 
progress, including rates of participant accrual, retention, completion of primary and 
main secondary endpoint assessments will take place approximately every 3 
months, and as needed.  At the time of these reviews, or at any other time, the 
Study Steering Committee may recommend that the study proceed as designed, 
proceed with design modifications, or be discontinued.  Two independent safety 
physicians experienced with monitoring of clinical trials among pregnant women will 
conduct interim safety reviews on a monthly basis or more frequently at the request 
of the Study Steering Committee.  
11 
DATA HANDLING AND RECORDKEEPING 
 
11.1 Data Management Responsibilities 
 
Study questionnaires will be developed by the study team in conjunction with data 
management.  
 
11.2 Source Documents and Access to Source Data/Documents 
 
The site will maintain source data/documents in accordance with current DAIDS 
policies. (http://rsc.tech-res.com/policiesandregulations/)  
 
The study team will maintain, and store securely, complete, accurate and current 
study records throughout the study. In accordance with U.S. regulations regarding 
testing investigational medications, the study investigator will maintain all study 
documentation for at least two years following the date of marketing approval for the 
study medications being tested for the indication in which they were studied. If no 
marketing application is filed, or if the application is not approved, the records will be 
retained for two years after the investigation is discontinued and the US FDA is 
notified. For research involving children, records shall be retained at least until the 
pediatric subject reaches the age of 23. 
 
Study records will be maintained on site for the entire period of study implementation.  
 
11.3 Quality Control and Quality Assurance 
 
The study site will conduct quality control and quality assurance procedures in 
accordance with site SOPs.  

 
 
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12 
CLINICAL SITE MONITORING 
 
As this is an investigator initiated IND study, monitoring will be performed by internal 
clinical study staff (i.e. QA/QC Reviewer), PoR, laboratory staff and local data 
management team.   Internal reviews will include: 
 
• Review informed consent forms, protocol procedures, and study 
documentation 
• Assess compliance with the study protocol, Good Clinical Practices (GCP) 
guidelines, and applicable regulatory requirements (US and non-US), 
including CFR Title 45 Part 46 and Title 21 Parts 50, 56, and 312  
• Perform source document verification to ensure the accuracy and 
completeness of study data 
• Verify proper collection and storage of biological specimens 
• Verify proper storage, dispensing, and accountability of investigational study 
medications 
 
The Education and Compliance Support for Human Subject Research (ECS-HSR),  
Office of Research Protections will also oversee study activities.  The ECS-HSR has 
extensive experience in the auditing and monitoring of clinical investigations for 
compliance with GCP standards and IND commitments. To ensure appropriate 
institutional oversight of University-based IND applications, the ECS-HSR will 
periodically monitor the research oversight programs of IND Sponsors, which will 
include compliance of the Sponsor and Investigator with applicable FDA regulations, 
applicable University of Pittsburgh policies and the IRB-approved protocol and 
consent document. The frequency of these monitoring visits shall be 
determined by the ECS-HSR. 
The study investigators also will allow inspection of all study-related documentation 
by authorized representatives of Gilead Sciences, FDA, OHRP, IRBs/ECs and other 
local and US regulatory authorities.  
13 
HUMAN SUBJECTS PROTECTIONS 
 
Study investigators will make efforts to minimize risks to participants. Informed 
consent will be reviewed in detail with potential participants and all questions will be 
adequately answered prior to obtaining written informed consent.  All eligibility 
criteria will be verified prior to initiation of investigational product.  Recruitment will 
begin after receiving IRB approval and after the protocol has been submitted to the 
FDA.  The study investigators will permit audits by the NIH, Gilead Sciences, the 
FDA, OHRP, IRB, and other local and US regulatory authorities or any of their 
appointed agents. 
 

 
 
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13.1 Institutional Review Boards 
 
The study staff will ensure that the protocol, associated informed consent form, and 
study-related documents (such as participant education and recruitment materials) 
are reviewed and approved by the University of Pittsburgh IRB prior to starting the 
study. Any amendments to the protocol or informed consent will be approved by the 
University of Pittsburgh IRB prior to implementation. 
 
13.2 Study Coordination 
 
Catherine Chappell, MD MSc holds the Investigational New Drug (IND) application for 
this study. Assignment of all sponsor responsibilities for this study will be specified in 
a Clinical Trials Agreement (CTA) executed by the University of Pittsburgh and Gilead 
Sciences.  Dr. Chappell will work closely with The University of Pittsburgh Office for 
Investigator-Sponsored IND and IDE Support (O3IS) who provides assistance to 
University researchers in order to ensure IND submission and notification 
requirements are met.   
 
Close coordination between the study team is necessary to track recruitment, 
enrollment, retention, AEs and unanticipated problems and to address other issues 
that may arise in a timely manner. The study investigators and the independent safety 
physician will address issues related to study eligibility, AE management/reporting and 
unanticipated problems as needed to assure consistency. Rates of accrual, protocol 
adherence, retention, and AE incidence will be reported by data management and 
monitored closely by the team as well as the Study Steering Committee. 
 
13.3 Risk Benefit Statement 
 
13.3.1 Risks 
 
General/Maternal 
 
As with any research study, there may be adverse events or side effects for the 
maternal participant or the fetus/infant that are currently unknown and certain of these 
unknown risks could be permanent, severe or life-threatening. 
 
There are no studies of SOF/VEL in pregnant women.  However there has been one 
study of a similar medication ledipasvir/sofosbuvir in 9 pregnant women.  There were 
no adverse events greater that grade 2 that were related ledipasvir/sofosbuvir.  There 
have been animal studies done in rats and rabbits as detailed in section 2.4.2.  No 
effects on fetal development have been observed in rats and rabbits at the highest 
doses tested.  However, animal reproductive studies are not always predictive of 
human response.  
 

 
 
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It is also not known if SOF/VEL is present in human breast milk.  If the participant 
delivers while still on study medication and intends to breast feed, study medication 
will be discontinued and HCV resistance testing will be done at the next study visit.  
 
There is a potential risk that the hepatitis virus may become resistant to SOF/VEL 
because the dose may not be adequate for treating pregnant women with hepatitis C 
or if the participant does not complete the entire 12 weeks of study medication.  If 
resistance occurs, this may limit the choices of effective therapy after pregnancy for 
the participant and/or possibly her infant.  
 
Overall, SOF/VEL was well tolerated by patients with chronic HCV infection (N=1035) 
with only 2 participants permanently discontinued treatment due to adverse events 
(0.2%).  The most common adverse reactions (adverse events assessed as causally 
related by the investigator and at least 10%) were headache and fatigue.  Adverse 
reactions, all grades, observed in greater than or equal to 5% of participants receiving 
12 weeks of treatment with SOF/VEL in ASTRAL-1 include: headache (22%), fatigue 
(15%), nausea (9%), asthenia (5%), and insomnia (5%). Of subjects receiving 
SOF/VEL, 79% had an adverse reaction of mild severity (Grade 1). With the exception 
of asthenia, each of these adverse reactions occurred at a similar frequency or more 
frequently in participants treated with placebo compared to participants treated with 
SOF/VEL (asthenia: 3% versus 5% for the placebo and SOF/VEL groups, 
respectively).  The adverse reactions observed in participants treated with SOF/VEL 
in ASTRAL-2 and ASTRAL-3 were consistent with those observed in ASTRAL-1. 
Irritability was also observed in greater than or equal to 5% of participants treated with 
SOF/VEL in ASTRAL-3.  In the ASTRAL-1 study, rash occurred in 2% of participants 
treated with SOF/VEL and in 1% of participants taking placebo. No serious adverse 
reactions of rash occured and all rashes were mild or moderate in severity.  In the 
ASTRAL-1 study, depressed mood occurred in 1% of participants treated with 
SOF/VEL and was not reported by any placebo participants. No serious adverse 
reactions of depressed mood occured and all events were mild or moderate in 
severity.   
 
Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected 
patients who were undergoing or had completed treatment with HCV direct acting 
antivirals, and who were not receiving HBV antiviral therapy. Some cases have 
resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported 
in patients who are HBsAg positive and also in patients with serologic evidence of 
resolved HBV infection (i.e., HBsAg negative and anti-HBc positive).  We will 
exclude participants that are anti-HBc positive for this reason.   Additionally, 
postmarketing cases of symptomatic bradycardia and cases requiring pacemaker 
intervention have been reported when amiodarone is coadministered with a 
sofosbuvir-containing regimen. Additionally, a fatal cardiac arrest occurred in a 
patient taking amiodarone that was co-administered with sofosbuvir.  For this 
reason, we will exclude participants who are taking amiodarone.   

 
 
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Laboratory abnormalities:  
Lipase Elevations: In ASTRAL-1, isolated, asymptomatic lipase elevations of greater 
than 3 times the upper limit of normal were observed in 3% and 1% of participants 
treated with SOF/VEL and placebo for 12 weeks, respectively; and in 6% and 3% of 
participants treated with SOF/VEL in ASTRAL-2 and ASTRAL-3, respectively.  
Creatine Kinase: In ASTRAL-1, isolated, asymptomatic creatine kinase elevations 
greater than or equal to 10 times the upper limit of normal were reported in 1% and 
0% of participants treated with SOF/VEL and placebo for 12 weeks, respectively; 
and in 2% and 1% of participants treated with SOF/VEL in ASTRAL-2 and ASTRAL-
3, respectively. 
 
There are known drug interactions with SOF/VEL and other prescription and non-
prescription medications.  A comprehensive list of medications will be obtained from 
participants including over-the-counter medications (i.e. antacids, St. John’s wort) and 
compared to the package insert to assess any contraindication to participation or 
necessary alterations in dosing schedules with use of the study medication.   
 
Phlebotomy or starting an IV may lead to excessive bleeding, discomfort, feelings of 
dizziness or faintness, and/or bruising, swelling and/or infection.  
 
Disclosure of HIV status may cause worry, sadness or depression. Disclosure of HIV-
positive status has been associated with depression, suicidal ideation, and denial as 
well as social isolation. Trained counselors will be available to help participants deal 
with these feelings.  
 
Participation in clinical research includes the risk of confidentiality loss. 
 
Participants will be asked to provide personal/protected health information (PHI).  All 
attempts will be made to keep PHI confidential within the limits of the law.  However, 
there is a chance that unauthorized persons will see PHI.  All paper records will be 
kept in a locked file cabinet or maintained in a locked room at Magee.  Electronic files 
will be password protected.  Only people who are involved in the conduct, oversight, 
monitoring, or auditing of this study will be allowed access to the PHI that is collected.  
Any publications from this study will not use information that will identify participants 
by name.  Organizations that may inspect and/or copy research records maintained 
at the participating sites for quality assurance and data analysis include groups such 
as the study sponsor, the National Institute of Health (NIH) or its designee and the US 
Food and Drug Administration (FDA). 
 
Technology assisted-directly observed therapy: There is a risk that people outside of 
the research team will see the directly observed dosing. The photo/video recording 

 
 
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of the dosing will be taken directly into the PittBox app and stored in this system for 
the research staff to access.  .  While the app is password protected, someone may 
access the information if they gain access to the password/app on the participant’s 
personal device.  Likewise, the telephone numbers for these communications could 
also be visible to third parties.  
 
Fetus/infant:   
There is not data on use of this medication during pregnancy so the effects on a 
fetus/unborn child are not known.  The study medication may cross the placenta and 
get to the fetus/unborn infant exposing the fetus to the study medication.  It is unknown 
whether a fetus/unborn infant whose mother took SOF/VEL during pregnancy will 
develop normally or have side effects.   
 
Obtaining blood samples from the infant may cause them to cry, cause bleeding, 
bruising or a clot and may be distressful to watch the infant have their blood drawn.   
 
13.3.2 Benefits 
 
This study is a safety study of use of SOF/VEL in pregnancy and as such the study 
medication may not treat HCV in pregnancy as it may not be the correct dose. 
Participants and others may benefit in the future from information learned from this 
study. Specifically, information learned in this study may lead evidence-based 
guidance for the treatment of chronic hepatitis C infection in pregnancy and prevention 
of perinatal HCV transmission.  
 
 
13.4 Informed Consent Process 
 
Written informed consent will be obtained from each study participant prior to 
performing study procedures. Consent may be obtained electronically if approved by 
the IRB and utilizing an IRB approved mechanism.  In obtaining and documenting 
informed consent, the study investigators will comply with applicable local and US 
regulatory requirements and will adhere to GCP and to the ethical principles that have 
their origin in the Declaration of Helsinki. Participants may be provided with a copy of 
the informed consent form if they chose. 
 
The informed consent process will cover all elements of informed consent required by 
research regulations. In addition, the process specifically will address the following 
topics of importance to this study: 
 
• The unknown safety and proven efficacy of the study medications 
• The importance of daily adherence to the study medication 
• The importance of adherence to the study visit and procedures schedule  
• The potential medical risks of study participation (and what to do if such risks 
are experienced) 

 
 
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• The benefits of study participation  
• The distinction between research and clinical care 
• The right to withdraw from the study at any time 
 
13.5 Participant Confidentiality 
 
All study procedures will be conducted in private, and every effort will be made to 
protect participant privacy and confidentiality to the extent possible. All study-related 
information will be stored securely at the clinical research unit. All participant 
information will be stored in locked areas with access limited to the clinical study staff. 
All laboratory specimens, study data collection, and administrative forms will be 
identified by coded number (PTID) only to maintain participant confidentiality. All 
records that contain names or other personal identifiers, such as locator forms and 
informed consent forms, will be stored electronically in the University of Pittsburgh 
REDCap system. Appropriate firewall and virus scanning software are installed and 
updated routinely by hospital support staff. Forms, lists, logbooks, appointment books, 
and any other listings that link participants’ ID numbers (PTID) to identifying 
information will be stored in a separate, locked area with limited access. Participants’ 
study information will not be released without their written permission, except as 
necessary for review, monitoring, and/or auditing by the following: 
 
• Representatives of the US Federal Government, including the US FDA, the 
US OHRP and other local and US regulatory authorities 
• Representatives of Gilead Sciences 
• Study staff  
• University of Pittsburgh IRB 
• University of Pittsburgh Education and Compliance Office for Human Subject 
Research (ECO-HSR) 
 
13.6 Special Populations 
 
13.6.1 Pregnant Women 
 
Pregnant women will be offered enrollment in this study in accordance with guidelines 
set forth in the US 45 CFR 46. 
 
13.6.2 Children 
 
Infant procedures will begin at the time of delivery if delivered at Magee-Womens 
Hospital or at iV1 visit if infant delivered outside of Magee-Womens Hospital in 
accordance with guidelines set forth in the US 45 CFR 46 and DAIDS policy 
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Document
s/enrollingchildrenrequirements.pdf).  
 

 
 
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13.7 Compensation 
 
 Participants will be compensated for time and effort in this study, and/or be 
reimbursed for travel to study visits and time away from work. Reimbursement 
amounts will be specified in the informed consent form.  Compensation may include 
parking/bus passes, assistance with transportation, and additional incentives for 
making study appointments within the window period.  If needed and desired, 
compensation for overnight stay during the PK-1 and PK-3 visits may be provided to 
participants.  
 
13.8 Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases 
including HIV-1 identified among study participants to health authorities. Participants 
will be made aware of reporting requirements during the informed consent process. 
 
13.9 Access to HIV-related Care 
 
13.9.1 HIV Counseling and Testing 
 
HIV testing will be performed at Screening. HIV test-related counseling will be 
provided to all potential study participants who consent to undergo HIV-1 screening to 
determine eligibility for participation.  Counseling will be provided in accordance with 
standard HIV counseling policies and methods.  Participants are expected to have 
HIV screening as part of routine prenatal care at 28 weeks’ gestation, and if clinically 
indicated during the study. 
 
13.9.2 Care for Participants Identified as HIV-Positive 
 
Identified as HIV-Positive Prior to Enrollment 
An individual who has been identified as infected with HIV-1 will not be eligible to 
participate and will be referred to the Pittsburgh AIDS Center for Treatment (PACT).  
 
Identified as HIV-Positive While on Study Medication 
The participant will continue with the study medication and study procedures, and will 
be immediately referred to PACT or another clinic/provider convenient for the patient.   
 
13.10 Study Discontinuation 
 
This study may be discontinued at any time by Gilead Sciences, the US FDA, the 
OHRP, other government or regulatory authorities, or the University of Pittsburgh IRB. 

 
 
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14 
PUBLICATION POLICY 
The University of Pittsburgh study investigators will be responsible for publication of 
the results of this study. The manuscript draft will be sent to Gilead Sciences 
approximately 30 days prior to submission for their review and approval.   
 
15 
APPENDICES 
 

 
 
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APPENDIX I: SCHEDULE OF STUDY VISITS AND EVALUATIONS (Mother) 
  
  
SCR 
(V1) 
ENR 
(V2) 
PK1, PK2, PK3 
(V3, V4, V5) 
 
PK1a, PK2a 
(V3a, V5a) 
End of 
Treatment 
(V6) 
Delivery** Post treatment  
(V7) 
ADMINISTRATIVE AND REGULATORY 
  
  
  
 
 
  
  
Informed consent 
X 
  
  
 
 
  
  
Assess informed consent comprehension 
X 
  
  
 
 
  
  
Assignment of PTID 
X 
  
  
 
 
  
  
Locator information 
X 
X 
X 
 
X 
X 
X 
Demographic information 
X 
  
  
 
 
  
  
Visit Questionnaire 
X 
X 
X 
X 
X 
X 
X 
In-depth Interview 
X 
 
 
 
X 
 
 
Eligibility assessment  
X 
  
  
 
 
  
  
Eligibility confirmation 
  
X 
  
 
 
  
  
Reimbursement 
X 
X 
X 
X 
X 
X 
X 
Record/ update AEs 
  
  
X 
X 
X 
X 
X 
Schedule next visit  
X 
X 
X 
 
 
X 
 
BEHAVIORAL 
  
  
  
 
 
  
  
HIV pre- and post- test counseling 
X 
* 
 
 
 
 
 
Protocol adherence counseling 
  
X 
X 
 
X 
X 
X 
Medication use/adherence counseling 
  
X 
X 
 
 
 * 
  
CLINICAL 
  
  
  
 
 
  
  
Medical history, review/obtain records  
X 
X 
X 
 
X 
X 
X 
Concomitant medications 
X 
X 
X 
 
X 
X 
X 
Document pre-existing conditions 
 X 
X 
  
 
 
  
  
Physical examination  
X(full) 
X(full) 
X (modified) 
 
X(modified) + (modified) 
X (modified) 
Assessment of fetal heart tones 
X 
X 
X 
 
X 
 
 
Provide available test results 
X 
X 
X 
 
X 
X 
X 
Collect Pregnancy Outcomes/MR review 
 
 
 
 
 
X 
 
LABORATORY  
  
  
  
 
 
  
  
HCV RNA viral load 
X 
X 
 X 
 
X 
X 
X 
HCV Genotype 
+ 
 
 
 
 
 
 
HCV Resistance testing 
 
 
* 
 
* 
* 
* 
HBV Testing 
X 
  
  
 
 
  
  
CBC with diff and platelets 
X 
 
X (V3, V4) 
 
 
 
X 
Creatinine 
X 
  
X (V3, V4) 
 
 
  
X 
Hepatic Function Panel 
X 
  
X (V3, V4) 
 
 
  
X 
Lipase 
X 
 
X (V3, V4) 
 
 
 
X  
Creatinine kinase 
X 
 
X (V3, V4) 
 
 
 
X 
HIV serology 
X 
 
 
 
 
 
 
PT/INR 
X 
 
X (V3, V4) 
 
 
 
X 
Intensive Plasma PK 
  
 
X (V3, V5) 
 
 
 
  
Sparse Plasma PK 
 
 
X (V4) 
X 
 
^ 
 
DBS for intracellular SOF 
 
 
X 
 
 
^ 
 
PBMC for intracellular SOF 
 
 
X 
 
 
^ 
 
Protein Binding Assay 
 
 
X (V3, V5) 
 
 
 
 
STUDY MEDICATION 
 
  
  
 
 
  
  
Provision of Study Medication  
  
X 
X 
 
 
*  
  
Administer Timed dose of study medication 
 
 
X (V3, V5) 
 
 
 
 
Review/collect of adherence tools 
 
X 
X 
 
X 
 
 
Collect Remaining Study Medication 
  
  
 
 
X 
 
  
*If indicated  
+May be performed or obtained from medical record 

 
 
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**May be performed during hospital admission for participants who deliver at Magee or applicable procedures 
conducted by phone for participants who deliver at outside locations.  For all participants, a chart review of the 
delivery records will be done as part of the Delivery Visit  
^ If still on study medication at the time of delivery 

 
 
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APPENDIX II: SCHEDULE OF STUDY VISITS AND EVALUATIONS (Infant) 
 
 
  
  
Delivery*** 
iV1 
(Month 1-3) 
iV2 
(Month 6) 
iV3 
(Month 12) 
ADMINISTRATIVE AND REGULATORY 
  
  
  
  
Assignment of PTID 
X 
  
  
  
Locator information 
X 
X 
X 
X 
Demographic information 
 
X 
  
  
Reimbursement 
X 
X 
X 
X 
Record/update AEs 
  
X  
X 
X 
Schedule next visit  
X 
X 
X 
 
CLINICAL 
  
  
  
  
Medical history ** 
X 
X 
X 
X 
Concomitant medications** 
X 
X 
X 
X 
Document pre-existing conditions** 
 X 
X 
  
  
Physical examination ** 
X 
X 
X 
X 
Collect growth parameters ** 
 
X 
X 
X 
Collect Baseline Information** 
X 
 
 
 
Provide available test results 
 
X 
X 
X 
Developmental Exam/Assessment 
 
 
X 
X 
LABORATORY  
  
  
  
  
HCV RNA viral load 
X 
X 
 X 
* 
HCV Resistance testing 
 
* 
* 
* 
Sparse PK from cord blood 
^ 
 
 
 
 
*If indicated 
**May be obtained from medical record as applicable 
*** May be performed during hospital admission for infants born at Magee or applicable procedures conducted 
by phone with mother for infants who deliver at outside locations.  For all participants, a chart review of the 
delivery records will be done as part of the Delivery Visit.  
^ If mother on study drug at the time of delivery and delivers at Magee-Womens Hospital 
 
 
 

 
 
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