Clinical trial NCT03312023
Conditions: Hepatitis B
Keywords: Hepatitis B HBsAg Ledipasvir/Sofosbuvir Hepatitis B treatment
Sponsor: University of Maryland, Baltimore
Start date: 2018-02-01; Completion date: 2021-06-30
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goals of therapy against chronic hepatitis B are to decrease the morbidity and mortality related to chronic HBV infection. Currently available antiviral therapy can suppress viral replication but only a small proportion attain functional cure, which is defined as HBV surface antigen-to-antibody seroconversion. Hepatitis B surface antigen (HBsAg) is a marker of persistent hepatitis B infection.

It has been observed that patients who had both hepatitis B and hepatitis C, and who were treated for their hepatitis C with 12 weeks of ledipasvir/sofosbuvir for had a decline in HBsAg levels. This study hypothesizes that a similar decrease would be seen in mono-infected hepatitis B subjects over the course of 12 weeks treatment with ledipasvir/sofosbuvir.

Detailed description:

Arms: arm 1: 12 week treatment with ledipasvir/sofosbuvir (Harvoni) for chronic hepatitis B in low replicative state. arm 2: 12 week treatment with ledipasvir/sofosbuvir (Harvoni) for chronic hepatitis B, virally suppressed. arm 3: 12 weeks treatment with sofosbuvir (Sovaldi) for chronic hepatitis B in low replicative state.

Randomized 1:1 with Group D. arm 4: 12 weeks treatment with ledipasvir for chronic hepatitis B in low replicative state.

Randomized 1:1 with Group C.
Interventions: intervention 1: Ledipasvir 90 MG / Sofosbuvir 400 MG Oral Tablet [Harvoni] intervention 2: Sofosbuvir 400 MG [Sovaldi] intervention 3: Ledipasvir 90 MG
Intervention descriptions: intervention 1: 1 pill once daily for 12 weeks for Group A intervention 2: 1 pill once daily for 12 weeks for Group C intervention 3: 1 pill once daily for 12 weeks for Group D

Protocol documents:
Prot_SAP_000.pdf: 
A Phase II Open-Label Study of Ledipasvir/Sofosbuvir 
for 12 Weeks in Subjects with Hepatitis B Virus Infection 
(APOSTLE) 
 
 
Protocol Number: HP-00074723 
 
National Clinical Trial (NCT) Identified Number:  NCT03312023 
Principal Investigator: Joel Chua, MD 
IND: 142791 
.  
Funded by: Gilead Sciences, Inc. Foster City, CA 
Version Number: 6.0 
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The information contained herein is the property of IHV and may not be reproduced, published or 
disclosed to others without written authorization. 
 
 


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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 4 
1 
PROTOCOL SUMMARY ............................................................................................................................... 4 
1.1 
Synopsis ................................................................................................................................................ 4 
1.2 
Schema ................................................................................................................................................. 6 
1.3 
ScheduleS of Activities (SoA) ............................................................................................................ 7 
2 
INTRODUCTION ............................................................................................................................................ 9 
2.1 
Study Rationale .................................................................................................................................... 9 
2.2 
Background........................................................................................................................................... 9 
2.3 
Risk/Benefit Assessment .................................................................................................................. 12 
2.3.1 
Known Potential Risks ................................................................................................... 12 
2.3.2 
Known Potential Benefits .............................................................................................. 14 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 14 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 14 
4 
STUDY DESIGN ........................................................................................................................................... 16 
4.1 
Overall Design .................................................................................................................................... 16 
4.2 
Scientific Rationale for Study Design.............................................................................................. 17 
4.3 
Justification for Dose ......................................................................................................................... 17 
4.4 
End of Study Definition ..................................................................................................................... 18 
5 
STUDY POPULATION ................................................................................................................................ 18 
5.1 
Inclusion Criteria ................................................................................................................................ 18 
5.2 
Exclusion Criteria ............................................................................................................................... 19 
5.3 
Lifestyle Considerations .................................................................................................................... 20 
5.4 
Screen Failures .................................................................................................................................. 20 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 21 
6 
STUDY INTERVENTION ............................................................................................................................ 22 
6.1 
Study Intervention(s) Administration ............................................................................................... 22 
6.1.1 
Study Intervention Description ..................................................................................... 22 
6.1.2 
Dosing and Administration ............................................................................................ 23 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 23 
6.2.1 
Acquisition and accountability ...................................................................................... 23 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 23 
6.2.3 
Product Storage and Stability ....................................................................................... 24 
6.2.4 
Preparation ...................................................................................................................... 24 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 24 
6.4 
Study Intervention Compliance ........................................................................................................ 24 
6.5 
Concomitant Therapy ........................................................................................................................ 25 
6.5.1 
Rescue Medicine ............................................................................................................ 27 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 27 
7.1 
Discontinuation of Study Intervention ............................................................................................. 27 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 28 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 29 
8.1 
Efficacy Assessments ....................................................................................................................... 29 
8.2 
Safety and Other Assessments ....................................................................................................... 29 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 30 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 30 


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8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 30 
8.3.3 
Classification of an Adverse Event .............................................................................. 30 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 31 
8.3.5 
Adverse Event Reporting .............................................................................................. 32 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 32 
8.3.7 
Reporting Events to Participants ................................................................................. 33 
8.3.8 
Events of Special Interest ............................................................................................. 33 
8.3.9 
Reporting of Pregnancy ................................................................................................ 33 
8.4 
Unanticipated Problems .................................................................................................................... 33 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 33 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 34 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 34 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 34 
9.1 
Statistical Hypotheses ....................................................................................................................... 34 
9.2 
Sample Size Determination .............................................................................................................. 35 
9.3 
Populations for Analyses .................................................................................................................. 35 
9.4 
Statistical Analyses............................................................................................................................ 35 
9.4.1 
General Approach .......................................................................................................... 35 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 35 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 35 
9.4.4 
Safety Analyses .............................................................................................................. 36 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 36 
9.4.6 
Planned Interim Analyses ............................................................................................. 36 
9.4.7 
Sub-Group Analyses ..................................................................................................... 36 
9.4.8 
Tabulation of Individual participant Data .................................................................... 36 
9.4.9 
Exploratory Analyses ..................................................................................................... 36 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 37 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 37 
10.1.1 
Informed Consent Process ........................................................................................... 37 
10.1.2 
Study Discontinuation and Closure ............................................................................. 38 
10.1.3 
Confidentiality and Privacy ........................................................................................... 38 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 39 
10.1.5 
Key Roles and Study Governance .............................................................................. 40 
10.1.6 
Safety Oversight ............................................................................................................. 40 
10.1.7 
Clinical Monitoring .......................................................................................................... 40 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 40 
10.1.9 
Data Handling and Record Keeping ............................................................................ 41 
10.1.10 
Protocol Deviations ........................................................................................................ 41 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 41 
10.1.12 
Conflict of Interest Policy .............................................................................................. 42 
10.2 
Additional Considerations ................................................................................................................. 42 
10.3 
Abbreviations ...................................................................................................................................... 42 
10.4 
Protocol Amendment History ........................................................................................................... 45 
11 
REFERENCES ............................................................................................................................................. 46 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
The protocol, informed consent form, recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
A Phase II Open-Label Study of Ledipasvir/Sofosbuvir for 12 Weeks 
in Subjects with Hepatitis B Virus Infection (APOSTLE) 
 
Study Description: 
Chronic hepatitis B affects approximately 350 million people worldwide.  
Chronic hepatitis B (CHB) infection leads to progressive liver disease, liver 
failure and liver cancer.  Treatment for CHB is aimed to suppress hepatitis 
B viral loads (HBV DNA levels) using nucleoside analog treatment, such as 
tenofovir disoproxil fumarate (TDF) and recently tenofovir alafenamide 
fumarate (TAF).  Suppressive therapy is associated with regression of liver 
fibrosis and reduced liver related outcomes, however, has to be continued 
lifelong.  Conversely, for chronic hepatitis C, with advent of direct acting 
antivirals (DAAs) such as ledipasvir/sofosbuvir (LDV/SOF) or Harvoni® 
functional cure is now easily attainable.  This study is aimed at evaluating 
the antiviral activity of LDV and SOF either in fixed dose combination (FDC) 
or as monotherapy in subjects infected with HBV, as well as its safety and 
tolerability.  Additionally, the relationship between LDV/SOF 
pharmacodynamics and HBV parameters will be explored. 
 
Objectives: 
 
Primary Objectives: To evaluate the change of serum hepatitis B surface 
antigen (HBsAg log10 IU/mL) as an indicator of antiviral activity of ledipasvir 
and/or sofosbuvir in subjects with chronic hepatitis B from baseline to end 
of 12 weeks of treatment.  To evaluate the safety and tolerability of the 
treatment regimen as assessed by review of the accumulated safety data. 
Secondary Objective: To evaluate the kinetics of circulating HBV DNA in 
subjects who are infected with HBV from baseline to end of 12 weeks of 
treatment. 
Exploratory Objectives:  To explore the relationship between 
pharmacodynamics biomarkers and viral parameters. 


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Endpoints: 
Primary: HBsAg quantitation at end of 12 weeks treatment. Reports of 
Grade 3 or 4 clinical or laboratory adverse events. 
Secondary: HBV DNA at end of 12 weeks treatment. 
 
Study Population: 
Adults affected with chronic viral hepatitis B (HBV), who are either in low 
replicative state not requiring treatment or are virally suppressed on HBV 
medications.  
Phase: 
2 
 
Description of Sites: 
Conducted by the University of Maryland, Institute of Human Virology 
(IHV) at the IHV Clinical Research Unit (CRU), with Collaborating Sites at 
the Chinese Culture and Community Service Center, Inc. (CCACC) and Unity 
Health Care Inc., Parkside. 
 
Description of Study 
Intervention: 
This study will involve 4 Dosing Groups:   
 
Group A: 10 chronic HBV subjects with chronic HBV in low replicate state, 
not on antivirals and not requiring therapy, will receive LDV/SOF once daily 
for 12 weeks. 
Group B:  5 virally suppressed chronic HBV subjects on treatment will 
receive LDV/SOF once daily for 12 weeks. 
Groups C & D: 10 subjects with chronic HBV in low replicative state, not on 
antivirals and not requiring therapy, will be randomized in a 1:1 ratio to 
receive either SOF 400 mg (Group C) OR LDV 90 mg once daily (Group D) 
for 12 weeks. 
 
Study Duration: 
 
 
 
Participant Duration: 
Twenty month enrollment, eight month study participation, four months 
data analysis. 
 
 
Subject participation may be up to eight months in duration. 
 
 


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1.2 
SCHEMA 
  
SCR 
Screening 
D0 
Day 0 
W1 
Week 1 
W2 
Week 2 
W4 
Week 4 
W8 
Week 8 
W12/EOT 
Week 12 / End of Treatment 
Week 13 
Post Treatment Week 1 
Week 16 
Post Treatment Week 4 
Week 24 
Post Treatment Week 12 
 
 
 


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1.3 
SCHEDULES OF ACTIVITIES (SOA) 
GROUPS A & B: Subjects receiving 12 weeks of Ledipasvir/Sofosbuvir 
Study Visit 
SCR 
-60 to -28 
 
D0 
W1 
(+/-3 days) 
W2 
(+/-3 days) 
W4 
(+/-3 days) 
W8 
(+/-3 days) 
W12 / EOT 
(+/-7 days) 
Week 13 
(+/-7 days) 
Week 16 
(+/-7 days) 
Week 24 
(+/-7 days) 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X 
X…………………………………………………………………………………………………..…………X 
Dispense Study Medication 
 
X 
 
 
X 
X 
 
 
 
 
Complete Physical Examination 
X 
X 
 
 
 
 
X 
 
 
 
Directed Physical Examination 
 
 
X 
X 
X 
X 
 
X 
 
X 
Height & Weight 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event monitoring 
 
X……………………………………………………………………………………………………………..X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
Hematologya 
X* 
X 
X 
X 
X 
X 
X 
  
X 
  
Chemistryb 
X* 
X 
X 
X 
X 
X 
X 
X  
X 
X  
Lipase and creatine kinase# 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationc 
X* 
X 
 
 
X 
 
X 
  
 
X  
HgbA1c 
X*** 
 
 
 
 
 
 
 
 
 
Serologiesd 
X* 
 
 
 
 
 
 
 
 
 
HBV Genotyping  (if not already 
on file, or if risk behavior 
identified) 
 
X 
 
 
 
 
 
 
 
 
HBsAg, AntiHBs 
X** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quantitative HBV DNA 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FibroSure 
X*** 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
Urine Drug screen 
X 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Teste 
X 
X 
  
X 
X 
X 
X 
 
X 
 
Quantitative HBsAg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quantitative HBcrAg & HBV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research Storage Labsf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pax DNA 
 
X 
 
 
 
 
 
 
 
 
Pax RNA 
 
X 
 
X 
 
X 
 
 
 
X 
*       May use outside labs within the last 30 days (or any historical hepatitis Delta result) 
**     May use outside labs within the last 90 days 
***   May use outside labs within the last 12 months 
aComplete blood count with differential 
bComplete metabolic panel: ALT, AST, albumin, alkaline phosphatase, total bilirubin, creatinine, calcium, carbon dioxide, 
chloride, eGFR calculation, globulin, glucose, potassium, protein, sodium 
cProthrombin time and International Normalised Ratio (INR) 
dAnti-HCV, Total antibody hepatitis delta, Human immunodeficiency virus screening, HBeAg, antiHBe 
eFor women of childbearing potential 
fSerum storage, plasma storage, and PBMC storage 
# For Group B 


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GROUPS C and D: Subjects receiving 12 weeks of monotherapy of either Sofosbuvir or Ledipasvir     
Study Visit 
SCR 
(60 day 
window)
 
D0 
W1# 
(+/-3 days) 
W2# 
(+/-3 days) 
W4 
(+/-3 days) 
W8# 
(+/-3 days) 
W12 / EOT 
(+/-7 days) 
Week 13# 
(+/-7 days) 
Week 16 
(+/-7 days) 
Week 24 
(+/-7 days) 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X 
X…………………………………………………………………………………………………..…………X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Dispense Study Medication 
 
X 
 
 
X 
X# 
 
 
 
 
Complete Physical Examination 
X 
X 
 
 
 
 
X 
 
 
 
Directed Physical Examination 
 
 
X# 
X# 
X 
X# 
 
X# 
 
X 
Height & Weight 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X# 
X# 
X 
X 
X 
X# 
X 
X 
Adverse Event monitoring 
X 
X 
X# 
X# 
X 
X 
X 
X# 
X 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
FibroScan (Transient 
Elastography) 
 
X 
 
 
 
 
X 
 
 
 
Hematologya 
X* 
X 
X 
X 
X 
X 
X 
  
X 
  
Chemistryb 
X* 
X 
X 
X 
X 
X 
X 
X  
X 
X  
Lipase and creatine kinase 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationc 
X* 
X 
 
 
X 
 
X 
  
 
X  
HgbA1c 
X*** 
 
 
 
 
 
 
 
 
 
Serologiesd 
X* 
 
 
 
 
 
 
 
 
 
HBV Genotyping  (if not already 
on file, or if risk behavior 
identified) 
 
X 
 
 
 
 
 
 
 
 
HBsAg, AntiHBs 
X** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quantitative HBV DNA 
X** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FibroSure 
X*** 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
Urine Drug screen 
X 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Teste 
X 
X 
  
X 
X 
X 
X 
 
X 
 
Quantitative HBsAg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quantitative HBcrAg & HBV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research Storage Labsf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pax DNA 
 
X 
 
 
 
 
 
 
 
 
Pax RNA 
 
X 
 
X 
 
X 
 
 
 
X 
*       May use outside labs within the last 30 days (or any historical hepatitis Delta result) or 90 days for those previously 
completing Group A 
**     May use outside labs within the last 90 days 
***   May use outside labs within the last 12 months 
# Those previously treated on Group A (tolerated LDV/SOF x 12 weeks) will have lab visits only (with dispensing and 
medication adherence week 8) 
aComplete blood count with differential 
bComplete metabolic panel: ALT, AST, albumin, alkaline phosphatase, total bilirubin, creatinine, calcium, carbon dioxide, 
chloride, eGFR calculation, globulin, glucose, potassium, protein, sodium 
cProthrombin time and International Normalised Ratio (INR) 
dAnti-HCV, Total antibody hepatitis delta, Human immunodeficiency virus screening, HBeAg, antiHBe 
eFor women of childbearing potential 
fSerum storage, plasma storage, and PBMC storage 


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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Chronic HBV (CHB) infection is endemic in several countries, with very high prevalence in certain areas 
of Asia and Africa. There are over half a million immigrants from Asia and Africa in the Baltimore-
metropolitan DC area [1] this, combined with the fact that Baltimore and Washington DC are among the 
highest for estimated prevalence of IDUs in 96 large U.S. metropolitan areas [2] means that there is a 
unmet need for hepatitis B (HBV) care and studies to advance HBV treatment research in this part of the 
country.  
 
Hepatitis B surface antigen (HBsAg) loss is the current accepted endpoint for anti-HBV therapy and has 
been associated with improvements in liver histology, including the reversal of cirrhosis, a decreased risk 
of hepatocellular carcinoma (HCC), and prolonged survival.  Recent treatment guidelines have 
acknowledged the importance of HBsAg clearance in CHB [3, 4].  An emerging theme is that HBsAg 
clearance is associated with definitive remission of the activity of CHB and an improved long term 
outcome [4]. Recent data show that the risk of HCC is lower if HBsAg clearance occurs before 50 years of 
age [5]. Loss of HBsAg is thus a primary goal of CHB therapy and is synonymous to a functional HBV cure. 
 
Nucleos(t)ide analogues (NA) are the current standard of care for CHB, providing durable on-treatment 
suppression of viral replication and resulting in long-term clinical benefits with a reduced risk of liver 
complications.  Although NAs are highly effective in suppressing HBV viral replication, the incidence of 
HBsAg loss during NA therapy is cumulative but low (ranging from 0-3% in the first year of NA therapy) 
[6].  As a result, continuous long-term use is recommended for most patients.  Moreover, NA therapy 
rarely results in HBsAg seroconversion [7].  Therefore, new therapies that that enhance rates of HBsAg 
loss and subsequent seroconversion after a finite treatment course are needed. 
 
2.2 
BACKGROUND  
 
Hepatitis B virus (HBV) chronically infects over 350 million people worldwide and over one million 
Americans. HBV is transmitted sexually, perinatally and percutaneously [6, 8-9].  The risk of developing 
chronic HBV after exposure is inversely related to difference in age at infection, ranges from 90% in 
infants infected via vertical transmission to less than 5% in immunocompetent adults [10]. Therefore, in 
areas where vertical transmission predominates, the prevalence of chronic disease is significantly 
greater than in areas in which HBV is transmitted among adults, primarily through sex and intravenous 
drug use. In the United States, since the advent of universal infant vaccination for HBV in 1991, there 
have been great reductions in acute HBV and chronic HBV, the reductions however have been offset by 
substantial migration of persons already chronically infected with HBV in the past 40 years, especially 
from the endemic region such as Eastern Asia and Sub-Saharan Africa [11]. According to National Health 
and Nutrition Examination Survey (NHANES), during 2007-2012, among the estimated 199,000 Non-
Hispanic blacks with CHB, prevalence of CHB infection was 2.5% among foreign-born non-Hispanic 
blacks; Correspondingly, during 2011-2012, among the estimated 427,000 non-Hispanic Asians with CHB 
infection, 93.1% were foreign born [12]. 
 
 


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Hepatitis B in Baltimore and Washington DC 
Baltimore has been cited as a leading city in terms of injection drug use, ranking second in the nation for 
intravenous drug use (IDU) per capita in 2004 [13].  A study in early 2000 looking at injection drug users 
all with chronic HCV in Baltimore, occult HBV was found in 45% of individuals [14]. A more recent study 
looking at patterns of drug use and infectious disease in Baltimore drug users found that 45% of recent 
users of cocaine or heroin were infected with hepatitis C [15]. In 2014, another study found that of the 
782 participants tested for HCV, only 19 % reported having received an HCV diagnosis in the past, while 
48% tested positive for HCV. Of those diagnosed, only 6% reported having received any form of 
treatment [16]. This draws attention to the ripple effects of under diagnosed HBV among the IDU 
population in Baltimore. 
 
In 2008, the National Institutes of Health and the DC Department of Health collaborated to establish the 
DC Partnership for HIV/AIDS Progress (DC PFAP), a partnership for community-based clinical care and 
research whose aim is to reduce the incidence and prevalence of HIV/AIDS in the District of Columbia. 
Led by Director Dr. Henry Masur, a plan was developed to create a research program to build a 
sustainable model for urban areas working to reduce the HIV/AIDS crisis. A needs assessment within the 
area’s medical community demonstrated a significant deficit in hepatitis C virus (HCV) care and 
treatment. This led to the development of a Hepatitis branch within DC PFAP, rooted in direct 
subspecialty medical services and clinical research addressing the limitations of standard of care 
therapy.  
 
The Hepatitis program is led by Scientific Director Dr. Shyamasundaran Kottilil, and is based out of three 
campuses: (1) clinical partners within Washington DC, (2) National Institutes of Health, Bethesda, MD 
and (3) University of Maryland Institute of Human Virology, Baltimore, MD. The overarching goals of the 
programs are to: 
• Improved access to subspecialty care for underinsured patients with HIV 
• Develop access to HIV and hepatitis related research for residents of DC 
• Build credibility and trust in the community for the research process 
• Expand integrated care for hepatitis B and C in the community HIV clinics 
• Initiate NIH and IHV-UMSOM research protocols at these DC clinics 
• Provide national leadership in the development and delivery of effective, safe, convenient  
therapies, including HBV and HCV. 
 
The clinical aspects of the DC Partnership for HIV/AIDS (DC PFAP) Progress program in Washington, DC 
are set within three partner centers: Unity Healthcare/Walker Jones and Unity Healthcare/Parkside and 
Chinese Culture and Community Services. At these locations, DC PFAP and IHV-SOM providers are 
embedded within established clinics to augment and enhance subspecialty medical care. Patients are 
managed by state of the art standard of care as well as offered opportunities to participate in clinical 
research as appropriate. To date, over 6000 HIV infected patients and over 2000 HCV patients have 
been linked to care and over 200 patients cured of hepatitis C through treatment with novel directly 
acting therapy within these subspecialties. 
 
Hepatitis B treatment 
Currently, there are two classes of drugs approved for the treatment of HBV: nucleos(t)ide reverse 
transcriptase inhibitors (NRTIs) and interferon-α (IFN-α). First line antiviral therapy includes entecavir 
(nucleoside analogue), tenofovir (nucleotide analogue), and pegylated IFN-α (PEG-IFN-α).  PEG-IFN is 
indicated for a course of 48-52 weeks.  Despite it having weaker antiviral activity than NRTIs, PEG-IFN-α 
has been associated with a higher rate of HBeAg and HBsAg loss, but rates are still extremely low (HBsAg 


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loss 2-7%, and 11% at 6 months and 3 years post treatment, respectively) and is associated with several 
side effects [6].  
 
Relationship between HBsAg levels, cccDNA and Hepatitis B Functional Cure 
The goals of antiviral treatment are to decrease the morbidity and mortality related to chronic HBV 
infection. Antiviral therapy can reverse hepatic fibrosis, and even cirrhosis, which result in reduction of 
cirrhosis complications and the risk of hepatocellular carcinoma (HCC) [17, 18].  Treatment success 
(cure) is categorized as (1) immunological cure: defined by HBsAg loss and sustained HBV DNA 
suppression; and (2) virologic cure defined by eradication of virus, including the covalently closed 
circular DNA (cccDNA) form.  Virologic cure is currently not a feasible or attainable goal at this time.  
With the currently available therapy, only a minority of patients achieve immunologic cure.  However, 
the vast majority will require chronic (often lifelong) suppressive therapy with, most frequently 
tenofovir or entecavir. 
 
A major obstacle in attaining HBV cure is the presence of covalently closed circular DNA (cccDNA) in the 
hepatocyte nucleus.  This non-integrated form of HBV DNA in the infected liver cells, serves as the 
primary template for transcription of all viral RNAs and plays a vital role in the HBV life cycle as well as 
drives the production of HBsAg and HBeAg, as well as progeny virions [19].   The half-life of cccDNA is 
long, perhaps measured in years, and this explains why HBV reactivates either spontaneously or 
following immune suppression [20].  Therefore, efficient eradication of cccDNA from the infected 
hepatocytes is now considered the most important task in achieving HBV cure [21].  Quantitation of 
intrahepatic HBV cccDNA could be accomplished but not without potential complications from liver 
biopsy.  Fortunately, it has been shown that serum HBsAg titer correlates well with intrahepatic HBV 
cccDNA in patients with chronic hepatitis B naïve to antiviral therapy [22].   
 
Though current HBV antiviral therapy is efficient in inhibiting viral replication by blocking reverse 
transcription of pgRNA to HBV DNA, it only has a marginal effect on cccDNA production, stability, or 
transcription [20].  Thus, continued transcription of cccDNA may explain the relatively low decline in 
serum HBsAg levels during NA therapy.  Additionally, it is estimated that it will take an estimated median 
36-52.2 years before HBsAg clearance is attained with NA therapy [23-24].  Nevertheless, a robust 
HBsAg decline during NA treatment is associated with immune responses and appear to lead to 
subsequent HBsAg loss [25].  In those patients with chronic hepatitis B treated with more than 10 years 
of lamivudine therapy, an on-treatment reduction of HBsAg by >0.166 log10 IU/mL per year predicted 
subsequent seroclearance with a negative predictive value of 97.8% [26].  Likewise, a decline of HBsAg 
>1 log after 1 year of therapy with antiviral telbivudine in HBeAg positive CHB patients was associated 
with HBsAg loss and enhancement in antiviral T cell reactivity, suggesting immune restoration against 
HBV infection [27]. 
 
Study Hypothesis: Ledipasvir-Sofosbuvir and HBsAg Decline 
When patients co-infected with both hepatitis B and hepatitis C have were treated for their hepatitis C 
(HCV) with twelve (12) weeks of fixed dose combination ledipasvir-sofosbuvir (Harvoni®) at 90 mg and 
400 mg daily, respectively, there was an observed decline in the mean quantitative HBsAg level on 
treatment with mean reduction of 0.14, 0.25, and 0.47 log10 IU/mL, at weeks 1, 4, and 12, respectively 
[28].  Overall, 37 of 111 (33%) subjects studied in this cohort had an HBsAg decline of greater than or 
equal to 0.5 log10 IU/mL at 12 weeks on ledipasvir-sofosbuvir [28].   In addition, a recently published 
study by Dr. Loggi and colleagues, found a similar case of HBV-HCV co-infected patient that was treated 
with anti-HCV direct-acting antivirals and observed a HBV DNA increase of more than 2 log but with 
simultaneous HBsAg decline, and subsequent HBsAg loss [29].   Whether these unexpected observations 


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are a result of direct antiviral properties of ledipasvir-sofosbuvir, or due to a complex interaction 
between the immune response and interactions between the HBV and HCV during DAA therapy, 
remains a mystery that this and future trials will hopefully enlighten.  This study hypothesizes that a 
similar reduction in HBsAg levels would be seen in mono-infected hepatitis B infected subjects, either in 
low replicative state or virally suppressed, over the course of 12 week treatment with ledipasvir-
sofosbuvir.  In addition, this pilot study will explore if the antiviral effects are due to either sofosbuvir, 
ledipasvir or both. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
The risks related to phlebotomy include pain, bruising, fainting and very rarely, infection. These risks will 
be minimized by having trained staff perform the procedures.  
 
The background risk of major birth defects and miscarriage for the indicated population is unknown. In 
the U.S. general population, the estimated background risk of major birth defects and miscarriage in 
clinically recognized pregnancies is 2–4% and 15–20%, respectively [30]. 
 
There is potential for loss of confidentiality, which will be minimized by providing privacy during study 
visits. In order to protect all participant confidentiality, all specimens and research records will be coded 
by number.  All paper records will be kept locked with limited access. Electronic data will be password 
protected and will not include participant names or contact details. 
 
Risk of using LDV/SOF (Harvoni®), SOF (Sovaldi®), or LDV (GS-5885 or ledipasvir) 
The most common side effects in all people who take LDV and SOF either in fixed dose combination or 
as monotherapy are fatigue, headache, nausea, diarrhea and insomnia.  In some people with advanced 
liver disease such as cirrhosis, other common side effects may include: asthenia, myalgia, irritability, 
dizziness, cough and dyspnea [30].  Discontinuation due to side effects is rare about 1%.   
 
This study also intends to evaluate the safety of using ledipasvir and/or sofosbuvir in subjects with 
hepatitis B alone, i.e. Not co-infected with hepatitis C.  It is well known that successful treatment of 
hepatitis C, including therapies with ledipasvir/sofosbuvir, in a patient co-infected with hepatitis B are at 
risk of hepatitis B reactivation, mostly presenting as elevation of liver enzymes but hepatic failures as 
well as death have been reported. In fact between November 2013 to October 2016, there have been 29 
cases reported to the FDA, of which there were two deaths, one requiring liver transplantation, and six 
hospitalizations [31].  This remains to be a small proportion of people treated for hepatitis C.  Of note, 
the two deaths were on treatment with a different direct acting HCV drugs daclatasvir-asunaprevir and 
were not on ledipasvir/sofosbuvir [31].  It is known that in people co-infected with both HBV and HCV, 
their hepatitis C virus usually predominates leading suppression of HBV viral replication [32-33].  
Therefore, it is believed that with HCV cure, there is a loss of inhibition against HBV resulting in higher 
chance of HBV reactivation.  We believe that in a different setting such as in subjects only mono-
infected with HBV, this risk of HBV reactivation is negligible at best.  Nevertheless, subjects in this study 
will be closely watched and followed with frequent monitoring of liver profile during and after ledipasvir 
and/or sofosbuvir therapy.  
 


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In patients with heart conditions that require them to take amiodarone, administration of LDV/SOF has 
the potential to cause serious symptomatic bradycardia, as well as fatal cardiac arrests, and cases have 
required pacemaker interventions.   Thus, potential volunteers for any study group who have taken 
amiodarone in the last 90 days or are required to take amiodarone will be excluded from this study. 
 
The risk profile of LDV/SOF FDC will be also utilized for those in the monotherapy arms as it more closely 
represents the risks of either medication than risk profiles stated from use of either ledipasvir or 
sofosbuvir with other hepatitis C treatments such as interferon or ribavirin.  Neither ledipasvir nor 
sofosbuvir have been studied alone as treatment in a viral hepatitis population, while LDV/SOF FDC has 
been safely used in the hepatitis C population with and without other concomitant medications. 
 
Risk of Blood Draws 
Collecting blood samples from a vein may cause pain, bruising, lightheadedness, fainting, bleeding and 
rarely infection at the site of the needle stick. 
 
Risk of Electrocardiogram (ECG) 
After an ECG, subjects may experience mild skin irritation, slight redness or itching where the recording 
patches were placed.  They may also need to have chest hair shaved for the procedure. 
 
Risk of FibroScan 
FibroScans are non-invasive procedures.  Subjects may experience a sense of vibration from the probe 
tip and a temporary red mark on the skin following the procedure. 
 
Risk of Allergic Reaction 
Allergic reaction is always possible.  Serious allergic reactions that may occur can sometimes be life-
threatening.  Allergic reactions may include pruritus, rashes, difficulty of breathing and wheezing, 
sudden drop in blood pressure, swelling around the mouth, throat, or eyes, palpitations, and sweating. 
 
Risk of Loss of Confidentiality 
There is always a potential for the loss of confidentiality.  This risk will be minimized by keeping all study 
data stored and secured.  Electronic data will be password protected. Private information will only be 
given out as listed in the HIPAA form. 
 
Unexpected Risks and Discomforts 
There may be risks in this study that are not yet known or happen rarely when subjects take these study 
drugs.  Subjects will be told of any new information that could impact their safety during study 
participation. 
 
Pregnancy and Breast-Feeding Risks 
Because the effects of LDV and/or SOF on an unborn baby or a nursing infant are not known, care must 
be taken to avoid pregnancy in female subjects or in female partners of male subjects during this study 
and following completion of study treatment (30 days after completion for women, 14 days after 
completion for men).  Subjects will not be enrolled if pregnant or while breast-feeding. 
 
 
 
 
 


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2.3.2 KNOWN POTENTIAL BENEFITS  
 
There is no direct benefit with participation. In this study, we will be evaluating whether or not LDV and 
SOF either in combination or as monotherapy will lead to decline in HBsAg levels in patients.  If this 
study finds that LDV/SOF has an effect, future studies may lead to evaluating benefit of LDV and/or SOF 
for HBV patients.   
 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
As there are limited treatment options available for chronic hepatitis B, to investigate agents such as 
LDV and SOF, which are already proven to be safe with limited side effects profile will provide more 
benefits than risks in the long term.  The risks to participants will be minimized by frequent scheduled 
and unscheduled visits as needed to monitor and ensure safety.  
 
The value of the information gained will outweigh the risks of participation in the study because any 
additional treatment options and potential cure for HBV will further eliminate financial and emotional 
burdens to the affected population globally.  
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
To evaluate the change of serum 
hepatitis B surface antigen 
(HBsAg log10 IU/mL) level as an 
indicator of antiviral activity of 
ledipasvir and sofosbuvir either 
FDC or as monotherapy in 
subjects with chronic hepatitis B 
from baseline to end of 12 weeks 
treatment. 
 
 
 
To evaluate the safety and 
tolerability of the treatment 
regimens as assessed by review of 
the accumulated safety data. 
The primary endpoint is 
HBsAg (log10 IU/mL) at 
the end of 12 weeks 
treatment. 
 
 
 
 
 
 
 
 
The primary safety and 
tolerability endpoint is 
any AE(s) leading to 
permanent 
discontinuation of study 
drug(s).  
HBV surface antigen (HBsAg) is a marker of 
HBV infection and an essential part of the 
HBV lifecycle. Based on data from a phase 2 
study evaluating 12 weeks of LDV/SOF in 
subjects coinfected with HCV and HBV, a 
decline from baseline in HBsAg was 
observed. This study will evaluate whether 
similar changes in HBsAg are observed in 
HBV monoinfected subjects as the primary 
efficacy endpoint. 
 
 
One of the study aims is to evaluate the 
safety and tolerability of LDV and SOF 
either FDC or as monotherapy in HBV 
monoinfected subjects, thus any AE leading 
to discontinuation should be an endpoint.  
Clinically significant laboratory 
abnormalities and vital sign changes will be 
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Secondary 
 
 
To evaluate the kinetics of 
circulating HBV DNA in subjects 
infected with chronic HBV. 
 
 
The secondary endpoint 
is HBV DNA (log10IU/mL) 
at the end of 12 weeks 
treatment. 
 
 
 
HBV DNA in the blood is the approved 
clinical marker to monitor for HBV 
replication.  Changes in HBV DNA would 
provide important information on the 
antiviral activity of LDV and/or SOF 
treatment. 
Exploratory  
 
 
To explore the relationship 
between pharmacodynamic 
changes and viral parameters. 
 
 
 
The exploratory 
endpoints may include 
immunologic changes, 
such as, change from 
baseline in cytokine 
profile, and changes in 
viral parameters 
including HBV RNA and 
HBV core related 
antigen during and 
after treatment with 
LDV and/or SOF. 
 
 
 
 
Immunologic changes may occur with a 
decline in HBsAg in HBV infected subjects. 
If HBsAg decline is observed during 
treatment, we will explore immunologic 
changes in relation to decline in HBsAg 
levels.   
Changes in viral parameters including 
serum HBV RNA and Hepatitis B core 
related antigen (HBcrAg) will be explored 
to further evaluate the antiviral activity of 
LDV and/or SOF.  Both serum HBV RNA and 
HBcrAg are experimental markers of HBV 
replication and reflect the transcriptional 
activity of intrahepatic cccDNA.  Changes in 
one or both of these viral parameters may 
provide important information on the 
antiviral activity of LDV and/or SOF 
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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This is a phase 2, open-label, interventional study for evaluating antiviral activity by measuring change of 
HBsAg quantification, safety and tolerability of LDV and/or SOF either FDC or as monotherapy for 
treatment of chronic HBV infection.    It is anticipated that approximately 40 HBV mono-infected 
subjects will be screened to enroll 25 subjects, which will include referrals from DC Partnership for 
HIV/AIDS Progress (DCPFAP) program.  Study subjects will be screened and enrolled at the Institute for 
Human Virology Clinical Research Unit (IHV CRU), Chinese Culture and Community Service Center, Inc. 
(CCACC) or Unity Health Care, Inc. Parkside by research study staff.  Eligible participants will receive 12 
weeks of LDV and/or SOF either as FDC or monotherapy, and continue for additional 12 weeks of follow 
up.  Serial measurement of viral, and safety labs will be performed.   
 
Groups A & B – Subjects enrolled will receive twelve weeks of combination therapy 
ledipasvir/sofosbuvir 400mg/90mg once daily.  Group A will enroll up to 10 chronic HBV subjects who 
are in a low replicative state and therefore, not requiring treatment. Group B will enroll 5 chronic HBV 
subjects virally suppressed on anti-HBV medications.  All subjects will be followed until 12 weeks post-
treatment.  Subjects will have study visits on Day 0 (Baseline), Week 1, Week 2, Week 4, Week 8, Week 
12, and post-treatment Weeks 13, 16 and 24. 
 
 
 
 
 


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Groups C & D – Ten subjects will be randomized in a 1:1 ratio to receive twelve weeks daily dose of 
either sofosbuvir (400 mg once daily) or ledipasvir (90 mg daily).  All subjects will be followed until 12 
weeks post-treatment.  Subjects will have study visits on Day 0 (Baseline), Week 1, Week 2, Week 4, 
Week 8, Week 12, and post-treatment Weeks 13, 16 and 24. 
 
 
 
It is anticipated that LDV and/or SOF will result in decline of mean quantitative HBsAg >0.4 log10/mL 
from baseline to end of treatment in HBV mono-infected patients similar to that observed in HBV/HCV 
co-infected patients.  With a small cohort, no interim analysis is planned.   
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Based on retrospective data from a phase 2 study evaluating 12 weeks of LDV/SOF in subjects coinfected 
with HCV and HBV, a decline from baseline in HBsAg was observed. This study is designed to evaluate 
whether similar changes in HBsAg are observed in HBV monoinfected subjects, either in low replicative 
state or virally suppressed, with LDV and/or SOF treatment for duration of 12 weeks and further 
translate the antiviral activity of LDV and/or SOF.  
  
 
4.3 
JUSTIFICATION FOR DOSE 
 
Dosing for this clinical trial will utilize the FDA approved dosing and length of treatment for chronic 
hepatitis C treatment as the most safety data is available for this choice.  Additionally, as declines in 
quantitative hepatitis B surface antigen levels were seen when LDF/SOF was taken by those with HCV 
and HBV, this study aims to replicate the treatment to compare quantitative changes in a monoinfected 
population.  LDV/SOF will be taken orally as a once-daily dose regardless of food.  As it is a fixed-dose 
combination, no dose adjustments will be made.   
 
Study medications used for the monotherapy arms will use corresponding dose as those used in 
combination LDV/SOF therapy (i.e. 400mg SOF or 90 mg LDV).  Likewise, there will be no dose 
adjustments made. 
 
 


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4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
The end of the study is defined as completion of the last visit or procedure by all subjects as shown in 
the SoA. 
 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
Participants in Groups A, C & D (Chronic HBV, low replicative state not requiring treatment): 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Male or female, aged 18 or older at screening 
4. Diagnosed with chronic hepatitis B infection defined as one of the following: 
a. HBsAg or HBV DNA positivity for at least 6 months 
b. Medical records indicating a chronic HBV infection   
5. HBeAg negative at screening 
6. HBV DNA > lower level of quantitation (LLOQ) 
7. Quantitative HBsAg at least 10 IU/mL at screening 
8. Ability to take oral medication and be willing to adhere to the twelve week study drug regimen 
9. For females of reproductive potential: usual practice of complete abstinence from sexual 
intercourse with a member of the opposite sex OR use of at least one form of highly effective 
contraception for at least 1 month prior to enrollment and agreement to use such a method 
during study participation and for an additional 30 days after the end of study drug 
administration  
10. For males of reproductive potential: usual practice of complete abstinence from sexual 
intercourse with a member of the opposite sex OR use of at least one form of highly effective 
contraception for at least 1 month prior to enrollment and agreement to use such a method 
during study participation and for an additional 14 days after the end of study drug 
administration  
11. Ability to communicate effectively with the study investigator and key staff 
12. Medical management provided by a primary care provider 
13. Ability to store medications at a room temperature of less than 86 degrees Fahrenheit 
14. Not on antiviral therapy or requiring treatment for HBV during screening 
 
 
 


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Participants in Group B (Chronic HBV, virally suppressed): 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Male or female, aged 18 or older at screening 
4. Diagnosed with chronic hepatitis B infection defined as one of the following: 
a. HBsAg or HBV DNA positivity for at least 6 months 
b. Medical records indicating a chronic HBV infection   
5. Receiving oral anti-HBV medications (either tenofovir alafenamide, tenofovir disoproxil 
fumarate, entecavir, or a combination of no more than 2 of these agents) for at least three 
months prior to enrollment 
6. HBV DNA ˂ lower level of quantitation (LLOQ) at screening and for at least three months prior 
7. Quantitative HBsAg at least 10 IU/mL at screening 
8. Ability to take oral medication and be willing to adhere to the twelve week study drug regimen 
9. For females of reproductive potential: usual practice of complete abstinence from sexual 
intercourse with a member of the opposite sex OR use of at least one form of highly effective 
contraception for at least 1 month prior to enrollment and agreement to use such a method 
during study participation and for an additional 30 days after the end of study drug 
administration  
10. For males of reproductive potential: usual practice of complete abstinence from sexual 
intercourse with a member of the opposite sex OR use of at least one form of highly effective 
contraception for at least 1 month prior to enrollment and agreement to use such a method 
during study participation and for an additional 14 days after the end of study drug 
administration  
11. Ability to communicate effectively with the study investigator and key staff 
12. Medical management provided by a primary care provider 
13. Ability to store medications at a room temperature of less than 86 degrees Fahrenheit 
 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Coinfection with hepatitis C, hepatitis D or human immunodeficiency virus (HIV) 
2. Pregnancy or lactation 
3. Known allergic reactions to sofosbuvir or ledipasvir 
4. Treatment with another investigational drug or other intervention within three months 
5. Evidence of cirrhosis or hepatic decompensation such as: 
o Platelets less than 100,000 /mm3 
o Albumin less than 3.5 g/dL 
o INR greater than 1.7 or Prothrombin time of 1.5 times the upper limit of normal (ULN) 
o Total bilirubin of 1.5 times the upper limit of normal 
o FibroTest (or FibroSure®) of 0.75 or greater 
6. Abnormal hematological and biochemical parameters at screening including: 
o White blood cell count less than 2500 cells/uL 
o Absolute neutrophil count (ANC) less than 1,000 cells/mm3 (less than 750 mm3 for 
African or African-American subjects) 
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o AST or ALT of two times the upper limit of normal 
o Estimated GFR less than 50 mL/min 
o Glycosylated hemoglobin (HbA1c) greater than 8.5% 
7. Current or prior history of any of the following: 
o Immunodeficiency disorders or autoimmune disease (e.g. Systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel diseases, sarcoidosis, 
psoriasis of greater than mild severity) 
o Severe pulmonary disorders, significant cardiac diseases 
o Gastrointestinal disorder with post-operative condition that could interfere with the 
absorption of the study drugs 
o Significant psychiatric illness that in the judgment of the Investigator, is a 
contraindication to protocol participation or impairs a volunteer’s ability to give 
informed consent 
o Any malignancy diagnosed within 5 years (not including recent localized treatment of 
squamous or non-invasive basal cell skin cancer; cervical carcinoma in situ appropriately 
treated prior to screening) 
o Solid organ transplantation 
o Poor venous access  
8. Screening ECG with clinically significant findings  
9. Evidence of HCC (e.g., α fetoprotein > 50ng/mL or radiologic evidence) 
10. Clinically significant illicit drug or alcohol abuse within 12 months of screening. Subjects on 
methadone maintenance treatment or prescribed opioid may be included. 
11. Use of amiodarone within 90 days of enrollment; or carbamazepine, phenytoin, phenobarbital, 
oxcarbazepine, rifabutin, rifampin, rifapentine, St. John’s wort, rosuvastatin, or interferon within 
30 days of enrollment or expected use of these prohibited drugs during study participation.  Use 
of or expected need of proton-pump inhibitors more than 20 mg omeprazole equivalent or H2 
receptor antagonist more than 40 mg famotidine BID equivalent within 7 days of enrollment. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Not Applicable 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently eligible or entered into the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a lab 
value may have a single retest of screening labs if there is reason to believe the retest value will be 
within accepted parameters, if the initial value was either due to a sample processing error or due to an 
extenuating circumstance such as intercurrent infection. Rescreened participants should be assigned the 
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5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
We anticipate screening 40 subjects from the local area outpatient clinic population and by 
advertisements in order for approximately 25 to complete study treatment.  Separate screening and 
enrollment consents will be utilized for this trial.  It is expected that at least 50% will be from minority 
populations with a near equal mix of genders based on the population affected by chronic hepatitis B in 
the local area. Subjects may be approached at outpatient visits by their clinicians, and referred to the 
study team if interested in the study or may come from ongoing study populations at the sites. 
 
UMB Study Team Roles at Collaborating Sites:  UMB Associate Investigators have been actively involved 
in patient care at the collaborating sites (Unity Parkside and Chinese Culture and Community Services).  
These sites will sign a UMB Reliance Agreement prior to initiating any study activities.  The site 
AI/Collaborating Investigator if applicable may see subjects at non-study visits and will communicate 
study relevant findings to UMB/IHV study team.  The UMB Associate Investigators will oversee all 
research operations at the sites. 
 
If Participants Are Seen at Collaborating Sites:  The UMB study staff will see participants for all study 
visits at the sites.  All phlebotomy will be done by a phlebotomist working in the clinic or clinic staff. A 
specimen bag and specimen tubes will be prepared by UMB staff and will be labeled with the 
participant’s study number.  All laboratory studies will be received and reviewed by UMB study staff. 
Clinic staff will not participate in study-related visits unsupervised by UMB study staff.  The primary 
responsibility of the site AI and the clinic is to provide timely and effective communication regarding any 
potential adverse events if a subject/patient is seen for care outside of the normal study visit.  Any visits 
required of subjects that do not occur when study staff are present will need to be scheduled at another 
participating site with research team staffing. Any medical problems not related to the study will be 
addressed by the participant’s primary care or hepatitis providers. This will be communicated to the 
participants when consented for the protocol. 
 
Pregnant women, those lacking consent capacity including mentally ill, prisoners, cognitively impaired 
subjects and children will not be eligible for enrollment.  However, in this academic research setting 
employees or students may participate if they desire, but will not be consented by an academic superior 
or supervisor and will be notified in the consent process that employment status or academic standing 
at will not be affected by participation or nonparticipation in this study.   Any subject imprisoned during 
the study will be removed, and may be replaced at the Investigator’s discretion. 
 
Subjects will receive remuneration of $120 cash or gift cards at each scheduled study visit, and parking 
vouchers will be provided to subjects.   Total compensation for each participant over the length of the 
study is $1200.00.  For subjects residing more than 20 miles from the research clinic, Uber gift cards may 
be used to reimburse transportation to and from study visits, or they can receive additional mileage 
compensation in the amount of 50 cents per mile. 
 
 
 


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6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Ledipasvir/Sofosbuvir FDC: 
Ledipasvir/Sofosbuvir (HARVONI®) is a fixed-dose combination tablet for daily oral administration.  It 
was approved by the Food and Drug Administration (FDA) for the treatment of chronic hepatitis C in 
2014. Ledipasvir (LDV) is an HCV NS5A inhibitor and sofosbuvir (SOF) is a nucleotide analog inhibitor of 
HCV NS5B polymerase. The pharmacokinetic properties of LDV, SOF, and the predominant circulating 
metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic 
hepatitis C.  Both were absorbed quickly with the peak median plasma concentration between 0.8 to 4.5 
hours post-dose.  Please refer to the product insert for additional information [30]. 
 
This fixed dose combination drug is not indicated for the treatment of chronic hepatitis B as is being 
studied in this clinical trial.  
 
Sofosbuvir: 
Sofosbuvir (SOF) is a nucleotide analog inhibitor of HCV NS5B polymerase that was approved by the 
Food and Drug Administration (FDA) for the treatment of chronic hepatitis C in 2013.  It’s FDA approved 
trade name is SOVALDI®.  The pharmacokinetic properties of SOF and its predominant circulating 
metabolite GS-331007 have been evaluated in health adult subjects and in subjects with chronic 
hepatitis C.  SOF is absorbed quickly with the peak median plasma concentration between 0.8 to 4.5 
hours post-dose.  Please refer to the SOVALDI® package product insert for additional information [34].   
 
SOF monotherapy is currently not indicated for the treatment of chronic hepatitis B as is being studied 
in this clinical trial.   
 
Ledipasvir (also known as GS-5885): 
Ledipasvir (LDV) is an HCV NS5A inhibitor which is approved by the FDA in combination with sofosbuvir 
for the treatment of chronic hepatitis C.  The pharmacokinetic properties of LDV have been evaluated in 
healthy adult subjects and in subjects with chronic hepatitis C.  LDV is absorbed quickly with the peak 
median plasma concentration between 0.8 to 4.5 hours post-dose.  Please refer to the Investigator’s 
Brochure for additional information [350].   
 
LDV monotherapy is currently not indicated for the treatment of chronic hepatitis B as is being studied 
in this clinical trial. 
 
 
 
 
 
 


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6.1.2 DOSING AND ADMINISTRATION 
 
Ledipasvir/Sofosbuvir FDC: 
Each tablet contains 90 mg LDV and 400 mg SOF for daily oral administration with or without food 
 
Sofosbuvir: 
Each tablet contains 400 mg SOF for daily administration with or without food.   
 
Ledipasvir (also known as GS-5885): 
Each tablet contains 90 mg LDV for daily administration with or without food.   
 
If a dose of FDC, SOF or LDV is missed, but discovered the same day the dose may be taken, however 
two doses must not be taken on the same day.  Subjects will be instructed to call for replacement study 
product if stored over 86 degrees Fahrenheit. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Gilead Sciences, Inc. will provide the study drug for this clinical trial.  It will be delivered to the 
investigational pharmacy at the Institute of Human Virology and dispensed by the Investigational 
Pharmacist to eligible subjects in four-week supplies at Day 0, Week 4, and Week 8 visits.  Unused pills 
and empty bottles will be returned by the subjects to the pharmacy and may be destroyed onsite per 
standard operating procedure (SOP) after Sponsor approval.   
 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
All bottle containers will be labeled to include the statement, “Caution: New Drug – Limited for Federal 
(or United States) law to investigational use only”.   
 
Sample label: 
 


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Ledipasvir/Sofosbuvir FDC: 
HARVONI tablets are orange, diamond-shaped, film-coated, debossed with “GSI” on one side and 
“7985” on the other side of the tablet. Each bottle contains 28 tablets (NDC 61958-1801-1), a silica gel 
desiccant, polyester coil, and is closed with a child-resistant closure [30]. 
 
Sofosbuvir: 
Sofosbuvir (SOVALDI®) tablets are as a yellow-colored, capsule-shaped, film-coated tablet debossed with 
“GSI” on one side and “7977” on the other side.  Each tablet contains 400 mg sofosbuvir [34].  Each 
bottle contains 28 tablets, a silica gel desiccant and polyester coil, and is closed with a child-resistant 
closure [34]. 
 
Ledipasvir (also known as GS-5885):   
Ledipasvir (GS-5885) tablets, 90 mg, are white, capsule-shaped, plain-faced, film-coated tablets.  The 
tablets are approximately 15 mm in length and 7 mm in width.  Thirty (30) tablets are packaged in 75-mL 
white, high density polyethylene bottles with polyester coil packing material.  Each bottle is capped with 
a white continuous thread, child-resistant polypropylene screw cap with an induction-sealed, aluminum-
faced liner [35]. 
 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Ledipasvir / Sofosbuvir FDC, Sofosbuvir or Ledipasvir: 
Bottles should be stored at room temperature below 30 °C (86 °F), dispensed in the original containers 
with intact seals [30, 34, 35].  
 
6.2.4 PREPARATION 
 
Bottles will be re-labeled by the Investigational Pharmacist as prescribed to each study subject after 
consent is given and subjects are found to be eligible. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Volunteers for Groups C and D will be randomized using block randomization in a 1:1 ratio of SOF:LDV. 
They will be block randomized in blocks of two.  This will be done by the research pharmacist utilizing a 
random number generator called Stattrek.  There will be a total of five blocks generated of two 
volunteers in each randomized block. 
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Study drug compliance will be assessed by subject recall at each visit. Drug records will be maintained by 
the IND pharmacist, and subjects will be instructed to return any unused pills or empty bottles for 
destruction at the site. 
 
 


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6.5 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the source documents are 
concomitant prescription medications, over-the-counter medications and supplements.  Concomitant 
medications taken from the time of screening through end of study treatment will be recorded at each 
study visit.  All subjects will be asked about prohibited agents and those to be used with caution taken 
within the 90 days preceding screening during the screening visit and available medical records will be 
reviewed. 
Treatment with the following drugs is either prohibited or to be used with caution due to the potential 
for drug-drug interactions and risk of adverse events.   
 
 


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Disallowed Concomitant Medications [30] 
Drug Class 
Prohibited Agents 
Clinical Comment 
Antiarrhythmics 
amiodarone 
Coadministration of amiodarone with 
HARVONI may result in serious 
symptomatic bradycardia. The 
mechanism of this effect is unknown.  
Anticonvulsants 
carbamazepine 
phenytoin 
phenobarbital 
oxcarbazepine 
Coadministration is expected to 
decrease the concentration of 
ledipasvir and sofosbuvir, 
leading to reduced therapeutic effect 
of HARVONI. 
Antimycobacterials 
rifabutin 
rifampin 
rifapentine 
Coadministration is expected to 
decrease the concentration of 
ledipasvir and sofosbuvir, leading to 
reduced therapeutic effect of 
HARVONI. 
Herbal Supplements 
St. John’s wort 
Coadministration of HARVONI with 
St. John’s wort, a P-gp 
inducer, is not recommended due to 
decreased concentration of ledipasvir 
and sofosbuvir. 
HMG-CoA Reductase Inhibitors rosuvastatin 
Coadministration may 
significantly increase the 
concentration of rosuvastatin 
which is associated with increased 
risk of myopathy, 
including rhabdomyolysis.  
 
 
Medications to be Used with Caution [30] 
Drug Class 
Used with Caution 
 
Antiarrhythmics 
digoxin 
Coadministration may increase the 
concentration of digoxin 
Antacids  
Tums, Maalox, etc. 
It is recommended to separate 
antacid and HARVONI administration 
by 4 hours to avoid decreased 
concentration of ledipasvir. 
H2-receptor antagonists 
Nizatidine 
Famotidine 
Cimetidine 
ranitidine 
H2-receptor antagonists may be 
administered 
simultaneously with or 12 hours 
apart from HARVONI at a dose that 
does not exceed doses comparable to 
famotidine 40 mg twice daily to avoid 
decreased concentration of 
ledipasvir. 
Proton-pump inhibitors 
Dexlansoprazole 
Esomeprazole 
Proton-pump inhibitor doses 
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Proton-pump inhibitors (cont). 
 
Lansoprazole 
Omeprazole 
Pantoprazole 
Rabeprazole 
20 mg or lower can be administered 
simultaneously with 
HARVONI under fasted conditions to 
avoid decreased concentration of 
lediipasvir. 
 
 
 
6.5.1 RESCUE MEDICINE 
Any subject from Groups A, C or D who meets criteria for HBV treatment during the study will be 
referred to their clinical provider for assessment or to study NCT02995252 which offers FDA approved 
treatment for up to two years for subjects willing to participate in every three-month research lab 
collection. 
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Subjects may withdraw consent at any time for any reason. Subjects may have study drug stopped by 
the investigator should any untoward effect occur but continue to participate in post-treatment visits. 
 
A subject must be discontinued from study drug but may continue with post-treatment visits if: 
 
The subject has a Grade 3 or 4 adverse event or tolerability issue related to study drug 
 
The subject has a GFR of <30 mL/min (confirmed by repeat measurement) or a two log increase 
in HBV DNA while on study drug (confirmed by repeat measurement) 
 
Significant study intervention non-compliance  
 
Discontinuation from treatment is permanent. Once a subject has been discontinued, they will not be 
allowed to restart study drug.  Subjects who require discontinuation will continue to follow the general 
study schedule of assessments unless unwilling to do so. 
 
Discontinuation from LDV/SOF does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE). 
 
 
 
 
 
 
 
 


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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
The subject withdraws consent. 
• 
The subject has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or Sponsor, places the subject at unnecessary risk through continued 
participation in the trial or does not allow the subject to adhere to the requirements of the 
protocol. 
• 
The subject fails to comply with the dosing, evaluations, or other requirements of the study. 
• 
An investigator feels it is in the best interest of the subject to discontinue 
• 
If a patient becomes pregnant during the course of the study, the patient will be 
discontinued from the study once safety is evaluated 
When a subject/patient discontinues/withdraws prior to study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation. Any adverse 
events which are present at the time of discontinuation/withdrawal should be followed as per protocol.   
The subject will then be referred back to their primary care physician for determination of appropriate 
management of the patient’s HBV infection.   
The reason for participant discontinuation or withdrawal from the study will be recorded in the RedCap 
database. Subjects who sign the informed consent form but do not receive the study intervention may 
be replaced.  Subjects who sign the informed consent form, and receive the study intervention, and 
subsequently withdraw, or are withdrawn or discontinued from the study, may be replaced at the 
discretion of the investigator. 
A participant will be considered lost to follow-up if they fail to return for two scheduled visits and are 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
 
The site will attempt to contact the participant and reschedule the missed visit within the study 
visit window if possible, and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain if the participant wishes to and/or should continue in the 
study. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address). These contact attempts should 
be documented in the participant’s medical record or study file.  
 
Should the participant continue to be unreachable after two missed study visits, they will be 
considered to have withdrawn from the study with a primary reason of lost to follow-up. 
 
 
 
 


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8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
Description of procedures / evaluations: 
 
Biological specimen collection and laboratory evaluations. Specimens will be obtained at the 
IHV CRU, CCACC Clinic or Unity Parkside Clinic.  Clinical laboratories will be sent out to LabCorp 
for processing, and results will be reviewed by a study practitioner.  Research labs will be 
delivered to the research processing lab within the IHV and research tests will be batched and 
performed from previously collected and frozen samples.    Serum storage samples (6ml) and 
plasma storage samples (6 ml) will be collected at each visit from Day 0 onward.  Quantitative 
HBsAg/HBcrAg (8 ml) will be collected at screening and every visit thereafter.  Optional PBMC 
storage will be collected (20-50 ml) each visit from Day 0 onward.  Optional Pax DNA samples 
(8.5ml) will only be collected if not already stored for the subject from previous study 
participation.  Optional Pax RNA samples (2.5ml) will be collected at timepoints noted in the 
SoA. 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Once subjects have signed the screening consent, assessment of eligibility may begin.  Screening may be 
completed from 60 to 28 days prior to Day 0  in order to collect two samples for HBsAg and HBcrAg at 
least 28 days apart prior to dosing for Groups A & B.  Groups C & D do not require the timing for the 
second quantitative samples, and have a 60 day screening window.  If found to be eligible at screening, 
medical history, physical exam and concomitant medications will be reviewed on Day 0 prior to study 
consenting by a licensed provider on the study team.  If ineligible, subject will not move on to sign study 
consent at that time. 
 
After study consent is obtained, the remaining Day 0 events listed in the SoA will be completed.  
Subjects will have laboratory assessments obtained prior to first dose of study medication to be given 
during the visit.  Subjects will be provided with labeled study medication for home dosing after Day 0. 
 
 
Physical examination is to include assessment of head, neck and thyroid; eyes, ears, nose, 
throat, mouth and tongue; respiratory; cardiovascular; lymph nodes and abdomen; skin, hair 
and nails; musculoskeletal; and neurological systems.   Targeted exams may be limited to the 
systems of concern.  Physical exams will be completed by a licensed practitioner. 
 
Outside clinical labs may be utilized for eligibility for CBC, chemistry panel, coagulation factors, 
Hepatitis C and D and HIV serologies from the last 30 days, or last 90 days for those re-enrolling 
who have previously completed Group A.  Outside clinical HBsAg and anti-HBs and quantitative 
HBV DNA results may be utilized from the last 90 days, and FibroSure and HgbA1C tests may be 
utilized from up to 12 months prior to screening for eligibility following local HIPAA 
requirements. 
 
Clinical lab results may be shared with the subject upon request, however research results will 
not be provided to subject medical providers. 
 
Study drug adherence will be assessed by subject recall and pill counts at all scheduled visits. 


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 
Assessment of adverse events will be completed as per the SoA. 
  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
The investigator will grade the severity of each AE according to the “NIH National Cancer Institute 
Common Terminology Criteria for Adverse Events ” (Version 4.03, June 2010; Published: May 08, 2009), 
which can be found at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
 
Adverse Events not found in the Toxicity Table will be assessed for severity and classified into one of the 
categories below: 
• 
Grade 1 (Mild): Event requires minimal or no treatment and do not interfere with the 
participant’s daily activities. 
• 
Grade 2 (Moderate): Event results in a low level of inconvenience or concern with the 
therapeutic measures.  Moderate events may cause some interference with functioning. 
• 
Grade 3 (Severe): Event interrupts a subject’s usual daily activity or functioning and may 
require systemic drug therapy or other treatment.  Severe events are usually incapacitating. 
• 
Grade 4 (Potentially Life threatening):  Events causing inability to perform basic self-care 
functions OR Medical or operative intervention indicated to prevent permanent 
impairment, persistent disability, or death. 
• 
Grade 5 (Death) 
 


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8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and clinical judgment. The 
degree of certainty about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
8.3.3.3 EXPECTEDNESS  
 
The Principal Investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
All adverse events (AEs) occurring from the time of ingesting one dose of the study drugs through the 
end of study will be documented, recorded, and reported.  Prior to the first dose, only events related to 
study procedures will be captured as AEs.  If a diagnosis is clinically evident, the diagnosis rather than 
the individual signs and symptoms or lab abnormalities will be recorded as the AE. 
 


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All AEs will be captured and tracked on an AE form in the subject’s research file as well as entered into 
the REDCap reporting database.   Information to be collected includes event description, date of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), and date of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution as long as the subjects are willing to participate. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE.  An elective surgery/procedure scheduled to occur during a study 
will not be considered an AE if the surgery/procedure is being performed for a pre-existing condition 
and the surgery/procedure has been pre-planned prior to study entry. However, if the study 
participant’s condition deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The Principal Investigator and/or study team will record all reportable events with start dates occurring 
any time after informed consent is obtained the last day of study participation.  At each study visit, the 
study team member will inquire about the occurrence of AE/SAEs since the last visit.   
 
8.3.5 ADVERSE EVENT REPORTING  
 
As per UMB policies, all Reportable New Information will be reported to the UMB IRB within allowed 
timeframes. 
 
Line listings, frequency tables, and other summary AE data will be submitted to the IND Sponsor (if 
required) when needed for periodic safety assessments, review of IND annual reports, review of IND 
safety reports, and preparation of final study reports. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the study sponsor and should be provided as soon as possible. 
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
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In addition, the sponsor must notify FDA and all participating investigators in an Investigational New 
Drug (IND) safety report of potential serious risks, from clinical trials or any other source, as soon as 
possible, but in no case later than 15 calendar days after the sponsor determines that the information 
qualifies for reporting as applicable with IND. 
 
Any SAE will be reported to the IRB per institutional guidelines. SAEs (regardless of relationship) must 
also be reported to Gilead Drug Safety & Public Health (DSPH) Office within 15 calendar days of first 
becoming aware of the event. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Any adverse event or serious adverse event that affects the risk/benefit ratio to subjects will prompt a 
revision to the informed consent document.  All subjects will be notified of the additional risk and re-
consented at their next visit, or earlier if the situation requires. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not Applicable 
 
8.3.9 REPORTING OF PREGNANCY  
 
Pregnancy itself is not an AE. However, complications of pregnancies are AEs and may be SAEs.  
Pertinent obstetrical information of all pregnancies will be reported to the Gilead DSHP via fax or email 
within 3 business days from site awareness of the pregnancy.  Study drug must be stopped immediately.  
The participant will be advised to notify her obstetrician of study agent exposure.   
 
Pregnancy outcome data (e.g., delivery outcome, spontaneous, or elective termination of the 
pregnancy, presence of absence of birth defects, congenital abnormalities, or other complications) will 
be reported to the Sponsor and DSPH within 3 business days of the site’s awareness on a protocol-
specified form.   
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
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• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Sponsor.   The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the study sponsor 
within 7 days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the study sponsor at the time of continuing 
review.  
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Any UP that affects the risk/benefit ratio to subjects will prompt a revision to the informed consent 
document.  All subjects will be notified of the additional risk and re-consented at their next visit, or 
earlier if the situation requires. 
 
 
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
The research study hypothesis is that in the HBV-monoinfected patients, LDV and/or SOF treatment has 
antiviral activity against HBV.  The corresponding endpoint to assess efficacy of treatment is the HBsAg 
level.  We expect that after 12 weeks of treatment the decline in HBsAg from baseline to end of 
treatment will be at least 0.4 log10/mL.   
 
The secondary endpoint to assess treatment’s antiviral activity against HBV is the level of HBV DNA. 
The expected decline in HBV DNA for HBV-monoinfected patients after 12 weeks of LDV and/or SOF 
treatment between baseline to end of treatment will be at least 2 log10 IU/mL. 
 
  


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9.2 
SAMPLE SIZE DETERMINATION 
 
Group A: 
A total of 10 eligible patients with CHB, not currently on oral antiviral therapy will be accrued.  Sample 
size and power calculations were based on a paired t-test approach assuming at least 0.4 log10/mL 
decline in in HBsAg between baseline (pre-LDV/SOF) and post-treatment. 
 
A sample size of 10 will have an adequate 80% power to detect a difference in mean levels of HBsAg of 
at least 0.4, assuming a standard deviation of differences of 0.4 ( based on preliminary data), and using 
a paired t-test with a 0.05 two-sided significance level. 
 
Groups B, C & D: 
A total of 15 subjects with chronic HBV (5 in each Group) is consistent with the number of subjects in 
proof-of-concept pilot studies evaluating antiviral effects of novel therapies for chronic HBV infection.  
No formal power and sample size calculations were done. 
 
 
9.3 
POPULATIONS FOR ANALYSES 
 
The intent-to-treat analysis population will include all subjects who received at least one dose of study 
drug.   All subjects on the study will be followed through end of study or censored at the date they were 
discontinued from study.  
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Subject’s on-study demographic and clinical characteristics will be estimated and reported using  the 
following summary statistics, means and standard deviations, medians and ranges, proportions and 
confidence intervals.  Baseline  parameters will include sex, self-identified race/ethnicity, age, body mass 
index, presence or absence of cirrhosis, HBsAg, HBV DNA level, HBV genotype and for group B, active 
HBV treatment.  
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
  
The mean (standard deviation) of HBsAg will also be reported at baseline and at post-treatment. The 
primary efficacy analysis will determine individual difference in HBsAg from baseline (Day 0) to post-
treatment using a paired t-test. HBsAg (log10/mL) will be expressed means ± standard deviation (SD). 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Safety will be evaluated by assessment of clinical laboratory test, physical examinations, and vital signs 
measurements at various time points during the study, as well as the documentation of AEs.  A 
treatment-emergent AE will be defined as any new or worsening adverse event that beings on or after 
the date of first dose of study drug up to the date of last dose of study drug plus 30 days. 
 


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The toxicity data will be monitored closely throughout the study for all 25 enrolled subjects.  AEs will be 
summarized based on the date of onset of the event for each subject.   Addressing the safety of LDV and 
SOF, a maximum width 95% confidence interval for any grade 3 or higher toxicity will be about 40%.  For 
25 patients in the study, if the true unknown probability of a rare toxicity is 10%, the probability of 
observing 1 or more toxicities is 93%, for 5% it is 74%, and, if the true toxicity rate is 3%, then the 
probability of observing one or more rare toxicities is 53%.  
 
 
9.4.4 SAFETY ANALYSES 
 
See 9.4.3 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Not Applicable 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
There is no planned interim analysis. 
 
9.4.7 SUB-GROUP ANALYSES 
 
Not Applicable 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Subject specific data will be tabulated by time point for HBV DNA and quantitative HBsAg. 
 
9.4.9 EXPLORATORY ANALYSES 
 
The exploratory endpoints may include immunologic changes, such as, change from baseline in cytokine 
profile, relationship between pharmacodynamics biomarkers and changes in viral parameters including 
HBV RNA and HBV core related antigen during and after treatment with LDV and/or SOF. The 
exploratory analysis will determine individual difference in the exploratory endpoints from baseline (Day 
0) to post-treatment using a paired t-test. All inferential test will be indicated statistical significance with 
a P-value of less than 0.05 (two-sided). 
 
 
 
 
 
 
 
 
 
 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol:  screening consent, study consent, HIPAA consent. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing.  
 
This study will utilize both screening and study consents.  The participants should have the opportunity 
to discuss the study consent with their family or surrogates or think about it prior to agreeing to 
participate, and may do the same with screening. The participant will sign the screening informed 
consent document prior to any procedures being done specifically for the screening, and the study 
consent prior to administration of the study drug. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. Copies of the 
informed consent documents will be given to the participants for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the 
screening form signed, before the participant undergoes any study-specific procedures. The rights and 
welfare of the participants will be protected by emphasizing to them that the quality of their medical 
care will not be adversely affected if they decline to participate in this study. 
 
Additionally, employees or students will be made aware that employment status or academic standing 
will not be affected by your participation or non-participation in this study.  Students or employees will 
not be consented by anyone in a supervisory role. 
 
Non-English-Speaking Participants 
If a non-English speaking participant is unexpectedly eligible for enrollment, the participant will be 
provided with the UMB Short Written Consent Form for Non-English Speaking Research Participants in 
the participant’s native language and a verbal explanation of the purpose, procedures and risks of the 


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study. The IRB-approved English consent form will serve as basis for the verbal explanation of the study. 
The investigator will obtain an interpreter, either in person or by phone translation service, unless the 
investigator is fluent in the prospective participant’s language. Preferably, the interpreter will be 
someone who is independent of the participant (i.e., not a family member).  
 
The IRB-approved English consent form will be signed by the investigator obtaining consent and a 
witness to the oral presentation. The UMB Short Written Consent Form will be signed by the participant 
and a witness who observed the presentation of information. The interpreter may sign the consent 
document as the witness and, in this case, will note, “Interpreter” under the signature line. A copy of 
both signed forms will be provided to the participant to take home.  The investigator obtaining consent 
will document the consent process in the participant’s medical record.  Further, all instances of use of 
the UMB Short Written Consent Form will be reported to the IRB at the time of annual review.  
 
Illiterate Subjects 
As the majority of the patient populations from which the study participants are drawn are literate, 
written consent will typically be provided for both screening and treatment consents.  However, oral 
consent will be obtained for illiterate participants as consistent with UMB IRB Policy without separate 
IRB approval for each specific use. At Continuing Reviews, the UMB IRB will be informed of the number 
of illiterate participants who provided consent verbally.  A non-study team witness will be present for 
the oral consenting process. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, the 
Investigational New Drug (IND) sponsor and regulatory authorities.  If the study is prematurely 
terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the 
Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination or 
suspension.  Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Demonstration of efficacy that would warrant stopping    
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination that the primary endpoint has been met 
 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, SMC, IRB and/or Food and Drug Administration (FDA) as appropriate. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor. This confidentiality is extended to cover testing of biological samples and genetic 


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tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be entered into the REDCap database for future analysis. This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by the 
IHV research staff will be secured and password protected. At the end of the study, all study databases 
will be de-identified and archived at the IHV. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at University of Maryland, Institute of Human 
Virology.  With the participant’s approval within the consent and as approved by local Institutional 
Review Board (IRB), de-identified biological samples may be shared with Gilead Sciences, Inc. with the 
goal of sharing of data.  These samples could be used to research immune response to hepatitis B, its 
complications and other conditions for which individuals with hepatitis B are at increased risk, and to 
improve treatment.  Gilead Sciences, Inc. will also be provided with a code-link that will allow linking the 
biological specimens with the phenotypic data from each participant, maintaining the blinding of the 
identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
optional biological specimens for future research stored, in which case they will be destroyed.   
 
When the study is completed, access to study data and/or samples will be provided by Dr. Kottilil.  
 
 
 
 
 
 
 


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10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Joel Chua, MD; Assistant Professor 
University of Maryland,  Institute of Human Virology 
725 W. Lombard Street 
410-706-5704 
JChua@ihv.umaryland.edu 
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Safety Monitoring Committee (SMC) composed of 
individuals with the appropriate expertise, including experience with the treatment and/or care of those 
with hepatitis B & C. At least two members of the SMC will be independent from the study conduct and 
free of conflict of interest, or measures should be in place to minimize perceived conflict of interest.  
The SMC will meet at least semiannually to assess safety and efficacy data. The SMC will provide its 
input to the study sponsor and PI. 
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
Monitoring will begin as the first two subjects screen for the clinical trial.  This will entail a 
clinical research nurse providing 100% verification of screening consent and data verification of 
the first two subjects.  An independent SMC member will be available for consultation as 
needed for any medical concerns.  
• 
Once subjects begin enrollment, consent and eligibility verification will continue at 100%, with 
15% targeted subject data review.   
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The IHV CRU will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion.  An individualized quality management plan will be 
developed. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
addressed. 
 
 
 
 


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10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
All research data and results will be recorded using data collection forms. Source documents will 
support the data collected and will include, but not limited to; clinical findings and observations, 
laboratory and test data, hospital medical records, physician or office charts, physician or nursing notes, 
recorded data from automated instruments, x-rays, etc. Research data will be entered into a secure 
electronic database.  REDCap tracks all data corrections made by authorized users, providing audit trails 
for monitoring or query. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
The investigator is responsible for retaining all essential documents listed in the ICH Good Clinical 
Practice (GCP) Guideline.  All essential documentation for all study subjects is to be maintained by the 
investigators in a secure storage facility for a minimum of 5 years.  The FDA requires study records to be 
retained for up to 2 years after marketing approval or disapproval (21 CFR 312.62), or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the investigational agent 
for a specific indication. These records are also to be maintained in compliance with IRB, state, and 
federal medical records retention requirements, whichever is longest. All stored records are to be kept 
confidential to the extent required by federal, state, and local law. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol or International Conference on 
Harmonisation Good Clinical Practice (ICH GCP). The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations that constitute Reportable New Information within 5 working days of identification of the 
protocol deviation as per local IRB requirements.  The site investigator is responsible for knowing and 
adhering to the reviewing IRB requirements 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted 
to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.   
 
 
 
 


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10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.   
 
10.2 ADDITIONAL CONSIDERATIONS 
 
Not Applicable 
 
 
10.3 ABBREVIATIONS 
 
Abbreviation Term 
AE 
Adverse event 
AI 
Associate Investigator 
AIDS 
Acquired immune deficiency syndrome 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
CBC 
Complete blood count 
cccDNA 
Covalently closed circular DNA 
CFR 
Code of Federal Regulations 
CHB 
Chronic Hepatitis B 
CMP 
Complete metabolic panel 
CRF 
Case report form 
CRU 
Clinical research unit 
DC PFAP 
DC Partnership for HIV/AIDS Progress 
DNA 
Deoxyribonucleic acid 
DSPH 
Gilead Drug Safety & Public Health 
ECG 
Electrocardiogram 
ELISA 
Enzyme-linked immunosorbent assay 
ELISPOT 
Enzyme-Linked ImmunoSpot 
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
GCP 
Good Clinical Practices 
HBV 
Hepatitis B virus 
HBcrAg 
Hepatitis B core related antigen 
HBeAg 
Hepatitis B envelope antigen 


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HBsAg 
Hepatitis B surface antigen 
HgbA1c 
Hemoglobin A1c 
HCC 
Hepatocellular carcinoma 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IDU 
Intravenous drug use 
IFN-α 
Interferon-α 
IHV 
Institute of Human Virology 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LDV 
Ledipasvir 
LLOQ 
Lower Limit of quantification 
MTA 
Material transfer agreement 
NA 
Nucleoside or nucleotide analogue 
NCT 
National Clinical Trial 
NHANES 
National Health and Nutrition Examination Survey 
NIH 
National Institutes of Health 
NRTIs 
Nucleos(t)ide reverse transcriptase inhibitors 
OAV 
Oral antivirals 
OHRP 
Office for Human Research Protections 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PEG-IFN-α 
Pegylated interferon-α 
PI 
Principal Investigator 
QA 
Quality assurance 
QC 
Quality control 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SC 
Study Coordinator 
SMC 
Safety monitoring committee 
SoA 
Schedule of Activities 
SOF 
Sofosbuvir 
SOP 
Standard operating procedure 
TAF 
Tenofovir alafenamide fumarate 
TDF 
Tenofovir disoproxil fumarate 


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UA 
Urinalysis 
ULN 
Upper limit of normal 
UMB 
University of Maryland Baltimore 
UMSOM 
University of Maryland School of Medicine 
UP 
Unanticipated problem 
UPnonAE 
Unanticipated problem that is not an adverse event 
WBC 
White blood cell 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Affected 
Sections 
Description of Change  
Brief Rationale 
1.1 
(10 Oct 2017) 
- 
Updated study background, rationale, 
sample storage & references  
Respond to IRB requests prior 
to approval 
 
2.0 
(05 Jan 2018) 
Title Page 
Updated IND number and removed 
KlinEra as Sponsor 
To be consistent with FDA 
filing and IND decisions 
 
3.0 
(04 Apr 2018) 
SoA 
Added qualifier removing need to 
repeat Hepatitis B genotype if on file 
 Unless new risk behavior 
identified, genotype will 
remain constant. 
 
4.0 
(04 Apr 2018) 
 
SoA 
Added qualifier removing need to 
repeat Hepatitis B genotype if on file. 
Unless new risk behavior 
identified, genotype will 
remain constant. 
 
5.0 
(01 Nov 2018) 
All 
Addition of 3 study treatment groups, 
increase total N.  Addition of two 
sites, CCACC and Unity Parkside. 
To explore effects of each 
drug individually and 
combined effect on 
quantitative HBsAg in virally 
suppressed HBV patients. 
6.0 
(18 Mar 2019) 
SoA, 
Eligibility 
Criteria, 
Title Page 
Addition of lipase & creatine kinase 
labs.  Clarification of inclusion OAVs 
and exclusion of interferon.  Add 
IND#. 
Changes made per FDA 
recommendations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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