Pharmacoepidemiology Study to Define the Long-term Safety Profile of Tenofovir Disoproxil Fumarate (Tenofovir DF, Viread®) and Describe the Management of Tenofovir DF-associated Renal and Bone Toxicity in Chronic Hepatitis B (CHB)-Infected Adolescents Aged 12 to <18 Years in Europe
Phase: PHASE4
Conditions: Hepatitis B
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
Pharmacoepidemiology study to define the long-term safety 
profile of tenofovir disoproxil fumarate (Tenofovir DF, Viread®) 
and describe the management of Tenofovir DF-associated renal 
and bone toxicity in Chronic Hepatitis B (CHB)-infected 
adolescents aged 12 to <18 years in Europe 
Sponsor:
Gilead Sciences International Ltd.,
Flowers Building, Granta Park
Cambridge, CB21 6GT, United Kingdom
IND Number:
This is a non-IND study
EudraCT Number:
2014-004939-39
Clinical Trials.gov 
Identifier:
Not Available
Indication:
Chronic Hepatitis B
Protocol ID:
GS-EU-174-1403
Gilead Study Director:
Name:
Telephone:
Fax:
Pager:
Gilead Medical Monitor:
Name:
Benedetta Massetto, MD
Telephone:
Fax:
European Union QPPV
Name:
Telephone:
Protocol Version/Date:
Amendment 2: 10 March 2015
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the drug described in the protocol. You will not 
disclose any of the information to others without written authorization from Gilead Sciences, 
Inc., except to the extent necessary to obtain informed consent from those persons to whom the 
drug may be administered.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................10
1.
INTRODUCTION ..............................................................................................................................................13
1.1.
Background ............................................................................................................................................13
1.2.
Medicinal Product Name:.......................................................................................................................14
1.2.1.
General Information .............................................................................................................15
1.2.2.
Preclinical Pharmacology and Toxicology:..........................................................................15
1.2.3.
Studies in HIV-1 and HBV Infected Pediatric Subjects.......................................................16
1.2.4.
Tenofovir DF Studies in HBV and HIV-1-Infected Pediatric and 
Adolescent Subjects .............................................................................................................16
1.3.
Information about Comparator Product: ................................................................................................18
1.4.
Rationale for This Study ........................................................................................................................18
1.5.
Compliance ............................................................................................................................................20
2.
OBJECTIVES.....................................................................................................................................................21
3.
STUDY DESIGN................................................................................................................................................22
3.1.
Endpoints ...............................................................................................................................................22
3.2.
Study Design..........................................................................................................................................22
3.3.
Study Treatments ...................................................................................................................................25
3.4.
Duration of Treatment............................................................................................................................26
3.5.
Discontinuation Criteria.........................................................................................................................26
3.6.
Source Data............................................................................................................................................26
4.
SUBJECT POPULATION..................................................................................................................................28
4.1.
Number of Subjects and Subject Selection ............................................................................................28
4.2.
Inclusion Criteria....................................................................................................................................28
4.3.
Exclusion Criteria...................................................................................................................................28
5.
ADMINISTRATION OF TENOFOVIR DF TREATMENT .............................................................................30
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................30
5.1.1.
Procedures for Breaking Treatment Codes:..........................................................................30
5.2.
Description and Handling of Tenofovir DF ...........................................................................................30
5.2.1.
Formulation..........................................................................................................................30
5.2.2.
Packaging and Labeling .......................................................................................................30
5.2.3.
Storage and Handling...........................................................................................................31
5.3.
Dosage and Administration of Tenofovir DF.........................................................................................31
5.4.
Prior and Concomitant Medications.......................................................................................................31
5.4.1.
Prior to Study Entry..............................................................................................................31
5.4.2.
During the Study ..................................................................................................................31
5.5.
Devices...................................................................................................................................................32
5.6.
Accountability for Tenofovir DF ...........................................................................................................32
5.6.1.
Tenofovir DF Return or Disposal.........................................................................................33
6.
STUDY PROCEDURES ....................................................................................................................................34
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................34
6.2.
Pre-treatment Assessments.....................................................................................................................34

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6.2.1.
Screening Visit .....................................................................................................................34
6.3.
Baseline Visit .........................................................................................................................................35
6.3.1.
Assignment...........................................................................................................................35
6.3.2.
Baseline Assessments...........................................................................................................35
6.4.
Treatment Assessments..........................................................................................................................36
6.4.1.
Group 1: Week 4 Assessments.............................................................................................36
6.4.2.
Group 1: Week 12 and 36 Assessments ...............................................................................37
6.4.3.
Groups 1 and 2: Week 24 and 72 Assessments....................................................................38
6.4.4.
Groups 1 and 2: Week 48 Assessments................................................................................39
6.4.5.
Groups 1 and 2: Week 60 and 84 Assessments....................................................................40
6.4.6.
Groups 1 and 2: Week 96 Assessments/End of Treatment Visit..........................................41
6.5.
Assessments for Premature Discontinuation from Study.......................................................................42
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................42
6.7.
End of Study...........................................................................................................................................42
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................43
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................43
7.1.1.
Adverse Events.....................................................................................................................43
7.1.2.
Serious Adverse Events........................................................................................................43
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as
Adverse Events or Serious Adverse Events .........................................................................44
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................44
7.2.1.
Assessment of Causality for Tenofovir DF Treatment and Procedures ...............................45
7.2.2.
Assessment of Severity ........................................................................................................45
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................45
7.4.
Gilead Reporting Requirements.............................................................................................................47
7.5.
Toxicity Management ............................................................................................................................48
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................48
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................48
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................49
7.5.4.
Management of Elevated Serum Creatinine and Decreased Creatinine 
Clearance..............................................................................................................................49
7.5.5.
Management of Reduced Serum Phosphate .........................................................................50
7.5.6.
Management of Bone Abnormalities....................................................................................50
7.5.7.
Management of ALT Flares .................................................................................................50
7.6.
Special Situations Reports......................................................................................................................53
7.6.1.
Definitions of Special Situations..........................................................................................53
7.6.2.
Instructions for Reporting Special Situations.......................................................................54
8.
STATISTICAL CONSIDERATIONS................................................................................................................56
8.1.
Analysis Objectives and Endpoints........................................................................................................56
8.1.1.
Analysis Objectives..............................................................................................................56
8.1.2.
Primary Endpoint .................................................................................................................56
8.1.3.
Secondary Endpoints............................................................................................................57
8.1.4.
Other Endpoints of Interest ..................................................................................................57
8.2.
Analysis Conventions.............................................................................................................................57
8.2.1.
Analysis Sets ........................................................................................................................57
8.3.
Data Handling Conventions ...................................................................................................................58
8.4.
Demographic Data and Baseline Characteristics ...................................................................................58
8.5.
Efficacy Analysis ...................................................................................................................................59
8.5.1.
Primary Analysis..................................................................................................................59
8.5.2.
Secondary Analyses .............................................................................................................59
8.6.
Safety Analysis.......................................................................................................................................59

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8.6.1.
Extent of Exposure...............................................................................................................59
8.6.2.
Adverse Events.....................................................................................................................60
8.6.3.
Laboratory Evaluations ........................................................................................................61
8.6.4.
Other Safety Evaluations:  Analyses of BMD......................................................................61
8.7.
Pharmacokinetic Analysis......................................................................................................................61
8.8.
Biomarker Analysis................................................................................................................................61
8.9.
Sample Size............................................................................................................................................62
8.10.
Data Monitoring Committee ..................................................................................................................62
8.11.
Endpoint Adjudication Committee.........................................................................................................62
8.12.
Investigator Responsibilities ..................................................................................................................62
8.12.1.
Good Clinical Practice..........................................................................................................62
8.12.2.
Independent Ethics Committee (IEC) Review and Approval...............................................63
8.12.3.
Informed Consent.................................................................................................................63
8.12.4.
Confidentiality......................................................................................................................63
8.12.5.
Study Files and Retention of Records ..................................................................................64
8.12.6.
Case Report Forms...............................................................................................................65
8.12.7.
Drug and Supplies Accountability and Return.....................................................................65
8.12.8.
Inspections............................................................................................................................66
8.12.9.
Protocol Compliance............................................................................................................66
8.13.
Sponsor Responsibilities ........................................................................................................................66
8.13.1.
Protocol Modifications.........................................................................................................66
8.13.2.
Study Report and Publications .............................................................................................66
8.14.
Joint Investigator/Sponsor Responsibilities ...........................................................................................67
8.14.1.
Payment Reporting...............................................................................................................67
8.14.2.
Access to Information for Monitoring..................................................................................67
8.14.3.
Access to Information for Auditing or Inspections ..............................................................67
8.14.4.
Study Discontinuation..........................................................................................................67
9.
REFERENCES ...................................................................................................................................................68
10.
APPENDICES ....................................................................................................................................................72
Appendix 1.
Investigator Signature Page....................................................................................................73
Appendix 2.
Study Procedures Table..........................................................................................................75
Appendix 3.
Management of Clinical and Laboratory Adverse Events......................................................77
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............78
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential............................102
Appendix 6.
Lactic Acidosis Guidelines...................................................................................................105
LIST OF IN-TEXT TABLES
Table 1-1.
Mean (± SD) Tenofovir Pharmacokinetic Parameters by Age Groups for Pediatric
Patients...................................................................................................................................15

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PROTOCOL SYNOPSIS
Gilead Sciences International Ltd.
Flowers Building, Granta Park
Cambridge, CB21 6GT, United Kingdom
Study Title: 
Pharmacoepidemiology study to define the long-term safety profile of 
tenofovir disoproxil fumarate (Tenofovir DF, Viread®) and describe 
the management of Tenofovir DF-associated renal and bone toxicity 
in Chronic Hepatitis B (CHB)-infected adolescents aged 12 to 
<18 years in Europe
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
This is a non-IND study
2014-004939-39
Not Available
Study Centers 
Planned:
Approximately 25 centers in Europe.
Objectives:
The primary objective of this study is as follows:

To characterize the long term (i.e., 96 weeks of follow up) bone 
safety profile of open-label Tenofovir DF treatment in 
CHB-infected adolescents.  This includes prospectively 
evaluating and comparing the bone mineral density (BMD) 
change between CHB- infected adolescents 12 to < 18 years of 
age treated with Tenofovir DF in European treatment centers who 
are assigned to one of two schedules for renal and bone laboratory 
monitoring and BMD measurement. Primary study outcome will 
be the percent changes in BMD from Baseline through study 
Week 96.
The secondary objectives of this study are as follows: 

To document all serious adverse drug reactions (SADR) and all 
renal- and bone-related adverse events (AEs), including renal and 
bone laboratory abnormalities

To determine the time to diagnosis of renal and bone AEs and 
document the resulting patient management and outcome(s)

To assess the clinical management and outcomes of renal- and 
bone-related ≥ Grade 3 laboratory markers and clinical SAEs

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
To assess the efficacy and tolerability of Tenofovir DF in 
adolescents with CHB infection

To assess the use of oral vitamin D, calcium and phosphate 
supplementation and explore the association between supplement 
use and rates of bone and renal AEs

To describe the demographics and disease characteristics of 
adolescents with CHB infection treated with Tenofovir DF.

To describe reasons for discontinuation of Tenofovir DF.
Study Design:
This is an interventional study involving two assigned monitoring 
groups of chronic HBV infected adolescents who will receive 
treatment with open-label, market-authorized Tenofovir DF and 
followed prospectively to a primary endpoint at 96 weeks.  Subjects
will be assigned to one of two monitoring groups (Group 1 or 2);
subjects in both groups will follow pre-set schedules for bone and 
bone biomarker monitoring.  Group 1 will receive more frequent
BMD, bone biomarker, and renal function monitoring compared to 
Group 2 over the 96 week period.  Subjects will be assigned but not 
blinded to one of the two monitoring groups.
Number of Subjects 
Planned:
100 subjects to receive treatment with Tenofovir DF and assigned to 
one of two monitoring groups (50 in each group)
Target Population:
Adolescents aged 12 to <16 years at the time of enrollment who are 
diagnosed with CHB and are Tenofovir DF treatment naïve
Duration of 
Treatment:
Subjects will be treated for 96 weeks with Tenofovir DF treatment
Diagnosis and Main 
Eligibility Criteria:
At screening, CHB subjects aged 12 to <16 years of age (e.g., 
HBsAg-positive for at least 6 months), weighing ≥35kg will be 
eligible for the study.  Subjects must be naïve to Tenofovir DF, but 
could have received interferon or any oral anti-HBV 
nucleoside/nucleotide therapy.  Subjects experienced on interferon 
must have discontinued therapy for a minimum of six months; 
treatment-experienced subjects receiving oral anti-HBV 
nucleoside/nucleotide treatment at screening must continue their 
current treatment regimen until Tenofovir DF is initiated; subjects 
previously treated with an oral anti-HBV nucleoside/nucleotide 
should initiate Tenofovir DF without a treatment washout period to 
prevent ALT flare. Pregnant or breastfeeding females will not be 
eligible for the study.

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Study Procedures/
Frequency:
Screening measures for Groups 1 and 2 will include determining a 
subject’s eligibility into the study with the following criteria:  current 
age, documentation of chronic HBV infection (e.g., positive 
laboratory results for HBsAg for at least 6 months prior to screening,
a medical assessment affirming CHB status), ability to swallow solid 
tablets, likelihood of adherence to treatment regimen, obtaining 
written informed consent from subject’s parent or legal guardian or 
obtaining informed assent from the subject.  
Baseline measures for Groups 1 and 2 will include laboratory 
assessments for HBV DNA, HBV serology, HCV, HDV, and HIV 
polymerase chain reaction (PCR) testing, HBV genotyping, serum 
renal and bone chemistries, liver function, hematology, urinalysis.  
Dual Energy X-ray Absorptiometry (DEXA) imaging and a physical 
exam, including current concomitant medications (including dietary 
supplements) and any renal or bone AEs, will also be collected.
FREQUENCY OF STUDY PROCEDURES (   Appendix 2):
Subjects enrolled to either Group 1 or 2 will have the following 
measures assessed: 

HBV DNA: every 12 weeks from Baseline to Week 96

HBV serology:  every 24 weeks from Baseline to Week 96

Liver chemistry (i.e., alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), aspartate aminotransferase (AST), total and 
direct bilirubin, total protein, albumin, gamma glutamyl 
transpeptide (GGT), lactate dehydrogenase (LDH), creatine 
kinase (CK): every 24 weeks from Baseline to Week 96

Hematology (i.e., complete blood count with differential and 
platelets, PT/INR): every 24 weeks from Baseline to Week 96

Physical Examination and Drug Dispensing:  every 12 weeks
from Baseline to Week 96
Subjects enrolled to Group 1 will have the following additional 
monitoring;

DEXA: every 24 weeks from Baseline to Week 96 (5 scans)

Serum bone chemistry (i.e., calcium, phosphorus, vitamin D 
levels (25-hydroxy and 1,25 dihydroxyvitamin), parathyroid 
hormone (PTH), osteocalcin, bone-specific alkaline phosphatase, 
N and C telopeptides): every 24 weeks from Baseline to Week 96

Serum renal chemistry (i.e., glucose, creatinine, calculated 
creatinine clearance, magnesium, bicarbonate, chloride, 
potassium, sodium): at 4 weeks and 12 weeks from Baseline and 
every 12 weeks thereafter to Week 96, according to SmPC

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
Urinalysis (i.e., protein, glucose, creatinine, phosphate, 
bicarbonate, blood, calcium): at 4 weeks and 12  weeks from 
Baseline and every 12 weeks thereafter to Week 96
Subjects enrolled to Group 2 will have the following monitoring:

DEXA: every 48 weeks from Baseline to Week 96 (3 scans)

Serum bone chemistry (i.e., calcium, phosphorus, vitamin D 
levels (25-hydroxy and 1,25 dihydroxyvitamin), PTH, 
osteocalcin, bone-specific alkaline phosphatase, N and C 
telopeptides): every 48 weeks from Baseline to Week 96

Serum renal chemistry and urinalysis according local standards of 
care
Product, Dose, and 
Mode of 
Administration:
300mg oral Tenofovir disoproxil fumarate (Tenofovir DF), which is 
equivalent to 245mg Tenofovir disoproxil, following enhanced 
patient monitoring protocol for bone and renal biomarkers
Reference Therapy, 
Dose, and Mode of 
Administration:
300mg oral Tenofovir DF following local standards of care for patient 
monitoring for renal biomarkers
Criteria for 
Evaluation:
Safety:
The primary safety endpoint is the indication of a cumulative 
incidence of a ≥4% decrease from Baseline BMD of the spine or 
whole body through Week 96. Secondary endpoints include bone and
renal AEs.  Bone AEs may include reports of bone pain or fractures. 
Renal AEs may include reductions in creatinine clearance, and 
clinical and laboratory evidence of Grade 3 or greater renal 
tubulopathy or toxicity (e.g. proximal renal tubulopathy, Fanconi 
syndrome).
Bone and renal AEs, concomitant medications (including dietary 
supplements) and specified clinical laboratory tests will be collected 
each time subjects from Group 1 or Group 2 return for scheduled 
monitoring by the study site over a 96 week period.
Efficacy:
An efficacy analysis will be conducted after the last assigned subject 
reaches Week 96.  The analysis will evaluate the difference in the 
proportion of subjects (Group 1 and 2 data will be pooled, as subjects 
have exposure to a single mode of therapy) achieving a composite 
endpoint of HBV DNA 400 copies/mL and ALT normal at 
Week 96.

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Pharmacokinetics:
Not applicable
Statistical Methods:
The primary safety analysis will be performed after the last subject 
reaches Week 96 on Tenofovir DF treatment among both monitoring 
groups.  The primary analysis will evaluate quantitative reductions in 
spine or whole body BMD compared to baseline assessments through 
DEXA scanning.  A key secondary study objective is to assess 
within-group and between-group differences in renal biomarker 
changes (e.g., creatinine clearance using the Schwartz formula, 
glucosuria, proteinuria) suggestive of renal toxicity.  To evaluate the 
time to detection of renal or bone AEs among the assigned 
monitoring groups, estimations of incidence rates (events over person 
time on Tenofovir DF) and time to event analysis will be determined.  
The evaluation of other clinically relevant endpoints such as sustained 
virologic response, serologic status, and development of Tenofovir 
DF resistance will also be assessed as secondary study outcomes for 
each monitoring group and as a combined cohort.  
Approximately 100 subjects are projected to enroll by the end of the 
study (50 in each group).  
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
ADR
Adverse drug reaction
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transferase
AST
aspartate transaminase
BMC
bone mineral content
BMD
bone mineral density
CRF
case report form
CHB
chronic hepatitis b
CDC
U.S. Centers for Disease Control and Prevention
CHIPS
CK
Collaborative HIV Pediatrics Study
creatine kinase
CRO
Contract research organization
CSR
clinical study report
DEXA
Dual energy x-ray absorptiometry
DMC
Data Monitoring Committee
DSPH
Drug Safety & Public Health
DSUR
Development  Safety Update Report
EDD
Estimated date of Delivery
EMA
European Medicines Agency
EU
European Union
FAS
Full Analysis Set
FDA
(United States) Food and Drug Administration
GPP
Good Pharmacoepidemiology Practices (guidelines for)
GSI
Gilead Sciences, Inc.
GVP
Good Pharmacovigilance Practices (guidelines for)
HAART
highly active anti-retroviral therapy
HCC
hepatocellular carcinoma
HDPE
high density polyethylene
HIPPA
Health Insurance Portability and Accountability Act
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug (Application)
INR
International Normalized Ratio
InVS
French Institute for Public Health Surveillance
IRB
LDH
institutional review board
lactate dehydrogenase
OBR
Optimized background regimen
PAS
Post-Authorization Study

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
PASS
PhRMA
Post-Authorization Safety Study
Pharmaceutical Research and Manufacturers of America
PI
protease inhibitor
PRT
proximal renal tubulopathy
REMS
Risk Evaluation and Mitigation Strategy
SADR
serious adverse drug reaction
SAE
serious adverse event
SAP
statistical analysis plan
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SOP
standard operating procedure
SSR
Special situation report
STI
sexually transmitted infection
SUSAR
TDF
Serious Unexpected Suspected Adverse Reaction
Tenofovir disoproxil fumarate
US, USA
United States, United States of America

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EPIDEMIOLOGIC TERMS AND DEFINITIONS
Analytical dataset
The minimum set of data required to perform the statistical analyses leading to the 
results of the primary objective(s) of the study
Bias
Systemic error in the design, conduct or analysis of a study that results in a mistaken 
estimate
Cases
Group of individuals with the condition of interest
Cohort
Group of people characterized by a common experience (e.g.,  occurrence of a specified 
disease, exposure to a given medication)
Confounder
Extraneous factor that accounts for a difference in disease frequency between the 
exposure groups; associated factors serving as surrogates for these factors are also 
commonly called confounders
Confounding by 
indication 
A patient characteristic that is related to the outcome of interest and which influences 
treatment choice (exposure)
Controls
Group of individuals without the condition of interest but are otherwise similar to cases, 
or unexposed to or not treated with the agent of interest
Date at which a study 
commences
Date of the start of data collection
Effect modifier 
If an effect measure varies within categories or levels of a variable, that variable is 
described as an effect-measure modifier 
End of data collection
The date from which the analytical dataset is completely available
Exposure
A variable whose effect is of interest and is being studied
External validity 
Whether or not the results from the study can be generalized to other populations
Internal validity
Whether or not the study provides an unbiased estimate of what it claims to estimate
Odds
The ratio of the probability that an event will happen to the probability that it will not 
happen
Outcome
An event (such as disease occurrence or death) that is studied in relation to exposure
Prevalence
Proportion of persons with the exposure/outcome at a specific point in time
Rate
A measure of event occurrence, calculated by dividing the total number of events by the 
total amount of person-time within an exposure category
Relative Risk (RR)
A general term that can refer to the ratio of 2 risks or the ratio of 2 rates
Risk
The proportion of a fixed cohort in which an outcome occurs during a specified period 
of time
Start of data collection
Date from which information on the first study subject is first recorded in the study 
dataset

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1.
INTRODUCTION
1.1.
Background
Chronic hepatitis B (CHB) infection continues to be an important worldwide cause of morbidity 
and mortality. Worldwide, an estimated 2 billion people have been infected with HBV, and more 
than 350 million have chronic long-term liver infections {26857}.  Up to 60% of the world’s 
population lives in a high HBV endemicity region, such as China or other regions in Asia.  Even 
after acute infection with HBV, approximately 3% to 5% of adults and up to 95% of children fail 
to clear the infection and develop CHB{1635}.
The incidence of HBV infection and patterns of transmission vary greatly throughout the world. 
HBV incidence rates have dramatically decreased {6666}, attributable in part to improved socio 
economic and sanitary conditions, but most importantly due to mass immunization programs, 
which have been recommended by the WHO since 1991. In Europe, Italy set an early example 
by offering a free HBV immunization program in 1984 and a mandatory program for infants and 
12-year-olds beginning in 1991. Between 1987 and 2011, HBV incidence reported to Italy’s 
longitudinal surveillance program declined from 10.4 per 100,000 inhabitants to 0.8 per 
100,000{10698}, {26852}.  Seroepidemiology studies in Italy have demonstrated that 56.1% of 
children 10 years old and under, and 53.8% of those aged 11 to 20 show vaccination-induced 
immunity to HBV, but only 11.3% of those above age 40 have vaccination-induced immunity.  
In France, the incidence of HBV infection appears to have been declining from 21 per 100,000 in 
1991 to 6 per 100,000 in 1996 {10789}.  Today, the French Institute for Public Health 
Surveillance (InVS) reports acute HBV infection at an incidence of 1.1 per 100,000 inhabitants 
among those 0 to 19 years, and 3.6 per 100,000 among 20 to 39 year olds {26853}.  Despite the 
marked reductions in population-based HBV susceptibility through vaccination, the burden of 
HBV morbidity and related mortality continue to present significant public health challenges.  
Western and northern Europe are areas of low endemicity (< 2% prevalence), while some 
countries of Eastern Europe are areas of high endemicity (> 8% prevalence) {19056}. In areas 
with high endemicity, such as Asia and sub-Saharan Africa, CHB infections are usually the result 
of perinatal (vertical) or child-to-child (horizontal) transmission. The mode of transmission has 
clinical implications because 90% of children infected in the first year of life and 30% to 50% of 
children infected between ages 1 and 4 years develop CHB.
Despite the availability of HBV vaccine programs in many countries, new HBV infections are 
still common, including areas of low endemicity such as the United States (US) and Europe
{26406}.  In Europe, 13.34 million people are chronically infected with HBV, with an estimated 
36,000 deaths from HBV related causes annually {24854}, {25143}.  Among 28 reporting EU 
countries, over 17,000 cases of HBV were reported in 2011; with over two-thirds of cases being 
newly identified CHB {26854}, {26858}.  Challenges with reporting acute and chronic HBV 
cases mean that calculations of burden are very likely underestimated.  CHB infection is the 
primary source of HBV-related morbidity and mortality, with up to 25% of early deaths 
associated with HBV cirrhosis or liver cancer {26858}.  Those with CHB infection have a 12 to 
300 times greater risk of hepatocellular carcinoma (HCC) than non-carriers {26858}.

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There is a paucity of aggregated incidence data on HBV in children in Europe, partly due to the 
difficulty in identifying cases, as affected children are often virtually asymptomatic while 
Hepatitis B surface antigen (HBsAg) or Hepatitis B e (core) antigen (HBeAg) positive.   A 
seroprevalence study conducted in 2007 within the Netherlands demonstrated an overall 
prevalence of 0.5% (95% CI 0.2-1.1) among children 0 to 14 years, and among indigenous 
children, the prevalence is only 0.1% (95% CI 0-1.0).  The overall prevalence of HBV in the 
Netherlands is estimated at 3.5% {26855}.  In a recent cross-sectional study among a large 
sample of UK schoolchildren aged 7 to 11 years old, 0.26% (95% CI 0.14-0.44) had persistent 
acute, or resolved HBV infection {26851}.   Unlike infection during adulthood, children often 
exhibit immune tolerance during their initial infection with HBV, with only a very small 
proportion of children clearing HBsAg and either exhibiting HBeAg loss or seroconversion 
{27079}
Following acute hepatitis B infection, up to 90% of children become chronic carriers of the virus. 
Hepatitis B virus infection in children is usually asymptomatic, with a low rate of disease 
progression during the first 2 decades of life. There are four characteristic immunologic phases 
to this disease. In the first phase, the immune tolerant phase, patients have high HBV DNA 
levels and have detectable HBsAg and HBeAg. The hallmark of this phase is a normal ALT. The 
second phase that follows, known as the immune active stage, is characterized by persistently 
elevated ALT levels, an indicator of liver damage, even though children may show no signs or 
symptoms of disease. The third phase, the inactive HBsAg carrier stage, is characterized by 
undetectable or low levels of HBV DNA and the presence of anti-HBe antibodies. This third 
stage can evolve into a fourth stage, reactivation, in which ALT levels are abnormal and HBV 
DNA levels are increased.
The management of CHB in children and adolescents is still evolving {17786}. Current 
consensus is that no treatment is indicated in the immune tolerant (phase 1) or the inactive carrier 
state (phase 3). For children and adolescents in stages 2 or 4; however, treatment may be 
warranted in order to suppress viral replication and to prevent the emergence of complications, 
such as cirrhosis, decompensated liver disease, and HCC. Among infants and young children 
infected with HBV, 15-25% will die prematurely from these conditions {2826}.   Although 
histological abnormalities are usually less severe in children than in adults, HBV infected infants 
and children are at higher risk for the eventual development of cirrhosis and primary HCC. In 
HBeAg-positive patients, treatment can lead to HBeAg loss and, more rarely, anti-HBe 
seroconversion, with the goal of subsequent HBsAg loss and seroconversion to anti-HBs. 
Achieving durable viral suppression in CHB infection usually requires long-term therapy, 
preferably utilizing potent oral regimens that limit the development of resistance.
1.2.
Medicinal Product Name:
300mg Tenofovir disoproxil fumarate, Tenofovir DF (Viread®), which is equivalent to 245mg 
Tenofovir disoproxil.

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1.2.1.
General Information
Tenofovir disoproxil fumarate (Tenofovir DF; 9-[(R)-2-[[bis[[(isopropoxycarbonyl) 
oxy]methoxy]phosphi-nyl] methoxy]propyl] adenine fumarate (1:1); GS4331-05) is an oral 
prodrug (bisPOC-PMPA) of tenofovir (PMPA), an acyclic nucleoside phosphonate (nucleotide) 
analogue of adenosine 5’-monophosphate. Tenofovir DF has activity against HBV and HIV, and 
is indicated for use in HBV infection and in combination with other antiretroviral agents in the 
treatment of HIV-1 infection in adults. Tenofovir DF is primarily excreted by the kidney by both 
filtration and an active tubular transport system with approximately 70 to 80% of the dose 
excreted unchanged in urine following intravenous administration of Tenofovir DF. (VIREAD 
Company Core Data Sheet (CCDS), May 2013). Tenofovir DF was approved for the treatment of 
CHB in adults within the EU in April 2008.
On November 27, 2012, Tenofovir DF was approved by the European Commission for the 
treatment of HIV in children 2 to less than 18 years of age, and for the treatment of chronic HBV
in children 12 to less than 18 years of age.  
Steady-state pharmacokinetics of Tenofovir DF were evaluated in 31 HIV-1 infected U.S. 
pediatric patients. Tenofovir DF exposure achieved in pediatric patients receiving oral daily
doses of VIREAD 300 mg (tablet) or 8 mg/kg of body weight (powder) up to a maximum dose
of 300 mg was similar to exposures achieved in adults receiving once-daily doses of 300 mg
(GS-US-104-0352 Week 48 Clinical Study Report, GS-US-104-0321 Week 48 Clinical Study 
Report).
Table 1-1.
Mean (± SD) Tenofovir Pharmacokinetic Parameters by Age Groups
for Pediatric Patients
Dose and Formulation
300 mg Tablet
8 mg/kg Oral Powder
12 to < 18 Years (N = 8)
2 to < 12 Years (N = 23)
Cmax (μg/mL)
0.38 ± 0.13
0.24 ± 0.13
AUCtau (μg•h/mL)
3.39 ± 1.22
2.59 ± 1.06
Tenofovir exposure in HBV infected pediatric patients (12 to < 18 years of age) receiving oral
daily dose of VIREAD 300 mg tablet was similar to exposures achieved in adults receiving
once-daily doses of 300 mg.  (GS-US-174-0115 Week 72 Study Report)
For further information on Viread®, refer to the investigator’s brochure for Viread®, 8th edition, 
dated 31 March 2014.
1.2.2.
Preclinical Pharmacology and Toxicology
Not applicable

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1.2.3.
Studies in HIV-1 and HBV Infected Pediatric Subjects
1.2.3.1.
Tenofovir DF Studies in HBV and HIV-1-Infected Pediatric and Adolescent 
Subjects
Study GS-US-174-0115 is an ongoing randomized, double-blind, double-dummy, multicenter 
study to evaluate the efficacy, safety, and tolerability of Tenofovir DF versus placebo in 
adolescents aged 12 to 17 years with CHB infection (hepatitis B early antigen [HBeAg]+ or 
HBeAg; HBV DNA 105 copies/ mL). Subjects had to be Tenofovir DF-naive, but could 
previously have received interferon or any other oral anti-HBV nucleoside/nucleotide therapy. 
Subjects were required to take a daily multivitamin that provided 100% of the recommended 
daily allowance of vitamin D. 
The study consisted of two parts, an initial 72-week, randomized, double-blind period in which 
subjects (n = 106) were randomized 1:1 to receive TDF (n = 52; 300 mg once daily) or placebo 
(n = 54), following which subjects were eligible to receive open-label TDF for a further 
120 weeks. This second part of the study is ongoing. DEXA scans of the spine and whole body 
were performed at baseline and at Weeks 24, 48, and 72, and will subsequently be performed at 
Week 96 and then annually until Week 192. Randomization was not performed until the baseline 
DEXA scan had been performed.
The primary safety endpoint was the cumulative incidence of at least a 6% decrease from 
baseline in BMD of the spine through Week 72. The cumulative incidence of at least a 6% 
decrease from baseline in BMD of the whole body through Week 72 was a secondary endpoint. 
Both of these proportions through Week 48 were also secondary endpoints, as were 
corresponding changes in lumbar spine and whole body Z-scores. Other safety endpoints 
included percent change from baseline in lumbar spine and whole body BMD. 
Recent data from the GS-EU-174-0115 trial reported HBV DNA lower than 400 copies/mL in 
88.5% of Tenofovir DF receiving patients after 72 weeks of treatment.  At this same study 
milestone, no subjects met the primary safety endpoint of a 6% decrease in lumbar spine BMD.   
As expected for an adolescent population, both treatment arms experienced an overall increase in 
mean spine BMD.  The mean (SD) change in lumbar spine BMD Z-score from baseline to 
Week 72 in the Tenofovir DF arm was -0.05 (0.310). The mean (SD) change in lumbar spine 
BMD Z score in the placebo arm was 0.07 (0.377). The mean change in whole body BMD 
Z score in the Tenofovir DF arm was -0.15 (0.379). The mean change in whole body BMD 
Z-score in the placebo arm was 0.06 (0.361). Using age and gender matched cohorts, the 
magnitude of the effect of Tenofovir DF on lumbar spine and whole body BMD also does not 
appear to be clinically relevant.  
The mean (SD) change in creatinine from baseline to Week 72 was 0.1 (0.10) for the Tenofovir 
DF group and 0.1 (0.09) for the placebo group. No subject had a confirmed increase from the 
baseline serum creatinine concentration of at least 0.5 mg/dL, a confirmed creatinine clearance 
rate of < 50 mL/min, or a confirmed serum phosphorus concentration < 2 mg/dL.  This study will 
continue to follow subjects to Week 192.

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Two open-label, single-arm, single-center clinical studies have been performed to evaluate the 
safety and pharmacokinetics of Tenofovir DF in a small number of HIV-1-infected children. 
Studies 926 and 927 were 96 Week pharmacokinetic and safety studies, which enrolled 
treatment-experienced children with advanced HIV disease. All subjects received open-label 
Tenofovir DF as a component of a new antiretroviral regimen.
Study 926 was a Phase 1 study in which subjects received six days of Tenofovir DF
monotherapy followed by the addition of individualized antiretroviral regimens. Monitoring for 
bone toxicity included measurement of lumbar spine bone mineral density by DEXA. Study 926 
was conducted at the National Cancer Institute, National Institutes of Health. Eighteen subjects 
with a median (range) age of 11.9 years (6.216.2 years) were studied. Subjects received 
Tenofovir DF at a dose of ~ 175 mg/m2 (administered in multiples of 75 mg tablets) once daily. 
Subjects had extensive treatment experience: median (range) duration of prior antiretroviral 
therapy was 9.7 years (4.813.5). At Week 48, median (range) decrease in log10 HIV RNA was 
1.52 (4.0 to 0.52). HIV RNA was 50 copies/mL in 4 children (400 copies/mL in 
6 children). Results from Study 926 demonstrated that Tenofovir DF-containing HAART 
regimens were effective and well tolerated in heavily treatment-experienced, HIV-infected 
children. However, five of 15 subjects evaluated at 48 weeks of treatment developed a 6% 
decrease from baseline in bone mineral density. Of these subjects, two required discontinuation 
of Tenofovir DF, but decreases in BMD had partially or completed resolved by week 96. One 
additional subject developed a 6% decrease from baseline in bone mineral density by Week 96.
None of the six subjects experienced a bone fracture {8548},{9505}.
Study 927 was designed to assess safety and single-dose and steady-state pharmacokinetics (PK) 
of Tenofovir DF in HIV-1 infected, treatment-experienced children. Seven subjects were 
enrolled, including three children who were naive to Tenofovir DF and four patients who were 
Tenofovir DF experienced. Subjects received Tenofovir DF once daily at a dose of 
approximately 5 mg/kg (administered in multiples of 75 mg tablets). In the three children who 
were naive to Tenofovir DF, single dose PK studies were assessed over 48 hours after the first 
dose. In the four Tenofovir DF-experienced children, steady-state PK studies were assessed over 
10 hours on Day 7, when Tenofovir DF was administered with an optimized background 
antiretroviral regimen.
The primary efficacy endpoint was virologic response, measured as a change from baseline in 
log10 HIV-1 RNA. Limited data available from these patients showed that, overall, treatment 
with Tenofovir DF resulted in a decline in mean plasma HIV-1 RNA of 0.95 log10 copies/mL 
from baseline to Week 72, and a decline in median plasma HIV-1 RNA of 0.39 log10 copies/mL 
from baseline at Week 108. These overall declines were seen despite high prior exposure and 
virological failure/intolerance to multiple antiretrovirals in all patients. Steady state PK 
parameters of Tenofovir DF in children and adolescents treated with Tenofovir DF-containing 
regimens were similar to those seen in HIV-infected adults treated with 300 mg once daily. 
Tenofovir DF was safe and well tolerated when given for a mean duration of 100 weeks in 
combination with other antiretrovirals. A renal tubular disorder and increase in urinary 
beta-2 microglobulin were the only events to occur that were considered possibly/probably 
related to Tenofovir DF. These events, in a subject who had a history of probable tubulopathy 

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while receiving Tenofovir DF before the study, resolved after withdrawal of Tenofovir DF. The 
limited available bone mineral density data in this study do not suggest a decline in BMD with 
increased exposure to Tenofovir DF. No bone fractures occurred during the study.
In a third study, 28 HIV-infected pediatric subjects (ages 5–17.9 years) receiving HAART 
therapy consisting of lamivudine, stavudine and a protease inhibitor (PI) with stable undetectable 
viral loads were randomized to switch the PI to efavirenz and stavudine to tenofovir at baseline 
(Group 1) or at Week 24 (Group 2). At 96 weeks, virological suppression and unchanged CD4 
counts were maintained in all subjects {11526}. Tenofovir DF therapy was well tolerated. 
Through 96 weeks, no child experienced a Grade 1 or higher increase in serum creatinine or 
phosphorus, and mean serum creatinine, phosphorus and bicarbonate values were unchanged 
{11445}. The authors concluded that no evidence of impaired glomerular filtration or tubular 
renal function was observed in HIV-infected children treated with Tenofovir DF for 96 weeks. 
The authors also evaluated bone mineral content (lumbar spine and whole-body bone mineral 
content (BMC) and BMD via DEXA scan in 16 subjects in this study through 12 months of 
Tenofovir DF treatment {10417}. DEXA scans were obtained 12 months prior to therapy switch, 
at baseline, and 12 months after switch to Tenofovir DF. The authors calculated expected 
changes in bone measurements from data obtained from 166 healthy children. The BMC and 
BMD increments observed before and after switching to Tenofovir DF did not differ 
significantly from those calculated in healthy controls. Although the sample size is small, results 
from this study suggest that 12 months of Tenofovir DF treatment does not impair bone mineral 
accrual in HIV-infected children.
Most recently, a clinical trial of Tenofovir DF in pediatric and/or adolescent HIV-1-infected 
subjects is ongoing. Study GS-US-104-352 is evaluating 100 HIV-infected children and 
adolescents (2 to 16 years of age) who are virologically suppressed (HIV-1 RNA 
400 copies/mL) on their current antiretroviral regimen containing either stavudine or 
zidovudine. Subjects are randomized 1:1 to continue on the same stavudine- or 
zidovudine-containing regimen, or to replace stavudine or zidovudine with Tenofovir DF while 
continuing their other background antiretroviral agents. The study will assess the efficacy, safety 
(including BMD) and tolerability of switching to Tenofovir DF, compared to continuing 
stavudine or zidovudine therapy. The study duration is 48 weeks. Enrollment is ongoing, with a 
total of 97 subjects enrolled to date.
1.3.
Information about Comparator Product:
Not applicable.
1.4.
Rationale for This Study
Tenofovir DF-associated bone toxicities have not been well understood in children.  One theory 
is that Tenofovir DF may stimulate bone reabsorption which can be detected with increases in 
bone markers and calcium excretion. Among children and adolescents, skeletal growth increases 
and these same indicators may be expected to be present in children without Tenofovir DF
exposure.  Bone events or abnormalities, such as fractures, related to both proximal renal 
tubulopathy (PRT) and loss of BMD have been documented in both control and 

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Tenofovir DF-receiving arms in adult HIV trials.  Among HIV-1 positive adolescents 
(GS-US-104-0321), the Tenofovir DF-receiving arm reported osteopenia in 6.7% of subjects 
(3/45) and 4.8% (2/42) in the placebo group, and among HBV infected adolescents, there were 
no reported bone events meeting the safety criteria of ≥6% BMD loss (GS-US-174-0115).  In 
pediatric clinical trials of HIV-1 infected children (2-11 years), no bone events associated with 
BMD loss were reported up through 144 weeks of follow up time (GS-US-104-0352).
In a limited study of six pediatric subjects taking Tenofovir DF, two children developed BMD 
decreases of greater than 6% over the course of treatment.  Contrary to these findings was a cross 
over trial from Italy where no notable decreases in BMD were detected when pediatric patients 
taking d4T and protease inhibitor HIV treatment regimens switched to Tenofovir DF/3TC/EFV.  
The Collaborative HIV Paediatric study (CHIPS) based in Ireland and the UK, reported no BMD 
decreases in their longitudinal cohort {15423}.  Among HIV infected adults taking Tenofovir DF, 
the observed pattern is that BMD loss is sustained early in the therapeutic course [TIME] and 
stabilizes with no further notable BMD loss; this pattern has not been established in the limited 
registered studies on either HIV or HBV infected children.     
Renal toxicity associated with Tenofovir DF has been previously identified in small subsets of 
study participants across randomized controlled clinical trials.  In an NIH systematic review of 
Tenofovir DF’s renal safety profile, the mean difference in reduction of creatinine clearance 
among subjects on Tenofovir DF was 3.92 mL/min (2.13-5.70 mL/min 95% confidence interval) 
compared to controls, and no clear associations between treatment and proteinuria, 
hypophosphatemia, nor fractures.  A modest increase in risk of acute renal injury (0.7%, 
0.2-1.2% 95% confidence interval) was noted.  The clinical impact of these findings is unknown
{16177}.  Among registered studies the detection on renal toxicities has been very low, ranging 
between 1 to 2%.  Detailed information and sequelae as a result of serious renal toxicities, such 
as Fanconi syndrome, come from case series or single reports.  A recent NIH report documented 
7 of 51 (14%) adult patients treated for CHB with Tenofovir DF (and/or adefovir) who 
developed renal tubular dysfunction after 22 to 94 months on therapy.  Subjects with renal 
tubular dysfunction had an average age of 58, and 6 of the 7 were male.  All affected subjects
had hypophosphatemia, with others having one or more indications of hypouricemia, increased 
serum creatinine, proteinuria, or glycosuria {20768}.  
The available data to characterize the incidence of renal toxicities in children is lacking, and 
collected primarily within registration studies of CHB and Tenofovir DF.  As Tenofovir DF also 
has the indication for treatment of pediatric HIV, the drug’s safety profile has some overlay to 
both the HIV and the HBV-infected populations.   Among pediatric subjects completing 
144 weeks of  treatment in clinical trial GS-US-104-0352, 4 of 89 (4.5%) patients discontinued 
Tenofovir DF treatment for HIV-1 as a result of new onset adverse reactions suggestive of PRT
(e.g., glycosuria, hypophosphatemia).  
Data from Collaborative HIV Pediatrics Study (CHIPS) in Ireland and the UK reported that 
among the 159 HIV-1 positive children taking Tenofovir DF (since 2001) of a cohort of 
1253 participants, 6 (3.8%) developed renal toxicities including PRT, Fanconi syndrome, and 
acute renal failure.  Five of the six were also taking concurrent NRTI and PI combinations, and 

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were receiving a higher concentration of Tenofovir DF (two were greater than 120% of the 
recommended Tenofovir DF dosing regimen), likely due to advanced disease {13569}. A study 
derived from the same CHIPS cohort evaluated renal toxicities and of those 456 participants on 
antiretroviral therapy, 20 developed hypophosphatemia (4.4%), 10 of whom were on Tenofovir 
DF (2.2%). Incidence of hypophosphatemia associated with Tenofovir DF was 4.3/100 person-
years and among controls (not exposed to Tenofovir DF) it was 0.9/100 person-years. 
Recommendations from these studies include longitudinal monitoring of renal function {15423}. 
Independent and sponsored studies in recent years have shown that Tenofovir DF use among 
adults with diagnoses of HBV or HIV carries a modest risk of BMD decreases or acute renal 
injury compared to placebo or other non-Tenofovir DF containing treatments.  Reported 
decreases in bone mineral density among patients on Tenofovir DF therapy compared to age-and 
height adjusted bone density scores are rare across all age strata seen in clinical trials and 
observational studies (GS-US-104-0321, GS-US-104-0352, GS-US-174-0115).  Among HIV-
and HBV-infected adolescents and children, understanding the longitudinal risk of changes in 
bone mineral density is critical for managing Tenofovir DF-treatment plans weighed against any 
possible alterations to bone development in children. 
Adverse event data from Gilead-sponsored trials have shown increases in creatinine among 0.2% 
of subjects, and renal failure in 0.06%.  In the Viread® Expanded Access Program, 0.04% of 
subjects were diagnosed with new onset PRT (including Fanconi syndrome). In pediatric HIV 
study GS-US-104-0352, 0.05% of patients between 2 and 12 years of age developed PRT; there 
were no reports of PRT in the parallel trial among adolescents with HIV.  Some mediating 
factors identified in past studies have included advancing age, pre-existing renal insufficiencies, 
use of known nephrotoxic medications, and low weight.  Renal injuries while on Tenofovir DF 
treatment have been reversible after discontinuation of Tenofovir DF with complete resolution 
within 4 months for the majority of subjects.  The follow up period and sample size of study 
subjects reporting renal injury have been limited and it is prudent to evaluate these potential risks 
over a longer timeframe and under real world conditions.  
Among adolescent patients with CHB, available interim 72 Week clinical trial data indicate that 
5.8% (95% confidence band of 1.2-15.9%) of subjects experienced a ≥4% decrease in BMD; by 
comparison 3.7% (95% CI 0.4-12.5%) of placebo controls had a BMD loss of ≥4%.  In this same 
trial, no renal adverse drug reactions were detected by Week 72.  Detecting renal or bone AEs in 
CHB adolescents taking Tenofovir DF are infrequent events, and the pool of Tenofovir DF-naïve 
subjects within the EU suitable for enrollment is limited. With a fixed sample size of 100 (50 in 
each monitoring group) one would expect to detect 4-5 renal or bone adverse drug reactions 
across both real-world groups (both receive equivalent treatment) over 96 weeks.  
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.

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2.
OBJECTIVES
The primary objective of this study is as follows:

To characterize the long term (i.e., 96 weeks of follow up) bone safety profile of open-label 
Tenofovir DF treatment in CHB-infected adolescents.  This includes prospectively evaluating 
and comparing the bone mineral density (BMD) change between CHB- infected adolescents 
12 to < 18 years of age treated with Tenofovir DF in European treatment centers who are 
assigned to one of two schedules for renal and bone laboratory monitoring and BMD 
measurement. Primary study endpoint will be the percent changes in BMD from Baseline 
through study Week 96.
The secondary objectives of this study are as follows: 

To document all serious adverse drug reactions (SADR) and all renal- and bone-related
adverse events (AEs), including renal and bone laboratory abnormalities

To determine the time to diagnosis of renal and bone AEs and document the resulting patient 
management and outcome(s)

To assess the clinical management and outcomes of renal- and bone-related ≥Grade 3 
laboratory markers and clinical SAEs.

To assess the efficacy and tolerability of Tenofovir DF in adolescents with CHB infection

To assess the use of oral vitamin D, calcium and phosphate supplementation and explore the 
association between supplement use and rates of bone and renal AEs

To describe the demographics and disease characteristics of adolescents with CHB infection 
treated with Tenofovir DF.

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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study is:

The identification of bone AEs occurring in subjects taking Tenofovir DF between Baseline 
and Week 96 of treatment including the identification of ≥4% reduction in BMD within 
subjects and between monitoring groups from Baseline.
The secondary endpoints of this study are:

Documentation of renal or bone AEs and outcomes among subjects receiving Tenofovir DF, 
including time to medication withdrawal or discontinuation

Subjects’ cumulative exposure time on Tenofovir DF at the time renal or bone AEs are 
detected up to and including Week 96 or to study discontinuation (subjects without renal or 
bone AEs will contribute cumulative exposure time on Tenofovir DF from Baseline to 
Week 96 or to study discontinuation). The cumulative time to renal or bone AEs will be 
expressed as incident rates.

Documentation of the medical management and classification of detected renal or bone 
laboratory abnormalities

Analysis of subjects’ virological and immunological status from Baseline to Week 96 under 
real world treatment practices

Report provider recommendations and subject adherence to dietary supplements (e.g., 
Vitamin D, calcium)

Documentation of subject demographics, new medical issues, medications, biometrics, 
treatment adherence

Reasons for discontinuation of Tenofovir DF
3.2.
Study Design
The study will be a prospective cohort comprised of HBV infected adolescents who initiate 
Tenofovir DF therapy in clinics across Europe.  The subjects will be assigned to one of two
monitoring groups using a validated computer-generated tool for randomization.  Subjects will 
be assigned to Group 1 or 2 upon enrollment into the study but prior to Baseline laboratory and 
DEXA imaging assessments.

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DEXA scans are non-invasive tests to measure bone mineral density as well as skeletal maturity 
and bone mass.  DEXA scans emit an average effective dose of 0.001 milli Sieverts (mSv) in 
adults {22238}. These scans emit very minor radiation (i.e., in comparison, one mammogram has 
an effective dose of 0.4 mSv), and with such low doses of radiation do not pose concerning 
health hazards.  Data are based on adult studies and may have a higher relative effective dose, 
particularly in very young children.  Repeated DEXA scans should be conducted using the same 
model of equipment, if possible, and scans should be read in a standardized manner.
Group 1 will receive Tenofovir DF for the treatment of CHB infection, followed over 96 weeks 
using an enhanced monitoring protocol which includes more frequent laboratory bone biomarker 
testing and lumbar spine and whole-body DEXA scans than specified for Group 2.  With the 
exception of an enhanced monitoring protocol for bone and renal outcomes, subjects will be 
managed according to local standards of care.
Group 2 will be the comparator group of subjects receiving Tenofovir DF for the treatment of 
CHB infection and with the exception of pre-specified bone monitoring, managed according to 
local standards of care.  Group 2 will receive bone biomarker testing, lumbar spine and whole-
body DEXA at Baseline, Weeks 48 and 96.
Both groups will be monitored for 96 weeks on Tenofovir DF during clinic visits for response to 
treatment, AEs, adherence to supplementary vitamins and mineral intake assessments.  
Both groups will be required to have DEXA (whole body and spine) scans for BMD at Baseline 
(week 0) and prior to receipt of Tenofovir DF, and at the end of the study period (Week 96). 
Group 2 will be a comparator cohort to Group 1 in evaluating the hypothesis of whether 
enhanced monitoring for renal and BMD changes and AEs provides a net benefit in preventing 
renal- or bone-related adverse outcomes to adolescents receiving Tenofovir DF therapy for HBV.
For this study design and limited age groupings, matching at enrollment on other factors such as 
demographics, would likely have a marginal benefit on the strength of the results; matching may 
occur (e.g., age, gender, ethnicity, duration of Tenofovir DF exposure) during the analysis phase 
as specified in the statistical analysis plan (SAP).  
The strengths of the study include a focus on long term outcomes related to renal and bone 
adverse event reporting in a vulnerable population.  Use of two real world cohorts will permit the 
evaluation of whether a schedule of more frequent clinical assessments of adolescent patients on 
Tenofovir DF benefit from early detection of potential AEs.  Previous studies across multiple 
HIV and HBV infected patient populations have demonstrated a modest risk for both bone and 
renal AEs related to Tenofovir DF-containing medications.  Understanding whether changes in 
monitoring frequency for serum and urine biomarkers and use of more frequent DEXA may
provide early detection to subtle changes in bone or renal dynamics and be beneficial in 
enhancing patient outcomes.  

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The feasibility of study design implementation has been assessed using clinical trials data from 
GS-US-174-0115.  Demographic, adverse event reporting, clinical and laboratory markers, and 
DEXA screen results at baseline and at regular intervals from clinical trials show a range of 
90-100% reporting adherence for key variables, when applicable.  
The primary safety analysis will be conducted after the last assigned subject reaches Week 96 of 
Tenofovir DF treatment.
Subjects with the following characteristics will be eligible for enrollment: 12 to <16 years of age 
with chronic HBeAg-positive or HBeAg-negative HBV infection (e.g., HBsAg-positive for at 
least 6 months) 
Subjects must be naïve to Tenofovir DF, but could have received prior treatment with other 
anti-HBV nucleoside/nucleotide therapy or interferon (e.g., treatment failure). Previous treatment 
with interferon should have ended at least six months prior to the Screening Visit. 
Screening measures for Monitoring Groups 1 and 2 will include determining a subject’s 
eligibility into the study with the following criteria:  current age, documentation of chronic HBV 
infection, prior Tenofovir DF exposure, weight, laboratory assessments, ability to swallow solid 
tablets, subject’s ability to adhere to treatment regimen, obtaining written informed consent from 
subject’s parent or legal guardian or obtain informed assent from the subject  
Baseline measures for Monitoring Groups 1 and 2 will include laboratory assessments for HBV 
DNA, HBV serology, HCV, HDV, and HIV polymerase chain reaction (PCR) testing, HBV 
genotyping, serum renal and bone chemistries, liver function, hematology, urinalysis.  DEXA 
imaging, a physical exam (including pregnancy testing for females), current concomitant 
medications and any reported prior bone and renal AEs, will also be collected.
FREQUENCY OF STUDY PROCEDURES (   Appendix 2):
Subjects enrolled to either Group 1 or 2 will have the following measures assessed: 

HBV DNA: every 12 weeks

HBV serology: every 24 weeks

Liver chemistry (i.e., alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), total and direct bilirubin, total protein, albumin, gamma glutamyl 
transpeptide (GGT), lactate dehydrogenase (LDH), creatine kinase (CK) every 24 weeks

Hematology (i.e., complete blood count with differential and platelets, PT/INR): every 
24 weeks

Physical Examination and Drug Dispensing:  every 12 weeks

Documentation of bone or renal AEs since the subject’s last visit

Documentation of medical management in the event of bone or renal AEs

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Subjects enrolled to Group 1 will have the following additional monitoring;

DEXA: every 24 weeks from Baseline to Week 96 (5 scans)

Serum bone chemistry (i.e., calcium, phosphorus, vitamin D levels (25-hydroxy and 1, 25 
dihydroxyvitamin), parathyroid hormone (PTH), osteocalcin, bone-specific alkaline 
phosphatase, N and C telopeptides): every 24 weeks

Serum renal chemistry (i.e., glucose, creatinine, calculated creatinine clearance, magnesium, 
bicarbonate, chloride, potassium, sodium): at 4 weeks and 12 weeks from Baseline and every 
12 weeks thereafter, according to SmPC

Urinalysis (i.e., protein, glucose, creatinine, phosphate, bicarbonate, blood, calcium): at 4 
weeks and 12 weeks from Baseline and every 12 weeks thereafter
Subjects enrolled to Group 2 will have the following monitoring:

DEXA: every 48 weeks from Baseline to Week 96 (3 scans)

Serum bone chemistry (i.e., calcium, phosphorus, vitamin D levels (25-hydroxy and 1,25 
dihydroxyvitamin), PTH, osteocalcin, bone-specific alkaline phosphatase, N and C 
telopeptides): every 48 weeks

Serum renal chemistry and urinalysis according to local standards of care 
Subjects who permanently discontinue Tenofovir DF will be asked to return for an end of 
treatment visit within 72 hours of the last dose of Tenofovir DF. Subjects who permanently 
discontinue Tenofovir DF will be followed for 24 weeks off treatment or up to initiation of local 
standard of care treatment, whichever occurs first. 
3.3.
Study Treatments
The proposed study is an open-label trial of 300mg oral Tenofovir DF which is equivalent to 
245mg Tenofovir disoproxil, taken once daily. Tenofovir DF is packaged in white, high-density 
polyethylene (HDPE) bottles with a white child resistant cap. There are 30 tablets per bottle. 
Each bottle also contains silica gel as a desiccant to protect the product from humidity and fiber 
packing to protect the product during handling and shipping.
During Weeks 0 to 96, subjects will be provided with sufficient supplies for 12 weeks of dosing. 
At a minimum, each bottle will be labeled with a lot number, the protocol number, 
administration instructions, storage instructions, expiration date, Sponsor name and address. 
Additional information will be included according to the requirements of the protocol and local 
law.
Tenofovir DF will be supplied by Gilead as per its current commercial tablet formulation for the 
EU (300mg Tenofovir DF) for patients greater than 35 kg.  There will be no difference in 

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medication formulation or frequency as per Tenofovir DF SmPC among subjects assigned to 
either Group 1 or Group 2.
3.4.
Duration of Treatment
Subjects will be treated with Tenofovir DF therapy for 96 weeks (each subject will receive a total 
of 96 weeks of Tenofovir DF treatment). Tenofovir DF is currently approved for use in patients 
across all specified study countries with participating study clinics aged 12 years of age and up.
3.5.
Discontinuation Criteria
Treatment medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in the toxicity management section of the protocol, or 
toxicity that, in the judgment of the investigator, compromises the ability to continue study-
specific procedures or is considered to not be in the subject’s best interest

Therapeutic failure

Subject or legal guardian requests to discontinue for any reason

Subject non-compliance with taking Tenofovir DF or sustained inability to adhere to 
Tenofovir DF treatment plan

Pregnancy during the study

Discontinuation of the study at the request of Gilead Sciences, regulatory agency or an IEC
3.6.
Source Data
Source data will include sequential notes containing at least the following information for each 
subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, i.e., history, physical examination and 
confirmation of diagnosis to support inclusion and exclusion criteria

Participation in study (including study number)

Study discussed and date of informed consent

Dates of all visits

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
Documentation that protocol specific procedures were performed

Results of monitored parameters, as required by the protocol

Start and end date of Tenofovir DF (preferably with drug dispensing information)

Record of all AEs and other safety parameters (start and end date, and preferably including 
causality and intensity);

Concomitant medications (including start and end dates, dose if relevant; dose changes)

Date of study completion and reason for early discontinuation, if applicable
All clinical study documents must be retained by the investigator until at least 2 years after the 
investigation is discontinued and regulatory authorities have been notified. Investigators may be 
required to retain documents longer if required by applicable regulatory requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead Sciences must be notified in advance.  If the investigator cannot guarantee this 
archiving requirement at the study site for any or all of the documents, special arrangements 
must be made between the investigator and Gilead Sciences to store these in sealed containers 
outside of the site so that they can be returned sealed to the investigator in case of a regulatory 
audit. When source documents are required for the continued care of the subject, appropriate 
copies should be made for storage outside of the site.

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
100 subjects to receive treatment with Tenofovir DF and assigned to one of two monitoring 
groups (50 in each group).  The subjects will be assigned to one of two monitoring groups using 
a validated computer-generated tool for randomization.  Subjects will be assigned to Group 1 or 
2 upon enrollment into the study but prior to Baseline laboratory and DEXA imaging 
assessments.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) 12 to <16 years of age
2) Documented chronic HBV infection (e.g. positive serum HBsAg6 months)
3) Weight 35 kg
4) Able to swallow oral tablets
5) Negative serum -HCG pregnancy test (for females of childbearing potential, see 
Appendix 5)
6) Estimated glomerular filtration rate (creatinine clearance) 80 mL/min/1.73m2
  
Estimated creatinine clearance using Schwartz Formula 
(mL/min/1.73m2) = k L/Scr
[(k is a proportionality constant: for adolescent females 12 years old, k = 0.55, and for 
adolescent males 12 years, k = 0.70); L is height in centimeters (cm); and Scr is serum 
creatinine (mg/dL)]
7) Parent or legal guardian of potential study subjects able to provide written informed consent 
prior to any screening evaluations and willing to comply with study requirements or subject 
able to provide written assent as determined by IEC/local requirements and at the 
Investigator’s discretion.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Prior Tenofovir DF therapy; subjects may have received prior interferon or oral anti-HBV 
nucleoside/nucleotide therapy (subjects experienced on interferon must have discontinued 

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therapy for a minimum of six months; treatment-experienced subjects receiving oral 
anti-HBV nucleoside/nucleotide treatment at screening should continue their current 
treatment regimen until Tenofovir DF is initiated (i.e., to prevent ALT flare))
2) Sexually-active males or females of reproductive potential who are not willing to use an 
effective method of contraception during the study. (see Appendix 5 for further details).  
3) Females who are pregnant or breastfeeding, or females who wish to become pregnant during 
the course of the study.
4) Known hypersensitivity to Tenofovir DF, the metabolites or formulation excipients
5) Any condition (including alcohol or substance abuse) or prior therapy that, in the opinion of 
the Investigator, would make the subject unsuitable for the study or unable to comply with 
treatment requirements

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5.
ADMINISTRATION OF TENOFOVIR DF TREATMENT
5.1.
Randomization, Blinding and Treatment Codes
After screening and once eligibility has been confirmed, subjects will be assigned a subject 
number and monitoring arm (i.e., Group 1 or Group 2). A centralized procedure will be used, to 
assign subjects to the respective monitoring arm. For the 96 weeks of the study, Tenofovir DF
will be dispensed to the subject in numbered bottles from supplies stored at the study site. 
Tenofovir DF monitoring groups will be randomly allocated, but the allocation to one or the 
other group will not be blinded.  Subjects will be informed of the two monitoring groups at the 
time of study screening and informed of their assignment to one of the two selected CHB 
management monitoring groups after consent is obtained at the subject’s screening appointment. 
All Baseline tests and procedures must be completed prior to the administration of the first 
dose of Tenofovir DF. Initiation of treatment with Tenofovir DF should take place within 
24 hours of the Baseline Visit.
For duration of the study, Tenofovir DF 300mg will be supplied by Gilead. 
5.1.1.
Procedures for Breaking Treatment Codes:
Not applicable
5.2.
Description and Handling of Tenofovir DF
5.2.1.
Formulation
Tenofovir DF tablets are light blue, almond-shaped, film-coated tablets containing 300mg of 
Tenofovir disoproxil fumarate (equivalent to 245mg Tenofovir disoproxil). Each tablet contains 
the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, 
pregelatinized starch, croscarmellose sodium, and magnesium stearate. The Tenofovir DF tablets 
are film-coated to mask taste. Each tablet is film-coated with a mixture of lactose monohydrate, 
hypromellose (hydroxypropyl methylcellulose), glycerol triacetate, titanium dioxide, and indigo 
carmine aluminum lake.
5.2.2.
Packaging and Labeling
Tenofovir DF is packaged in white, high-density polyethylene (HDPE) bottles with a white child 
resistant cap. There are 30 tablets per bottle. Each bottle also contains silica gel as a dessicant to 
protect the product from humidity and fiber packing to protect the product during handling and 
shipping.
During Weeks 0 to 96, subjects will be provided with sufficient supplies for 12 weeks of dosing. 
At a minimum, each bottle will be labeled with a lot number, the protocol number, 
administration instructions, storage instructions, expiration date, Sponsor name and address. 
Additional information will be included according to the requirements of the protocol and local 
law.

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5.2.3.
Storage and Handling
Tenofovir DF tablets should be stored at 25C (77F); excursions are permitted to 15-30C 
(59–86F).
To ensure product stability, Tenofovir DF should not be dispensed in a container other than the 
one supplied.
5.3.
Dosage and Administration of Tenofovir DF
Subjects will be assigned to receive one of the following treatments in an unblinded fashion:
Group 1: open-label Tenofovir DF 300mg PO once daily, enhanced monitoring
Group 2: open-label Tenofovir DF 300mg PO once daily, Tenofovir DF, local standards of care
for monitoring
Subjects will be instructed to take one tablet by mouth daily. Tenofovir DF should be taken with 
food.
After 96 weeks of protocol-guided monitoring, each subject will switch to medical management 
for CHB as per local standards of care.  
Active study subjects will be dispensed Tenofovir DF at baseline and through the end of the 
study (until each subject reaches Week 96). Subjects will be instructed to return empty 
containers as well as unused study medication in the original container at each study visit. The 
investigator will be responsible for maintaining accurate records for Tenofovir DF and 
Tenofovir DF bottles dispensed and returned. The inventory must be available for inspection by 
the study monitor. Study medication supplies, including partially used or empty bottles, must be 
accounted for and the dispensing logs must be verified by the study monitor prior to destruction 
or return.
5.4.
Prior and Concomitant Medications
5.4.1.
Prior to Study Entry
Refer to Exclusion Criteria in Section 4.3. 
5.4.2.
During the Study
Use of the following medications is prohibited while subjects are taking Tenofovir DF, and 
subjects should be followed closely by their providers:

Antiviral agents with anti-HBV activity, including lamivudine, emtricitabine, entecavir, 
adefovir, telbivudine, clevudine, or others

Antiviral agents associated with potential renal impairment (e.g., cidofovir, acyclovir, 
valacyclovir, ganciclovir, valgancicyclovir)

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
Interferon and pegylated interferon

Nephrotoxic agents (e.g., aminoglycoside antibiotics,  cisplatin, foscarnet, 
IV amphotericin B, IV pentamidine, cyclosporine, tacrolimus, chronic daily non-steroidal 
anti-inflammatory drugs)

Hepatotoxic agents (e.g., anabolic steroids, isoniazid, itraconazole, ketoconazole, lovastatin, 
rifabutin, rifampin, simvastatin)

Competitors of renal excretion, such as probenecid

Systemic chemotherapeutic agents

Interleukin-2 [IL-2] and other immunomodulating agents

Systemic corticosteroids

Investigational agents, except with written approval of the Sponsor
All concomitant medications, including vitamin supplements, herbal remedies and hormonal 
contraception, must be recorded in the appropriate section of the Case Report Forms.
5.5.
Devices
Not applicable
5.6.
Accountability for Tenofovir DF
The investigator is responsible for ensuring adequate accountability of all used and unused 
Tenofovir DF. This includes acknowledgement of receipt of each shipment of Tenofovir DF
(quantity and condition). All used and unused Tenofovir DF dispensed to subjects must be 
returned to the site.
Tenofovir DF accountability records will be provided to each study site to:

Record the date received and quantity of Tenofovir DF

Record the date, subject number, subject initials, the Tenofovir DF lot numbers dispensed

Record the date, quantity of used and unused Tenofovir DF returned, along with the initials 
of the person recording the information.

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5.6.1.
Tenofovir DF Return or Disposal
At study initiation, the monitor will evaluate the site’s standard operating procedure for drug 
disposal/destruction in order to ensure that it complies with Gilead requirements. Drug may be 
returned or destroyed on an ongoing basis during the study if appropriate. At the end of the 
study, following final drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused drug supplies, including empty containers, according these procedures.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.

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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in    Appendix 2 and described in the text that follows. 
The investigator must document any deviation from protocol procedures and notify the study 
sponsor or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
The study population will consist of HBV-infected adolescents who are between 12 to <16 years 
of age at the commencement of the study and receiving Tenofovir DF for the treatment of CHB
during study treatment.  The study population will also be enrolled through one of the
approximately 25 participating European clinics across several countries (eg., Bulgaria, Poland, 
Romania, Italy, France, Spain, and the United Kingdom) projected to commence in June 2015.
Eligibility criteria will include a confirmed diagnosis of HBV infection in subjects who are 
Tenofovir DF treatment naïve. At screening, adolescent subjects (12 to<16 years of age) with 
documented chronic hepatitis B (e.g HBsAg-positive for ≥6 months), weighing 35 kg will be 
eligible for the study. 
Subjects must be naïve to Tenofovir DF, but could have received interferon or any oral anti-HBV 
nucleosides/nucleotide therapy. Subjects experienced on oral anti-HBV nucleoside/nucleotide 
therapy must have discontinued therapy prior to screening. Subjects must have discontinued 
interferon at least six months prior to screening. 
Data will be collected from subjects prospectively from initial enrollment into the study 
(baseline) and up to 96 weeks, study completion, loss to follow-up or death, whichever occurs 
first.  Subjects who discontinue Tenofovir DF as a consequence of an AE will be monitored for 
up to 6 months from the date of the observed AE. 
The data will contain medical records, demographics, diagnoses, procedures, medications, and 
laboratory tests (including DEXA).
6.2.
Pre-treatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 30 days before assignment to determine eligibility for 
participation in the study. The following will be performed and documented at screening:
1) Obtain written informed consent
2) Obtain medical history
3) Complete physical examination including, vital signs, body weight, and height

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4) Screen for pregnancy (serum screen) and contraceptive use 
5) Conduct preliminary liver chemistry tests (ALT, ALP, AST, total and direct bilirubin, total 
protein, albumin, GGT, LDH, CK), serum renal chemistry (glucose, creatinine, creatinine 
clearance (calculated), magnesium, bicarbonate, chloride, potassium, sodium ) and urinalysis 
(glucose, protein, creatinine, phosphate, bicarbonate, blood, calcium) (to be averaged with 
Baseline renal chemistry values), fasting required
6) HBV serology (HBeAg and HBsAg; anti-HBe and anti-HBs (if Ag negative))
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days after screening for commencement into the study.
From the time of obtaining informed consent through the first administration of Tenofovir DF, 
record all renal and bone AEs and any SAEs (not limited to bone or renal) on the adverse events 
case report form (CRF/eCRF).  All other untoward medical occurrences observed during the 
screening period, including exacerbation or changes in medical history are to be captured on the 
medical history CRF/eCRF.  See Section 7 Adverse Events and Toxicity Management for 
additional details.
6.3.
Baseline Visit 
The Baseline Visit should occur within 30 (3) days of the initial Screening Visit. All baseline 
tests and procedures should be completed prior to the receipt of the first dose of Tenofovir DF. 
Subjects will be dispensed Tenofovir DF medication at their Baseline Visit. Tenofovir DF should 
be initiated within 24 hours of the Baseline Visit.
6.3.1.
Assignment
Once eligibility has been confirmed, subjects will be assigned a subject number and monitoring 
group. 
6.3.2.
Baseline Assessments
The following assessments and procedures will be performed and recorded on CRFs for 
Groups 1 and 2 at the Baseline Visit and prior to the subject’s first dose of Tenofovir DF:

Changes in medical status since screening

Physical exam including body weight and height

Blood samples for:
HBV DNA and HBV genotyping (A-H)
HBV serology (HBeAg and HBsAg; anti-HBe and anti-HBs (if Ag negative))

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HCV, HDV, HIV testing
Hematology (CBC with differential and platelets,PT/INR)
Serum renal chemistry (glucose, creatinine, creatinine clearance (calculated) , 
magnesium, bicarbonate, chloride, potassium, sodium), fasting required
Liver chemistry tests (ALT, ALP, AST, total and direct bilirubin, total protein, albumin, 
GGT, LDH, CK), fasting required
Serum bone chemistry (calcium, phosphorus, 1,25 hydroxy vitamin D, PTH, osteocalcin, 
bone alkaline phosphatase, N and C telopeptides), fasting required

Urinalysis (glucose, protein, creatinine, phosphate, bicarbonate, blood, calcuim), fasting 
required

DEXA scan of spine and whole body (DEXA may be performed between Screening and 
Baseline Visits, but must be performed no later than the Baseline Visit), and prior to receipt 
of Tenofovir DF.

Review of bone and renal AEs and any associated medical management

Concomitant medications (including dietary supplements such as calcium, vitamin D, 
phosphorus)

Tenofovir DF dispensing and instructions on appropriate dosing and administration

Screening for pregnancy (urine screen)
6.4.
Treatment Assessments
Unless fasting is required (i.e., serum renal chemistry and urinalysis, serum bone chemistry, liver 
chemistry) for the study visit, subjects should take their dose of Tenofovir DF prior to the visit
with food.
6.4.1.
Group 1: Week 4 Assessments
The following evaluations will be performed at Week 4 unless otherwise specified. Study visits 
are to be completed 7 days of the protocol-specified visit date, based on the Baseline Visit. 
Week 4 assessments are outlined in the following section (Section 6.4.4). Group 2 subjects will 
follow local standard of care for renal monitoring and AE collection.  
The following assessments and procedures will be performed and recorded on CRFs:

Changes in medical status or symptoms from prior visit

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
Body weight and height 

Blood samples for:
Serum renal chemistry (creatinine, glucose, creatinine clearance (calculated), magnesium, 
bicarbonate, chloride, potassium, sodium), fasting required

Urinalysis (protein, glucose, creatinine, phosphate, bicarbonate, blood, calcium) , fasting 
required

Assessment of medication adherence

Review of bone and renal AEs and any associated medical management

Tenofovir DF dispensing and instructions on appropriate dosing and administration

Concomitant medications (including dietary supplements such as calcium, vitamin D, 
phosphorus)
6.4.2.
Group 1: Week 12 and 36 Assessments
Study Visit for Weeks 12 and 36 should be completed 7 days of the protocol-specified visit 
date, based on the Baseline Visit. Group 2 subjects will follow local standard of care for renal 
monitoring and AE collection. The following assessments and procedures will be performed and 
recorded on CRFs:

Complete physical examination including, vital signs, body weight and height

Group 1: Urinalysis (protein, glucose, creatinine, phosphate, bicarbonate, blood, calcium), 
fasting required

Blood samples for:
Group 1: Serum renal chemistry (creatinine, glucose, creatinine clearance (calculated), 
magnesium, bicarbonate, chloride, potassium, sodium), fasting required
Plasma HBV DNA (PCR method)

Review of bone and renal AEs and any associated medical management

Concomitant medications (including dietary supplements such as calcium, vitamin D, 
phosphorus)

Assessment of medication adherence

Tenofovir DF dispensing and instructions on appropriate dosing and administration

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
Screening for pregnancy (urine screen)
Subjects who discontinue the study prior to the Week 12 or 36 Visit will complete all Week 12 
or 36 assessments and procedures at an Early Drug Discontinuation Visit, to be completed within 
72 hours of last dose of Tenofovir DF. Subjects who have received at least one dose of 
Tenofovir DF and permanently discontinue treatment will be followed for 24 weeks off 
treatment or up to initiation of an alternative treatment regimen, whichever occurs first.
6.4.3.
Groups 1 and 2: Week 24 and 72 Assessments
Study Visit for Weeks 24 and 72 should be completed 7 days of the protocol-specified visit 
date, based on the Baseline Visit. Group 2 subjects will follow local standard of care for renal 
monitoring. The following assessments and procedures will be performed and recorded on 
CRFs:

Complete physical exam including vital signs, body weight and height

Blood samples for:
Plasma HBV DNA (for PCR)
HBV serology (HBeAg and HBsAg; anti-HBe and anti-HBs (if HBsAg negative))
Hematology (CBC with differential and platelets, PT/INR) 
Group 1: Serum renal chemistry (glucose, creatinine, creatinine clearance (calculated), 
magnesium, bicarbonate, chloride, potassium, sodium), fasting required
Liver chemistry (ALT, ALP, AST, total and direct bilirubin, total protein, albumin, GGT, 
LDH, CK), fasting required
Group 1 Only: Serum bone chemistry (calcium, phosphorus, 1,25 hydroxy vitamin D, 
PTH, osteocalcin, bone alkaline phosphatase, N and C telopeptides), fasting required

Group 1 Only: DEXA (+/- 14 days of the Week 24 or Week 72 visit) scan of spine and whole 
body 

Group 1: Urinalysis (glucose, protein, creatinine, phosphate, bicarbonate, blood, calcium), 
fasting required

Review of bone and renal AEs and any associated medical management

Concomitant medications (including dietary supplements such as calcium, vitamin D, 
phosphorus)

Assessment of medication adherence

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
Tenofovir DF dispensing and instructions on appropriate dosing and administration

Screening for pregnancy (urine screen)
Subjects who discontinue the study prior to the Week 24 or 72 Visit will complete all Week 24 
or 72 assessments and procedures at an Early Drug Discontinuation Visit, to be completed within 
72 hours of last dose of Tenofovir DF. Subjects who have received at least one dose of 
Tenofovir DF and permanently discontinue treatment will be followed for 24 weeks off 
treatment or up to initiation of an alternative treatment regimen, whichever occurs first.
6.4.4.
Groups 1 and 2: Week 48 Assessments 
Study Visit for Weeks 48 should be completed 7 days of the protocol-specified visit date, 
based on the Baseline Visit. Group 2 subjects will follow local standard of care for renal 
monitoring.  The following assessments and procedures will be performed and recorded on 
CRFs:

Complete physical exam including vital signs, body weight and height

Blood samples for:
Plasma HBV DNA (for PCR)
HBV serology (HBeAg and HBsAg; anti-HBe and anti-HBs (if HBsAg negative))
Hematology (CBC with differential and platelets, PT/INR) 
Group 1: Serum renal chemistry (glucose, creatinine, creatinine clearance (calculated), 
magnesium, bicarbonate, chloride, potassium, sodium), fasting required
Liver chemistry (ALT, ALP, AST, total and direct bilirubin, total protein, albumin, 
GGT,LDH, CK), fasting required
Groups 1 and 2: Serum bone chemistry (calcium, phosphorus, 1,25 hydroxy vitamin D, 
PTH, osteocalcin, bone alkaline phosphatase, N and C telopeptides), fasting required

Group 1: Urinalysis (glucose, protein, creatinine, phosphate, bicarbonate, blood, calcuim), 
fasting required

Groups 1 and 2: DEXA scan (+/- 14 days of the Week 48 visit) of spine and whole body 

Review of bone and renal AEs and any associated medical management

Concomitant medications (including dietary supplements such as calcium, vitamin D, 
phosphorus)

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
Assessment of medication adherence

Tenofovir DF dispensing and instructions on appropriate dosing and administration

Screening for pregnancy (urine screen)
Subjects who discontinue the study prior to the Week 48 Visit will complete all Week 48 
assessments and procedures at an Early Drug Discontinuation Visit, to be completed within 
72 hours of last dose of Tenofovir DF. Subjects who have received at least one dose of 
Tenofovir DF and permanently discontinue treatment will be followed for 24 weeks off 
treatment or up to initiation of an alternative treatment regimen, whichever occurs first.
6.4.5.
Groups 1 and 2: Week 60 and 84 Assessments
Study Visit for Weeks 60 and 84 should be completed 7 days of the protocol-specified visit 
date, based on the Baseline Visit. Group 2 subjects will follow local standard of care for renal 
monitoring.  The following assessments and procedures will be performed and recorded on 
CRFs:

Complete physical exam including vital signs, body weight and height

Blood samples for:
Plasma HBV DNA (for PCR)
Group 1: Serum renal chemistry (glucose, creatinine, creatinine clearance (calculated), 
magnesium, bicarbonate, chloride, potassium, sodium), fasting required

Group 1: Urinalysis (glucose, protein, creatinine, phosphate, bicarbonate, blood, calcium), 
fasting required

Review of bone and renal AEs and any associated medical management

Concomitant medications (including dietary supplements such as calcium, vitamin D, 
phosphorus)

Assessment of medication adherence

Tenofovir DF dispensing and instructions on appropriate dosing and administration

Screening for pregnancy (urine screen)
Subjects who discontinue the study prior to the Week 60 or 84 Visit will complete all Week 60 
or 84 assessments and procedures at an Early Drug Discontinuation Visit, to be completed within 
72 hours of last dose of Tenofovir DF. Subjects who have received at least one dose of 

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Tenofovir DF and permanently discontinue treatment will be followed for 24 weeks off 
treatment or up to initiation of active treatment, whichever occurs first.
6.4.6.
Groups 1 and 2: Week 96 Assessments/End of Treatment Visit
The Study Visit for Week 96/End of Treatment should be completed 7 days of the protocol-
specified visit date, based on the Baseline Visit. The following assessments and procedures will 
be performed and recorded on CRFs:

Complete physical exam including vital signs, body weight and height

Blood samples for:
Plasma HBV DNA (for PCR)
HBV serology (HBeAg and HBsAg; anti-HBe and anti-HBs (if Ag negative))
Hematology (CBC with differential and platelets, total and direct bilirubin, total protein, 
albumin, GGT, PT/INR) 
Serum renal chemistry (glucose, creatinine, creatinine clearance (calculated), magnesium, 
bicarbonate, chloride, potassium, sodium), fasting required
Liver chemistry (ALT, ALP, AST, total and direct bilirubin, total protein, albumin, GGT, 
LDH, CK), fasting required
Serum bone chemistry (calcium, phosphorus, 1,25 hydroxy vitamin D, PTH, osteocalcin, 
bone alkaline phosphatase, N and C telopeptides),  fasting required

Urinalysis (glucose, protein, creatinine, phosphate, bicarbonate, blood, calcium), fasting 
required

Groups 1 and 2: DEXA scan (+/- 14 days of the Week 96 visit) of spine and whole body 

Review of bone and renal AEs and any associated medical management

Concomitant medications (including dietary supplements such as calcium, vitamin D, 
phosphorus)

Assessment of medication adherence

Tenofovir DF accountability

Screening for pregnancy (urine screen)

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Subjects who discontinue the study prior to the Week 96 Visit will complete all Week 96 
assessments and procedures at an Early Drug Discontinuation Visit, to be completed within 
72 hours of last dose of Tenofovir DF. Subsequent off-study therapy, if any, is at the discretion 
of the subject/physician and will not be provided by Gilead Sciences. Subjects who have 
received at least one dose of Tenofovir DF and permanently discontinue Tenofovir DF treatment 
will be followed for 24 weeks off treatment or up to initiation of standard of care treatment, 
whichever occurs first.
The study treatment will end after the each subject reaches Week 96.  
6.5.
Assessments for Premature Discontinuation from Study
If a subject discontinues Tenofovir DF (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 6.6, Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.
6.6.
Criteria for Discontinuation of Study Treatment
Study medication (Tenofovir DF) may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 

Unacceptable toxicity, as defined in the toxicity management section of this protocol, or 
toxicity that, in the judgment of the investigator, compromises the ability to continue study-
specific procedures or is considered to not be in the subject’s best interest

Therapeutic failure 

Subject request to discontinue for any reason

Subject non-compliance with taking Tenofovir DF or sustained inability to adhere to 
Tenofovir DF treatment plan

Pregnancy during the study; refer to Appendix 5

Discontinuation of the study at the request of Gilead, a regulatory agency or independent 
ethics committee (IEC)
6.7.
End of Study
The end of study is defined as the completion of Tenofovir DF therapy and close-out monitoring 
by the last enrolled subject (e.g., last enrolled subject completes 96 Weeks of treatment and 
monitoring). 

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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae, unless the subject is hospitalized (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.

Uncomplicated pregnancy

An induced elective abortion to terminate a pregnancy without medical reason
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

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
In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. 
Examples of medically important events include intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; and development of drug dependency or drug abuse. For the avoidance of doubt, 
infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements.
The purposes of this study, in addition to the above criteria, the following must be reported as 
an SAE:
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory or imaging abnormalities without clinical significance are usually not recorded as 
AEs or SAEs. However, laboratory abnormalities (eg, renal or bone lab values, hematology, liver 
chemistry, urinalysis) or imaging abnormalities (eg, DEXA) that require medical or surgical 
intervention or lead to Tenofovir DF interruption, modification, or discontinuation must be 
recorded as an AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal 
assessments (eg, electrocardiogram, x-rays, vital signs) that are associated with signs and/or 
symptoms must be recorded as an AE or SAE if they meet the definition of an AE or SAE as 
described in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a syndrome, record 
the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Appendix 4.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub investigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.

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7.2.1.
Assessment of Causality for Tenofovir DF Treatment and Procedures
The investigator or qualified sub investigator is responsible for assessing the relationship to 
Tenofovir DF therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than Tenofovir DF. For 
SAEs, an alternative causality must be provided (eg, pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the medicinal 
product (i.e., Tenofovir DF).  
The site investigator or sub-investigator may further classify renal or bone AEs as an ADR or 
SADR, if an association of the clinical event to Tenofovir DF and the degree of AE seriousness
can be ascertained.  All SAEs (i.e., not limited to renal or bone events) will be reported. 
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity
Severity should be recorded and graded according to the GSI Grading Scale for Severity of
Adverse Events and Laboratory Abnormalities (Appendix 4). For AEs associated with laboratory 
abnormalities, the event should be graded on the basis of the clinical severity in the context of 
the underlying conditions; this may or may not be in agreement with the grading of the 
laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead 
Requirements for collection prior to Tenofovir DF initiation:
After informed consent, but prior to initiation of Tenofovir DF, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and AEs related to 
protocol-mandated procedures.
Adverse Events
Following initiation of Tenofovir DF, collect all bone and renal AEs, regardless of cause or 
relationship, until 30 days after last administration of Tenofovir DF must be reported to the 
CRF/eCRF database as instructed.

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All bone and renal AEs should be followed up until resolution or until the adverse event is stable, 
if possible. Gilead Sciences may request that certain AEs be followed beyond the protocol 
defined follow up period.
Serious Adverse Events
All bone and renal SAEs, regardless of cause or relationship, that occurs after the subject first 
consents to participate in the study (i.e., signing the informed consent) and throughout the 
duration of the study, including the protocol-required post treatment follow-up period, must be 
reported to the CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as 
instructed. This also includes any bone and renal SAEs resulting from protocol-associated 
procedures performed after informed consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30-days of the 
last dose of Tenofovir DF, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek bone and renal SAEs after the protocol defined 
follow up period, however, if the investigator learns of any SAEs that occur after study 
participation has concluded and the event is deemed relevant to the use of Tenofovir DF, he/she 
should promptly document and report the event to Gilead DSPH.

All bone and renal AEs and (S)ADRs and all SAEs (not limited to bone and renal events)
will be recorded in the CRF/eCRF database within the timelines outlined in the CRF/eCRF 
completion guideline.

At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. Gilead will notify sites in writing and provide training and account information prior 
to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All pre-specified SAEs will be recorded on the serious adverse event report form and
submitted by faxing or emailing the report form within 24 hours of the investigator’s 
knowledge of the event to the attention of Gilead DSPH or to the designated CRO.
CRO (TBD)
Contacts (TBD)
Gilead Sciences DSPH 
Representative:
Fax:
+1 650 522 5477
E-mail:
safety_fc@gilead.com
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

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
If for any reason it is not possible to record the SAE information electronically, i.e, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours as described above.

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the EU Clinical Trials Directive 
(2001/20/EC) and relevant updates, and other country-specific legislation or regulations, Gilead 
may be required to expedite to worldwide regulatory agencies reports of SAEs, SADRs, or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any Tenofovir DF treatment. The investigator should notify the IEC of SUSAR reports as 
soon as is practical, where this is required by local regulatory agencies, and in accordance with 
the local institutional policy. 

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7.5.
Toxicity Management 
All clinical toxicities and/or abnormal laboratory findings should be investigated for etiology and 
graded according to the uniform guidelines detailed in Appendix 5. The Gilead Sciences Medical 
Monitor is available for consultation on all medical and toxicity-related issues and may be 
contacted as shown below:
Gilead Sciences Medical Monitor
Name:
Benedetta Massetto, MD
Telephone:
Mobile:
Fax:
Email:

All clinical and clinically significant laboratory toxicities will be managed according to 
uniform guidelines detailed in Appendix 5.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before drug discontinuation, unless 
such a delay is not consistent with good medical practice. 

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
(Appendix 4).

When restarting Tenofovir DF following resolution of the adverse event, the drug should be 
restarted at full dose or modified dose that is dependent upon discussion with the 
Gilead Sciences Medical Monitor.

Any recurrence of the Tenofovir DF-related Grade 3 or 4 clinical or clinically significant 
laboratory adverse event following dose interruption mandates permanent discontinuation of 
drug.

Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue Tenofovir DF at the discretion of the investigator.
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, Tenofovir DF may 
be continued if the event is considered to be unrelated to drug.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to Tenofovir DF, drug should be withheld until 
the toxicity returns to Grade 2.
PPD
PPD
PPD
PPD

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
If a laboratory abnormality recurs to Grade 3 following restarting Tenofovir DF and is 
considered related to Tenofovir DF, then Tenofovir DF should be permanently discontinued 
and the subject managed according to local practice. Recurrence of laboratory abnormalities 
considered unrelated to Tenofovir DF may not require permanent discontinuation.
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event
For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality confirmed 
by repeat testing that is considered related to Tenofovir DF, Tenofovir DF should be 
permanently discontinued and the subject managed according to local practice. The subject 
should be followed as clinically indicated until the laboratory abnormality returns to baseline or 
is otherwise explained, whichever occurs first. A clinically significant Grade 4 laboratory 
abnormality that is not confirmed by repeat testing should be managed according to the 
algorithm for the new toxicity grade. 
Tenofovir DF may be continued without dose interruption for a clinically non-significant 
Grade 4 laboratory abnormality (e.g., Grade 4 CPK after strenuous exercise, or triglyceride 
elevation that is non-fasting or that can be medically managed) or a clinical event considered 
unrelated to Tenofovir DF.
7.5.4.
Management of Elevated Serum Creatinine and Decreased Creatinine 
Clearance

Glomerular filtration rate (estimated creatinine clearance) will be calculated at each visit 
using the Schwartz Formula for subjects ages 12–17 as follows:
Schwartz Formula (mL/min/1.73 m2) = k L/Scr
[(k is a proportionality constant, for adolescent females 12 years old is 0.55; and for 
adolescent males 12 years old is 0.70); L is height in centimeters (cm); and Scr is serum 
creatinine (mg/dL)]

If creatinine clearance decreases to 50 mL/min/1.73 m2 (confirmed) at any time during the 
study, Tenofovir DF should be permanently discontinued, followed by 24 weeks of monthly 
monitoring in treatment-free follow up if alternative HBV therapy is not initiated.

Subjects with estimated creatinine clearance 70 mL/min/1.73 m2 and serum creatinine 
increased 0.5 mg/dL above baseline should have the serum creatinine and creatinine 
clearance confirmed by repeating testing within three calendar days of receipt of results and 
before Tenofovir DF discontinuation, unless such a delay is not consistent with good medical 
practice.

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
Subjects with confirmed estimated creatinine clearance 70 mL/min/1.73 m2 and serum 
creatinine increased 0.5 mg/dL above baseline should have Tenofovir DF discontinued, and 
the subject should be followed weekly for two weeks. After two weeks, if the estimated 
creatinine clearance is 70 mL/min/1.73/m2, Tenofovir DF may be resumed, with 
monitoring as described below. If the estimated clearance remains 70 mL/min/1.73 m2, 
Tenofovir DF should be permanently discontinued, followed by 24 weeks of monthly 
monitoring in treatment-free follow up if alternative HBV therapy is not initiated.

The serum creatinine and estimated creatinine clearance should be rechecked within two 
weeks after restarting treatment to ensure that the subject has stabilized. Once this has been 
determined, the subject should be evaluated at regularly scheduled study visits.

If creatinine clearance decreases to 70 mL/min/1.73 m2 (confirmed) following restarting 
Tenofovir DF treatment, Tenofovir DF should be permanently discontinued, followed by 
24 weeks of monthly monitoring in treatment-free follow up if alternative HBV therapy is 
not initiated.
7.5.5.
Management of Reduced Serum Phosphate
If serum phosphate is confirmed to be < 3.0 mg/dl (0.96 mmol/l) in any paediatric patient 
receiving Tenofovir DF, renal function should be re-evaluated within one week, including 
measurements of blood glucose, blood potassium and urine glucose concentrations. If renal 
abnormalities are suspected or detected then consultation with a nephrologist should be obtained 
to consider interruption of Tenofovir DF treatment.
7.5.6.
Management of Bone Abnormalities
Among Group 1 subjects, if bone abnormalities are detected or suspected in paediatric patients, 
consultation with an endocrinologist and/or nephrologist should be obtained. Group 2 subjects with 
detected or suspected bone abnormalities should be managed as per the local standard of care.
7.5.7.
Management of ALT Flares
Flares on treatment: Spontaneous exacerbations in CHB are relatively common and are 
characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT 
may increase in some patients.  In patients with compensated liver disease, these increases in 
serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or 
hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic 
decompensation following hepatitis exacerbation, and therefore should be monitored closely 
during therapy.
Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported 
in patients who have discontinued HBV therapy. Post-treatment exacerbations are usually 
associated with rising HBV DNA, and the majority appears to be self-limited. However, severe 
exacerbations, including fatalities, have been reported. Hepatic function should be monitored at 
repeated intervals with both clinical and laboratory follow-up for at least 6 months after 

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discontinuation of HBV therapy. If appropriate, resumption of HBV therapy may be warranted. 
In patients with advanced liver disease or cirrhosis, treatment discontinuation is not 
recommended since post-treatment exacerbation of hepatitis may lead to hepatic 
decompensation.  Patients should be placed on commercially available HBV therapy following 
study drug discontinuation.   Liver flares are especially serious, and sometimes fatal in patients 
with decompensated liver disease.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis are defined as: 

Serum ALT 2 baseline and 10 ULN, with or without associated symptoms OR

Confirmed ALT elevation (defined as 1-grade shift or 2 previous value) associated with 
confirmed changes outside of the normal range in other laboratory parameters suggestive of 
worsening hepatic function (total bilirubin 2 mg/dL above baseline, abnormal 
PT 2 seconds or INR 0.5 over baseline, abnormal serum albumin 1 g/dL below baseline 
or elevated serum lactate levels (if available), defined as 2 ULN per the Adult AIDS 
Clinical Trials Group (AACTG) guidelines).
7.5.7.1.
Management of ALT Flare in Subjects Receiving Tenofovir DF
If laboratory results indicate (1) elevation of ALT 2 baseline and 10 ULN OR 
(2) abnormal laboratory parameters suggestive of worsening hepatic function (abnormal 
bilirubin 2mg/dL above baseline, abnormal PT 2 sec above baseline, INR 0.5 above 
baseline, abnormal albumin 1 g/dL decrease from baseline or elevated serum lactate 
levels 2 ULN along with any ALT elevation (i.e., grade shift or 2 previous value), the 
following is recommended:

Schedule the subject to return to the clinic as soon as possible and ideally no later than 
one week after the initial labs were drawn. During the visit, perform a clinical assessment of 
the subject. The assessment should include a physical examination and evaluation of the 
subject’s mental status. 

Draw blood samples, request lactate testing and send for confirmation of elevated serum 
transaminases (ALT/AST), total bilirubin and PT/INR, and albumin. [Note: If, in the 
investigator’s judgment, the central laboratory cannot provide adequate turn around time, the 
confirmation test may also be performed at a local laboratory. However, the central 
laboratory results are considered definitive].
If the elevations are confirmed, request the central clinical laboratory to conduct reflex testing 
for serum HBV DNA, HBV serology (HBeAg, HBeAb, and HBsAg), HDV, HAV IgM, and 
HCV serology. 
Based on the results of the confirmatory tests, the following treatment modifications are 
recommended:

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Elevated Liver Enzymes, Normal Bilirubin, Normal PT/INT, Normal Albumin, Normal 
Lactate
If ALT and/or AST levels are elevated (i.e., 2 baseline and 10 ULN) but total bilirubin 
and PT/INR, albumin and lactate are normal, the subject may remain on Tenofovir DF and 
should be monitored every week until ALT/AST return to normal or baseline levels. During 
monitoring:

If ALT/AST levels decline within 4 weeks, the subject should remain on study and return to 
the clinic per protocol.

If after 4 weeks of monitoring, ALT/AST values remain elevated (e.g., 2 baseline 
and 10 ULN) or have worsened, with bilirubin 2.5 × ULN, PT 1.5 ULN, or 
abnormal albumin or lactate levels, the investigator should consult with the Gilead Medical 
Monitor.

If ALT remains 2 baseline and 10 ULN and the bilirubin or PT values are confirmed 
at 2.5 ULN or 1.5 ULN, respectively, the investigator should consider discontinuing 
Tenofovir DF and initiating alternative HBV therapy (see below). However, prior to 
initiating alternative therapy, medical management of the subject should be discussed with 
the Gilead Medical Monitor. (Note: Once a subject has started alternative therapy, s/he must 
be discontinued from the study.)
Elevated Liver Enzymes, Elevated Bilirubin and PT/INR (Grade 2) Symptomatic 
Elevated Lactate (2 ULN) or Asymptomatic Elevated Lactate (4 ULN)
If ALT/AST values are elevated (i.e., 2 baseline and 10 ULN) and bilirubin or PT values 
are confirmed at 2.5 ULN or 1.5 ULN , respectively, or lactate levels are increased 
(symptomatic and 2 ULN or asymptomatic and 4 ULN) the investigator should consider 
discontinuing Tenofovir DF and initiating alternative HBV treatment. The subject must be 
monitored weekly for as long as enzyme levels and bilirubin and PT/INR remain elevated or 
above baseline values. Refer to Appendix 6
for specific guidelines for the management of symptomatic and asymptomatic hyperlactatemia.

If the ALT/AST levels return to the baseline level and/or Grade 2 or lower during the first 
8 weeks of monitoring, Tenofovir DF may be resumed. 

If the ALT/AST levels, bilirubin, PT/INR or lactate levels remain elevated up through 
Week 8 or deteriorate at any point, the investigator should consult with the Gilead Medical 
Monitor.

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7.5.7.2.
Management of Exacerbation of Hepatitis in Subjects Who Have Discontinued 
Study Medication (Tenofovir DF)
If laboratory results indicate (1) an ALT elevation 2 baseline and 10 ULN OR 
(2) abnormal laboratory parameters suggestive of worsening hepatic function 
(bilirubin 2 mg/dL above baseline, abnormal PT 2 secs above baseline, abnormal 
albumin 1 g/dL below baseline or elevated lactate levels 2 ULN) along with any ALT 
elevation (i.e., 1 grade shift or 2 previous value) and the subject is on no post-study therapy for 
HBV, the following is recommended:

Schedule the subject to return to the clinic as soon as possible and ideally no later 
than 1 week after the initial labs were drawn. During the visit, perform a clinical assessment 
of the subject. The assessment should include a physical examination and evaluation of the 
subject’s mental status.

Draw blood samples and request lactate testing and confirmation of elevated serum 
transaminases (ALT/AST), bilirubin, PT/INR, and albumin. [Note: If, in the investigator’s 
judgment, the central lab cannot provide adequate turn around time, the confirmation test 
may also be performed at a local lab. However, the central lab results are considered 
definitive].

If the elevations are confirmed (e.g., ALT 2 baseline and > 10 ULN) OR (2) abnormal 
laboratory parameters suggestive of worsening hepatic function (abnormal bilirubin 2 
mg/dL above baseline, abnormal PT 2 secs above baseline, abnormal albumin 1 g/dL 
below baseline, or elevated lactate levels 2 ULN) along with any ALT elevation (i.e., 1 
grade shift or 2 previous value), request the clinical laboratory to conduct reflex testing for 
serum HBV DNA, HBV serology (HBeAg, HBeAb, and HBsAg), HDV, HAV IgM and HCV. 
If serum HBV DNA is increasing, the investigator should consider immediate initiation of 
approved therapy. 
The subject should be followed until the abnormal ALT/AST values, bilirubin, PT/INR, albumin 
or lactate laboratory parameters return to normal or baseline up to a maximum of 6 months after 
the initial occurrence of the event.  Refer to Appendix 6
for specific guidelines for the management of symptomatic and asymptomatic hyperlactatemia.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include reports of pregnancy; medication error, abuse, misuse, or 
overdose; lack of effect; adverse reactions in infants following exposure from breastfeeding; and 
adverse reactions associated with product complaints and occupational exposure. 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.

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Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
Lack of effect is defined as the failure of the expected or intended pharmacologic action or 
therapeutic effect as described in the pharmacology and/or indications section of the current 
product labeling. 
Occupational exposure is defined as exposure to a medicinal product as a result of one’s 
professional or non-professional occupation.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication (i.e., Tenofovir DF) and throughout the study to the CRO or Gilead 
DSPH Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.

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The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to CRO [TBD] or Gilead DSPH using the pregnancy 
outcome report form. If the end of the pregnancy occurs after the study has been completed, the 
outcome should be reported directly to Gilead DSPH. Gilead DSPH contact information is as 
follows: Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve Tenofovir DF and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications donot need to be reported on 
the special situations report form; however, for special situations that result in renal or bone AEs
due to a non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is:

To characterize the long term (i.e., 96 weeks of follow up) bone safety profile of open-label 
Tenofovir DF treatment in CHB-infected adolescents.  This includes prospectively evaluating
and comparing the BMD change between CHB infected adolescents 12 to < 18 years of age
treated with Tenofovir DF in European treatment centers who are assigned to one of two 
schedules for renal and bone laboratory monitoring and BMD measurement. The primary 
study endpoint will be the percent changes in BMD from Baseline through study Week 96.
The secondary objectives of this study are as follows: 

To document all SADRs and all renal- and bone-related AEs including renal and bone 
laboratory abnormalities, as applicable

To determine the time to diagnosis of renal and bone AEs and document the resulting patient 
management and outcome(s)

To assess the clinical management and outcomes of any renal- or bone related ≥Grade 3 
laboratory markers and clinical SAEs

To assess the efficacy and tolerability of Tenofovir DF 300mg once daily in adolescents aged 
12 to <18 years with CHB infection

To assess the use of oral vitamin D, calcium and phosphate supplementation and explore the 
association between supplement use and rates of bone and renal AEs

To describe the demographic characteristics, the disease characteristics, of adolescents with 
CHB infection treated with Tenofovir DF

To describe reasons for discontinuation of Tenofovir DF.
8.1.2.
Primary Endpoint
The primary endpoint of this study is:

The identification of bone AEs occurring in subjects taking Tenofovir DF between Baseline 
and Week 96 of treatment, including the identification of ≥4% percent reduction in BMD 
within subjects and between monitoring groups from Baseline.

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8.1.3.
Secondary Endpoints

Documentation of renal or bone AEs and outcomes among subjects receiving Tenofovir DF, 
including rates of medication withdrawal or drug discontinuation

Subjects’ cumulative exposure time on Tenofovir DF at the time renal or bone AEs are 
detected up to and including Week 96 or to study discontinuation (subjects without renal or 
bone AEs will contribute cumulative exposure time on Tenofovir DF from Baseline to 
Week 96 or to study discontinuation).  The cumulative time to renal or bone AEs will be 
expressed as incident rates.

Documentation of the medical management and classification of detected renal or bone 
laboratory abnormalities

Analysis of subjects’ virological and immunological status from Baseline to Week 96 under 
real world treatment practices

Report provider recommendations and subject adherence to dietary supplements (e.g., 
Vitamin D, calcium)

Documentation of subject demographics, new medical issues, medications, biometrics, 
treatment adherence

Reasons for discontinuation of Tenofovir DF
8.1.4.
Other Endpoints of Interest
Not applicable
8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS® software (SAS Institute, Cary, North Carolina, USA) or other standard 
software tools including the STATA software (STATACorp LP, College Station, TX, USA).
8.2.1.
Analysis Sets
The analysis set will be the Full Analysis Set (FAS), which includes all subjects enrolled in the 
study.
8.2.1.1.
Efficacy
An efficacy analysis will be conducted after the last assigned subject reaches Week 96.  The 
analysis will evaluate the difference in the proportion of subjects (Group 1 and 2 data will be 
pooled, as subjects have exposure to a single mode of therapy) achieving a composite endpoint 
of HBV DNA 400 copies/mL and ALT normal at Week 72, using a two-sided Fisher exact test 
with a non-completer equals failure approach.

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The primary analysis set for safety analyses will include all randomized subjects who received at 
least one dose of Tenofovir DF. All data collected during the course of the study (on treatment 
and during the treatment-free follow up window) will be included in the safety summaries.
Normalized bone biomarker ranges (i.e., calcium, phosphorus, vitamin D levels, PTH, 
osteocalcin, bone alkaline phosphatase, N and C telopeptides) in pediatric populations have not 
been established.  Bone serum biomarkers will be collected in parallel to DEXA scan schedules 
for Groups 1 and 2 and summarized and compared to DEXA z-score findings.
8.2.1.2.
Interim Analysis
An analysis for collected renal and bone adverse event data will be conducted after the first 
50 patients are enrolled and complete Week 48 of the study.  Final analyses will be conducted 
after all subjects have completed the study.  All data collected during treatment plus 30 days will 
be included in the safety summaries.
8.2.1.3.
Pharmacokinetics
Not applicable
8.2.1.4.
Biomarkers
Not applicable
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. In general, values for 
missing data will not be imputed.
For the primary endpoint and categorical secondary efficacy endpoints, missing data will be 
detailed in a separate statistical analysis plan.
Sensitivity analyses will be performed if warranted.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods 
Demographic summaries will include sex, race/ethnicity, randomization stratification group, and 
age.
Baseline data will include a summary of body weight, height, body mass index, log10 (HBV 
DNA) level, HBV serology, liver tests, creatinine clearance calculations using the Schwartz 
formula, hematology, previous nucleoside and interferon exposure, genotype, bone mineral 
density (via DEXA scan), and serum bone biochemical markers.

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For categorical demographic and baseline characteristics, a two-sided Fisher exact test may be 
used to compare monitoring groups. Similarly, for continuous demographic and baseline 
characteristics, a Wilcoxon rank sum test may be used to compare monitoring groups.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
An efficacy analysis will be conducted after the last assigned subject reaches Week 96.  The 
analysis will evaluate the difference in the proportion of subjects (Group 1 and 2 data will be 
pooled, as subjects have exposure to a single mode of therapy) achieving a composite endpoint 
of HBV DNA 400 copies/mL and ALT normal at Week 96, using a two-sided Fisher exact test 
with a non-completer equals failure approach.
8.5.2.
Secondary Analyses 
Not applicable
8.6.
Safety Analysis
All safety data collected on or after the date that Tenofovir DF was first dispensed up to the date 
of last dose of Tenofovir DF will be summarized by monitoring group. Data for any pre-
treatment and treatment-free follow up periods will be included in data listings. 
The primary safety analysis will be performed after the last assigned subject reaches Week 96. 
The analysis will evaluate the difference between renal or bone AEs recorded within each of the 
monitoring groups with respect to the primary safety endpoint, estimating the cumulative 
incidence proportions using time-to-event methodology and performing comparisons using 
95% confidence intervals for differences in proportions. 
The proportion of subjects in each monitoring group with renal or bone AE leading to permanent 
discontinuation of Tenofovir DF through Week 96 will be summarized. Descriptive statistics 
such as n, mean, standard deviation, median, Q1, Q3, minimum and maximum) by monitoring
group will be used to report demographics and time to event summaries, and a Wilcoxon rank 
sum test may be used to compare AEs between monitoring groups.
For categorical safety data including incidence of AEs and categorizations of laboratory data, a
Fisher’s exact test will be used to compare monitoring groups. For continuous safety data 
including laboratory data, a Wilcoxon Rank sum test will be used to compare monitoring groups. 
Subgroup analyses of safety endpoints will include analyses by assigned monitoring group, age 
groups, and geographical location of study site.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to drug treatment will be generated from the Tenofovir DF drug 
administration page of the CRF. Exposure data will be summarized by monitoring group.

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8.6.2.
Adverse Events
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Term (HLGT), 
High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be attached to 
the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event that begins on or after the date of first dose up 
to the date of last dose of Tenofovir DF plus 30 days.
Summaries (number and percentage of subjects) of treatment-emergent AEs related to bone or 
renal SOCs (hierarchically ordered by SOC, HLT, and PT) will be provided by treatment group:

all treatment-emergent bone or renal AEs, 

all related treatment-emergent bone or renal AEs, 

combined Grade 2, 3, and 4 treatment-emergent bone or renal AEs, 

combined Grade 3 and 4 treatment-emergent bone or renal AEs, 

combined Grade 2, 3, and 4 related treatment-emergent bone or renal AEs, 

combined Grade 3 and 4 related treatment-emergent bone or renal AEs, 

all AEs that caused permanent discontinuation from Tenofovir DF, 

all AEs that caused permanent discontinuation from study, 

all AEs that caused change in dose or temporary interruption of Tenofovir DF, 

all serious AEs (all SOCs, i.e., not limited to bone or renal SOCs), and

all serious bone or renal related AEs.
Events will be summarized based on the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event that begins on or after the date of first dose of 
Tenofovir DF. Events that occur prior to the first dose of Tenofovir DF or after the last dose of 
Tenofovir DF will be included in data listings.
 
PPD

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8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.
Selected laboratory data (using conventional units) will be summarized by the observed data and 
by the change from baseline across time. 
Graded laboratory abnormalities will be defined using the grading scheme defined in 
Appendix 4. Grading of laboratory abnormalities for analysis purposes will be performed by the 
central laboratory.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline, will be summarized by monitoring 
group. If baseline data are missing, then any graded abnormality (i.e., at least a Grade 1) will be 
considered treatment-emergent.
Laboratory abnormalities that occur before the first dose of Tenofovir DF or after the last dose of 
Tenofovir DF plus 30 days will be included in a data listing.
8.6.4.
Other Safety Evaluations:  Analyses of BMD
Cumulative incidence of at least a 4% decrease from baseline in BMD (spine BMD and whole 
body BMD) using time-to-event methodology will be summarized and compared between 
treatment groups using 95% confidence intervals for difference in person time rates.
The percent change from baseline in BMD (spine BMD and whole body BMD) will be 
summarized over time and compared between treatment groups using the Generalized Linear 
Model. Lumbar spine and whole body z-scores (derived from DEXA-derived BMD assessments) 
and the changes in z-scores from Baseline will be summarized.
BMD (via DEXA scan) and serum bone biochemical markers will be summarized over time. 
Changes from study baseline in bone biochemical markers will also be summarized after 
adjusting for potential confounders such as age and gender..
8.7.
Pharmacokinetic Analysis
Not applicable
8.8.
Biomarker Analysis
Not applicable

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8.9.
Sample Size
Pediatric patients receiving Tenofovir DF may exhibit renal toxicities (e.g., proximal renal 
tubulopathy) among 4.5% of subjects (95% confidence band of 0.4-8.6%).   Among adolescent 
patients with CHB, available interim 72 Week clinical trial data indicate that 5.8% (95% 
confidence band of 1.2-15.9%) of subjects experienced a ≥4% decrease in BMD; by comparison 
3.7% (95% CI 0.4-12.5%) of placebo controls had a BMD loss of ≥4% .  In this same trial, no 
renal adverse drug reactions were detected by Week 72.  Detecting renal or bone AEs in CHB 
adolescents taking Tenofovir DF are infrequent events, and the pool of Tenofovir DF-naïve 
subjects within the EU suitable for enrollment is limited. With a fixed sample size of 100 (50 in 
each monitoring group) we would expect to detect 4-5 renal or bone adverse drug reactions
across both real-world groups (both receive equivalent treatment) over 96 weeks.  
The study employs two monitoring protocols which specify the same laboratory and imaging 
tests for bone and renal markers, but differ in the frequency of testing.  Group 1 will receive 
more frequent monitoring which is protocol-defined or SmPC specified, and Group 2 will be 
monitored according to a less frequent DEXA schedule for BMD and will follow the local 
standard of care for renal monitoring.  It is hypothesized (H0) that there will be no difference in 
the timing, management, or subject outcomes resulting from renal or bone AEs among the two 
monitoring regimens.  With a one-tailed test of α=0.05, and assuming a non-inferiority margin of 
0.10, the study has at least 80% power to detect a difference between the monitoring regimens 
beyond the specified margin of non-inferiority.  
8.10.
Data Monitoring Committee
Not applicable
8.11.
Endpoint Adjudication Committee
Not applicable
8.12.
Investigator Responsibilities
8.12.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator and all applicable sub investigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the drug under study. This documentation must be provided prior to the investigator’s 
(and any sub investigator’s) participation in the study. The investigator and sub investigator 
agree to notify Gilead of any change in reportable interests during the study and for 1 year 
following completion of the study. Study completion is defined as the date when the last subject 
completes the protocol-defined activities.

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8.12.2.
Independent Ethics Committee (IEC) Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IEC. The investigator will not begin any study subject activities until 
approval from the IEC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IEC any modifications made to the protocol or any accompanying material to be provided to 
the subject after initial IEC approval, with the exception of those necessary to reduce immediate 
risk to study subjects.
8.12.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. Informed 
consent will be obtained by the parent or legal guardian of the subject, or informed assent will be 
obtained by the individual aged <18 years with the provision that the subject fully understands 
the terms of the study and understands their right to withdraw assent from the study at any time.  
The investigator must use the most current IEC approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 
and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IEC local 
requirements.
8.12.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IEC, or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the trial. Subject data will be processed in accordance with all applicable 
regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, Tenofovir DF, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.

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8.12.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IEC
and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters;

Start and end date (including dose regimen) of Tenofovir DF, including dates of dispensing 
and return;

Record of all AEs and other safety parameters (start and end date, and including causality 
and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 

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authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
8.12.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in 
the audit trail of the system.  Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (e.g. data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy 
of the data entered by that site. This archive must be stored in accordance with the records 
retention requirements outlined in Section 8.12.5.
8.12.7.
Drug and Supplies Accountability and Return
Gilead recommends that used and unused Tenofovir DF and supplies be returned to the shipping 
facility from which it came for eventual destruction. The study monitor will provide instructions 
for return. If return is not possible, the study monitor will evaluate each study center’s drug
disposal procedures and provide appropriate instruction for destruction of unused Tenofovir DF
and supplies. If the site has an appropriate standard operating procedure (SOP) for drug 
destruction as determined by Gilead QA, the site may destroy used (empty or partially empty) 
and unused drug and supplies in accordance with that site’s approved SOP. A copy of the site’s 
approved SOP will be obtained for central files. 

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If Tenofovir DF is destroyed on site, the investigator must maintain accurate records for all drug
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of Tenofovir DF. Upon study completion, copies of
drug accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review Tenofovir DF and supplies and associated records at periodic 
intervals.
8.12.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IECs, or to regulatory authority or health authority 
inspectors.
8.12.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
8.13.
Sponsor Responsibilities
8.13.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. All protocol modifications must be submitted to the EC in accordance with 
local requirements. Approval must be obtained before modifications can be implemented.
8.13.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies)). 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be 
prepared in certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 8.12.4).

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The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
8.14.
Joint Investigator/Sponsor Responsibilities
8.14.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
8.14.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
8.14.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
8.14.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies) and IECs. In terminating the study, Gilead and the investigator will 
assure that adequate consideration is given to the protection of the subjects’ interests.

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9.
REFERENCES
1635
Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337 (24):1733-45.
2826
McMahon BJ, Alberts SR, Wainwright RB, Bulkow L, Lanier AP. Hepatitis B-related 
sequelae. Prospective study in 1400 hepatitis B surface antigen-positive Alaska native 
carriers. Arch Intern Med 1990;150 (5):1051-4.
6666
Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and 
emerging prevention and control measures. J Viral Hepat 2004;11 (2):97-107.
8548
Hazra R, Gafni RI, Maldarelli F, Balis FM, Tullio AN, DeCarlo E, et al. Tenofovir 
disoproxil fumarate and an optimized background regimen of antiretroviral agents as 
salvage therapy for pediatric HIV infection. Pediatrics 2005;116 (6):e846-54.
9505
Gafni RI, Hazra R, Reynolds JC, Maldarelli F, Tullio AN, DeCarlo E, et al. Tenofovir 
disoproxil fumarate and an optimized background regimen of antiretroviral agents as 
salvage therapy: impact on bone mineral density in HIV-infected children. Pediatrics 
2006;118 (3):e711-8.
10417 Giacomet V, Mora S, Martelli L, Merlo M, Sciannamblo M, Vigano A. A 12-month 
treatment with tenofovir does not impair bone mineral accrual in HIV-infected children. J 
Acquir Immune Defic Syndr 2005;40 (4):448-50.
10698 Stroffolini T, Mele A, Tosti ME, Gallo G, Balocchini E, Ragni P, et al. The impact of the 
hepatitis B mass immunisation campaign on the incidence and risk factors of acute 
hepatitis B in Italy. J Hepatol 2000;33 (6):980-5.
10789 Flahault A, Maison P, Farran N, Massari V. Six years surveillance of hepatitis A and B in 
general practice in France. Euro Surveill 1997;2 (7):56-7.
11445 Vigano A, Zuccotti GV, Martelli L, Giacomet V, Cafarelli L, Borgonovo S, et al. Renal 
safety of tenofovir in HIV-infected children: a prospective, 96-week longitudinal study. 
Clin Drug Invest 2007;27 (8):573-81.

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11526 Vigano A, Brambilla P, Cafarelli L, Giacomet V, Borgonovo S, Zamproni I, et al. 
Normalization of fat accrual in lipoatrophic, HIV-infected children switched from 
stavudine to tenofovir and from protease inhibitor to efavirenz. Antivir Ther 2007;12 
(3):297-302.
13569 Riordan A, Judd A, Boyd K, Cliff D, Doerholt K, Lyall H, et al. Tenofovir use in human 
immunodeficiency virus-1-infected children in the United kingdom and Ireland. Pediatr 
Infect Dis J 2009;28 (3):204-9.
15423 Judd A, Boyd KL, Stohr W, Dunn D, Butler K, Lyall H, et al. Effect of tenofovir 
disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on 
antiretroviral therapy: a nested case-control study. AIDS 2010;24 (4):525-34.
16177 Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and 
meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin 
Infect Dis 2010;51 (5):496-505.
17786 Jonas MM, Block JM, Haber BA, Karpen SJ, London WT, Murray KF, et al. Treatment 
of children with chronic hepatitis B virus infection in the United States: patient selection 
and therapeutic options Hepatology 2010;52 (6):2192-205.
19056 World Health Organization (WHO). Global Alert and Response (GAR): Hepatitis B. 
October 2011. Available at 
http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index1.html. Accessed 
04 October 2011.  2011:
20768 Gara N, Zhao X, Collins MT, Chong WH, Kleiner DE, Jake Liang T, et al. Renal tubular 
dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. 
Aliment Pharmacol Ther 2012;35 (11):1317-25.
22238 Mettler FA, Jr., Huda W, Yoshizumi TT, Mahesh M. Effective doses in radiology and 
diagnostic nuclear medicine: a catalog. Radiology 2008;248 (1):254-63.

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24854 Hope VD, Eramova I, Capurro D, Donoghoe MC. Prevalence and estimation of hepatitis 
B and C infections in the WHO European Region: a review of data focusing on the 
countries outside the European Union and the European Free Trade Association. 
Epidemiol Infect 2013:1-17.
25143 World Health Organization (WHO). Hepatitis B Fact Sheet No. 204.  2012:
26406 Department Of Health & Human Services Centers for Disease Control and Prevention 
Division of Viral Hepatitis. Hepatitis B General Information. Publication No. 21-1073.  
2010.
26851 Balogun MA, Parry JV, Mutton K, Okolo C, Benons L, Baxendale H, et al. Hepatitis B 
virus transmission in pre-adolescent schoolchildren in four multi-ethnic areas of England. 
Epidemiol Infect 2013;141 (5):916-25.
26852 Boccalini S, Pellegrino E, Tiscione E, Pesavento G, Bechini A, Levi M, et al. Sero-
epidemiology of hepatitis B markers in the population of Tuscany, Central Italy, 20 years 
after the implementation of universal vaccination. Human vaccines & 
immunotherapeutics 2013;9 (3).
26853 Brouard C, Heraud-Bousquet V, Leon L, Pioche C, Antonal D, Lot F, et al. Incidence 
And Routes Of Transmission Of Hepatitis Bvirus In France, 2003–2011 [Abstract 968]. 
Journal of Hepatology (EASL Abstracts) 2013;58:S399.
26854 European Centre for Disease Prevention and Control (ECDC). Hepatitis B and C 
surveillance in Europe, 2006–2011. Stockholm: ECDC.  2013.
26855 Hahne SJ, De Melker HE, Kretzschmar M, Mollema L, Van Der Klis FR, Van Der Sande 
MA, et al. Prevalence of hepatitis B virus infection in The Netherlands in 1996 and 2007. 
Epidemiol Infect 2012;140 (8):1469-80.
26857 World Health Organization (WHO). Hepatitis B. Fact sheet N°204. Updated July 2013. 
2013.

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26858 Centers for Disease Control and Prevention (CDC). Hepatitis B.  Epidemiology and 
Prevention of Vaccine-Preventable Diseases. 12 ed. Washington DC: Public Health 
Foundation; 2012: 115-38. 
27079 Alward WL, McMahon BJ, Hall DB, Heyward WL, Francis DP, Bender TR. The long-
term serological course of asymptomatic hepatitis B virus carriers and the development of 
primary hepatocellular carcinoma. J Infect Dis 1985;151 (4):604-9.

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10.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential
Appendix 6.
Lactic Acidosis Guidelines

PPD
PPD

PPD
PPD

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INVESTIGATOR STATEMENT
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated.
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences International Ltd. I will discuss this material with them 
to ensure that they are fully informed about the drugs and the study.
Principal Investigator Name (Printed)
Signature
Date
Site Number

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* Group 2 will follow local standard of care for renal monitoring, which may include the Tenofovir DF SmPC recommended screening intervals
ⱡ Group 2 subjects may have changes in medical status or symptoms and new AE assessed upon return for renal monitoring, as per standard of care and within the 12 week intervals of scheduled 
physical examinations
Definitions:
HBV serology
HBeAg, HBsAg, anti-Hbe, anti-HBs
Serum bone chemistry
calcium, phosphorus, 25-hydroxy and 1, 25 dihydroxyvitamin, PTH, osteocalcin, bone alkaline phosphatase, N and C telopeptides
Serum renal chemistry
glucose, creatinine, creatinine clearance (calculated), magnesium, bicarbonate, chloride, potassium, sodium
Liver chemistry
alanine aminotransferase (ALT), alkaline aminophosphatase (ALP), aspartate aminotransferase (AST), total and direct bilirubin, total protein, albumin, 
gamma glutamyl transpeptide (GGT), LDH, CK
Hematology
PT/INR,  complete blood count (CBC) with differential, platelets
Urinalysis
Complete physical exam     
glucose, protein, creatinine, phosphate, bicarbonate, blood, calcium
includes vital signs, body weight and height

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Appendix 3.
Management of Clinical and Laboratory Adverse Events
Grade 1
(Mild)
Grade 4
(Possibly Life-Threatening)
Grade 3
(Severe)
Grade 2
(Moderate)
May continue 
dosing at the 
discretion of the 
investigator
Repeat lab to 
confirm toxicity 
grade
Repeat lab to 
confirm toxicity 
grade
If confirmed and possibly and/or probably related to 
study drugs:
1.
Withhold study drugs until Grade 2
2.
Restart all study drugs at full dose
If confirmed and unrelated to study 
drugs, dosing may continue at the 
discretion of the investigator
If confirmed and possibly 
or probably related to 
study drugs, discontinue 
study drugs dosing 
permanently and follow at 
periodic intervals at least 
weekly until a return to 
baseline or is otherwise 
explained
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to study drugs, discontinue all study drugs dosing 
permanently
If Grade 3 or 4 recurrence that is considered unrelated to 
study drugs, continue all study drugs at the same dose at the 
discretion of the investigator

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Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18Junel2012
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L

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

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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.12 mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Bicarbonate
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*Calcium should be corrected for albumin if albumin is < 4.0 g/dL

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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA

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

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

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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA

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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated

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OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)

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

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

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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)

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

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

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

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

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

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

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

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

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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential 
1. Pregnancy and Contraception Requirements for Males and Females of Childbearing 
Potential 
The risks of treatment with Tenofovir DF during pregnancy have not been evaluated. Pregnancy 
must be excluded before the start of treatment with Tenofovir DF and prevented thereafter by 
reliable contraceptive methods. Pregnancy tests will be performed regularly throughout this 
study. Data available at this time suggest that this drug does not have a drug-drug interaction
(DDI) with hormones used for contraception. Please refer to the latest version of the 
investigator’s brochure for additional information. 
2. Definition of Female of Childbearing Potential
For the purposes of this study, a female subject of childbearing potential is a woman who has not 
had a hysterectomy, bilateral oophorectomy, or medically documented ovarian failure. This 
definition includes pubertal females regardless of whether or not she has had a menses 
(premenarchal, Tanner Stage 3) and perimenopausal women who have had a spontaneous 
menses in the last 12 months. A woman who has had a tubal sterilization is considered to be of
childbearing potential.
Women ≤ 54 years of age with amenorrhea of any duration will be considered to be of 
childbearing potential unless they have had a hysterectomy, bilateral oophorectomy, or medically 
documented ovarian failure.
Women > 54 years of age with cessation (for ≥12 months) of previously occurring menses due to 
ovarian failure will not be considered to be of childbearing potential.
3. Contraceptive Requirements for Females
Female subjects of childbearing potential must agree to use protocol specified method(s) of 
contraception from the screening/enrollment visit throughout the study period and for 30 days 
following the last dose of Tenofovir DF or choose continuous heterosexual abstinence as a 
lifestyle choice. The investigator should counsel subjects on the protocol specified method(s) for 
avoiding pregnancy during the study. These methods are recommended due to the low failure 
rate (ie, less than 1% per year). See Appendix Table 1 for the protocol specified contraceptive 
methods. Protocol specified contraceptive methods are as follows: (1) a combination of one 
hormonal method and one barrier method; (2) two barrier methods where one method is the male 
condom; or (3) use of an intrauterine device (IUD) or tubal sterilization; see below. Acceptable 
hormonal methods include injectable progesterone, progesterone implants, combination oral 
contraceptives, transdermal contraceptive patch, and vaginal ring. Acceptable barrier methods 
include diaphragm with spermicide, cervical cap with spermicide, and the male condom. Female 
subjects must use either a hormonal method or a barrier method if the partner has a vasectomy. If 
a subject has undergone tubal sterilization or has had a Copper T 380A IUD or LNg 20 IUD 
inserted, no other contraception is needed.  

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Complete abstinence from intercourse. Abstinence is an acceptable method of contraception only 
when it is in line with the subject’s preferred and usual lifestyle. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
Female study subjects who are not heterosexually active must have periodic confirmation of 
continued abstinence from heterosexual intercourse and regular pregnancy testing while taking 
Tenofovir DF. The investigator should counsel subjects on the protocol specified method(s) for 
avoiding pregnancy in case the subject chooses to engage in heterosexual intercourse.
Female subjects of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test at baseline (Day 1) prior to receiving the first dose of 
Tenofovir DF. Lactating females must discontinue nursing before Tenofovir DF administration.
Appendix Table 1.
Protocol Specified Contraceptive Methods
Methods to Use by Themselves
Combination Methods
Hormone Methods
(choose one and use with a barrier 
method)
Barrier Methods
(use both OR choose one and use with 
a hormone method)
Intrauterine Devices (IUDs)
Copper T 380A IUD
LNg 20 IUD
Tubal Sterilization
Estrogen and Progesterone
Oral contraceptives
Transdermal patch
Vaginal ring
Progesterone
Injection
Implant
Diaphragm with spermicide
OR
Cervical cap with spermicide
Male condom (with or without 
spermicide)
Partner’s vasectomy must be used with a hormone or barrier method.
If tubal sterilization is via the Essure procedure, verification of tubal blockage by 
hysterosalpingogram (HSP) must be performed approximately 3 months after microinsertion. 
Prior to verification, Essure is not considered a reliable form of contraception and another 
contraception method described above should be used.
4. Contraceptive Requirements for Males
Male subjects must agree to use condoms and avoid sperm donation from the 
screening/enrollment visit throughout the study period and for 30 days after administration of the 
last dose of Tenofovir DF.
Use of condoms (except for lambskin) has been proven to decrease the risk of transmission of 
HIV and other sexually transmitted diseases. The use of spermicide is not recommended if the 
subject or subject’s partner is infected with HIV.

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5. Procedures to be Followed in the Event of Pregnancy
Subjects should be instructed to notify the investigator if they become pregnant at any time 
during the study, or if they become pregnant within 30 days of last Tenofovir DF dose. Subjects 
who become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator. The investigator should report all pregnancies to the Gilead 
DSPH using the pregnancy report form within 24 hours of becoming aware of the pregnancy.
Instructions for reporting pregnancy, and pregnancy outcome are outlined in Section 7.6.2.1.

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Appendix 6.
Lactic Acidosis Guidelines
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported 
with the use of nucleoside analogues alone or in combination with other antiretrovirals. A 
majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be 
risk factors; however, cases have also been reported in subjects with no known risk factors. 
Guidelines for management of symptomatic hyperlactatemia and asymptomatic hyperlactatemia 
are outlined in Section A and B below and are derived from the AIDS Clinical Trials Group 
(ACTG) Lactic Acidosis Guidelines. Section C outlines venous lactate collection techniques.
Section A. Symptomatic Hyperlactatemia
Symptomatic hyperlactatemia is defined as a clinical suspicion of hyperlactatemia characterized 
by new, otherwise unexplained and persistent (2 weeks) occurrence of 1 or more of the 
following symptoms:

Nausea and vomiting

Abdominal pain or gastric discomfort

Abdominal distention

Increased LFTs

Unexplained fatigue

Dyspnea
AND

Venous lactate level greater than twice the upper normal limit (ULN) confirmed by repeat 
venous lactate analysis within 1 week and, if persistently elevated, arterial lactate with blood 
gas analysis. 
If the repeat venous lactate is elevated confirmation with an arterial lactate specimen and arterial 
blood gas (pH, PO2, PCO2, bicarbonate, oxygen saturation) should be performed within 48 hours. 
If the arterial specimen contains lactate at a level more than two times the upper limit of normal, 
the patient should be discontinued from the study and alternative therapy instituted. Subjects 
should be monitored weekly until signs and symptoms resolve. Hyperlactatemia should be 
followed until levels return to below two times the ULN and the patient.
An elevated anion gap in a patient with metabolic acidosis suggests the diagnosis of lactic 
acidosis. It can be suspected when the sum of cations minus the sum of anions [(Na+ + K+) (Cl-
+ HCO3
-)] exceeds 18 mEq/L (18 mmol/L) in the absence of other causes of increased anion gap 
such as renal failure, salicylate ingestion or other poisoning, or significant ketonemia 
(e.g., diabetic ketoacidosis, alcohol). 

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Management of symptomatic subjects with lactate levels of 1 to 2 times the ULN is left to the 
discretion of the Investigator. As some of the symptoms are sufficiently vague (e.g., fatigue) to 
be present in everyone, serial repeat testing is encouraged with plans to modify the regimen if the 
lactate level rises to greater than two times the ULN as outlined above.
Section B. Asymptomatic Hyperlactatemia
In ASYMPTOMATIC subjects, lactic acidosis will be defined as hyperlactatemia greater than 
four times the ULN. Any patient with a lactate level more than two times the ULN but less than 
or equal to four times the ULN, should be questioned closely for symptoms (described above) 
and have a repeat venous sample obtained in 1 week, and, if confirmed, subsequently at monthly 
intervals. 
If the patient fulfills the definition for ASYMPTOMATIC hyperlactatemia, repeat venous lactate 
should be obtained within a week with confirmation of a more than 4-fold venous elevation in 
lactate by arterial lactate measurement and arterial blood gas (pH, PO2, PCO2, bicarbonate, 
oxygen saturation) within 48 hours. If confirmed, the patient should be discontinued from the 
study and alternative therapy instituted. Hyperlactatemia should be followed until levels return to 
below two times the ULN.
Section C. Specimen Collection
Venous lactate levels are highly dependent on collection techniques. It is therefore recommended 
that the instructions below be followed closely. High lactate levels should be repeated for 
verification. If carefully collected, venous lactate level is equivalent to an arterial collection in 
most clinical situations. If it is not possible to collect the specimen without hand clenching or 
prolonged tourniquet time, an arterial lactate should be considered, as this will help exclude 
falsely elevated lactate levels. 
1. Have subject sit, relaxed for 5 minutes prior to venipuncture.
2. Instruct subject to not clench the fist before or during the procedure and to relax the hand as 
much as possible.
3. If possible, do not use a tourniquet. If a tourniquet is necessary, then apply tourniquet lightly 
and draw lactate first before the other samples with the tourniquet still in place.
4. Collect the blood in a chilled gray-top (sodium fluoride-potassium oxalate) tube.
5. Place the specimen immediately on ice and send to the laboratory for immediate processing, 
preferably within 30 minutes of collection.
6. If random lactate is elevated, then repeat as above with the following additional patient 
instructions: no alcohol within 24 hours, no exercise within 8 hours, and no food or drink 
except water within 4 hours of the draw.