Conditions: Chronic Hepatitis D Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 55
Healthy volunteers: no

Brief summary:
An Open-label, Dose-ranging Study to Evaluate the Safety and Efficacy of Lonafarnib with Ritonavir Boosting +/- Peginterferon alfa-2a in Patients Chronically Infected with Delta Hepatitis (HDV) (LOWR-2).

Detailed description:
Chronic delta hepatitis is a serious form of chronic liver disease caused by infection with the hepatitis D virus (HDV), a small RNA virus that requires farnesylation of its major structural protein (HDV antigen) for replication. Up to sixty subjects with chronic delta hepatitis will be randomized to receive one of ten different doses of lonafarnib. Dosing will occur over 12-48 weeks, and during that time, evidence of antiviral response will be assessed by frequent measurements of HDV-RNA. The primary therapeutic endpoint will be an improvement in quantitative serum HDV RNA levels after treatment with lonafarnib therapy. The primary safety endpoint will be the ability to tolerate the drug at the prescribed dose for the treatment duration. Several secondary endpoints will be measured, including side effects, ALT levels, and symptoms. Therapy will be stopped for intolerance to lonafarnib. This study is designed as a Phase 2a study assessing the safety, tolerance and antiviral activity of nine dosing combinations of lonafarnib with ritonavir boosting with and without peginterferon alfa-2a (PEG IFN-a).

Arms:
arm 1: lonafarnib 100 mg BID + ritonavir 100 mg QD arm 2: lonafarnib 100 mg BID + ritonavir 50 mg BID arm 3: lonafarnib 100 mg QD + ritonavir 100 mg QD arm 4: lonafarnib 150 mg QD + ritonavir 100 mg QD arm 5: lonafarnib 75 mg BID + ritonavir 100 mg BID (+ PEG IFN-a 180 ug QW on Week 12) arm 6: lonafarnib 25 mg BID + ritonavir 100 mg BID arm 7: lonafarnib 50 mg BID + ritonavir 100 mg BID arm 8: lonafarnib 50 mg BID + ritonavir 100 mg BID (+ PEG IFN-a 180 ug QW on Week 12) arm 9: lonafarnib 25 mg BID + ritonavir 100 mg BID + PEG IFN-a 180 ug QW arm 10: lonafarnib 50 mg BID + ritonavir 100 mg BID + PEG IFN-a 180 ug QW

Interventions: intervention 1: lonafarnib intervention 2: ritonavir intervention 3: Pegylated interferon-alfa-2a
Intervention descriptions: intervention 1: antiviral farnesyl transferase inhibitor intervention 2: CYP 3A4 inhibitor, lonafarnib booster intervention 3: immunomodulator

Protocol document:
Prot_SAP_000.pdf: 
Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
Confidential Information of Eiger BioPharmaceuticals Inc. 
1 
TITLE: 
 
A Phase 2, Open Label Pilot Study of the Safety, Tolerability 
Pharmacokinetic and Pharmacodynamic Activity of EBP-994 
Given Orally in Subjects Chronically Infected with HDV 
  
PROTOCOL NO.  
EIG-300 
 
INVESTIGATIONAL 
DRUG: 
 
EBP-994  
 
INVESTIGATOR: 
Cihan Yurdaydin, MD (Turkey) 
 
 
 
SPONSOR: 
Eiger BioPharmaceuticals (United States) 
 
 
 
 
 
 
 
 
350 Cambridge Ave, Suite 350 
 
 
 
 
 
 
 
 
Palo Alto, CA  94306 
 
 
Sigma CRO 
 
Turkey 
 
MEDICAL MONITOR: 
Eduardo B. Martins, MD, DPhil  
 
 
ORIGINAL VERSION 
DATE: 
April 16, 2013 
 
AMENDMENT 1: December 1, 2014 
AMENDMENT 2: October 2, 2015 
AMENDMENT 3: May 10, 2016 
 
 


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Table Of Contents 
LIST OF ABBREVIATIONS ........................................................................................................5 
PROTOCOL SIGNATURE SHEET ..............................................................................................7 
INVESTIGATOR SIGNATURE SHEET .......................................................................................8 
PROTOCOL SUMMARY .............................................................................................................9 
1 BACKGROUND ..................................................................................................................14 
1.1 
Rationale ...............................................................................................................15 
1.2 
Anticipated Risks To Subjects ...............................................................................17 
2 STUDY OBJECTIVES ..........................................................................................................20 
3 STUDY DESIGN .................................................................................................................20 
4 ELIGIBILITY CRITERIA ....................................................................................................21 
4.1 
Inclusion Criteria ...................................................................................................21 
4.2 
Exclusion Criteria ..................................................................................................22 
4.3 
Withdrawal Of Subjects ........................................................................................24 
4.4 
Study Termination ................................................................................................24 
5 STUDY TREATMENT ........................................................................................................24 
5.1 
EBP-994 .................................................................................................................24 
5.1.1 
Description of EBP-994 ............................................................................24 
5.1.2 
Description of Study Treatment ..............................................................25 
5.1.2.1 
Dosage Form of EBP-994 ..................................................................25 
5.1.2.2 
Dosage Form of Ritonavir .................................................................25 
5.1.2.3 
Dosage Form of Pegylated Interferon ................................................25 
5.2 
Administration ......................................................................................................26 
5.3 
Concomitant Medications .....................................................................................26 
5.4 
Measuring Subject Compliance ............................................................................26 
5.5 
Drug Accountability ..............................................................................................26 
6 STUDY PROCEDURES .......................................................................................................26 
6.1 
Screening; Visit 1 ...................................................................................................26 
6.2 
Study Visit 2 (Day 1) – Treatment Period ............................................................27 
6.3 
Study Visit 3 (Day 2) – Treatment Period ............................................................29 
6.4 
Study Visit 4 (Day 3) - Treatment Period .............................................................30 
6.5 
Study Visit 5 (Day 7±2 days) - Treatment Period ................................................31 
6.6 
Study Visit 6 (Day 14±2days) - Treatment Period ...............................................32 
6.7 
Study Visit 7 (Day 28±2days) - Treatment Period ...............................................33 
6.8 
Study Visit 8 (Week 8 = Day 56±2days) - Treatment Period ...............................34 


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6.9 
Study Visit 9-18 (Week 12-48) - Treatment Period .............................................35 
6.10     Study Visit 19 – Four Week Post-Treatment Follow-Up ......................................37 
6.11 
Supplemental Safety Evaluation Visit(s) ..............................................................37 
7 ASSESSMENT OF SAFETY ................................................................................................37 
7.1 
Procedures For Recording Adverse Events ..........................................................37 
7.1.1 
Routine Reporting of Adverse Events.....................................................37 
7.1.2 
Reporting of Serious Adverse Drug Experiences, including Deaths ....38 
7.1.3 
Severity of Adverse Drug Experiences ...................................................39 
7.1.4 
Relationship of Adverse Events to the Study Drug ................................39 
7.2 
Withdrawal From Study Treatment Due To Adverse Experience .......................40 
7.3 
Management Of Toxicity Related To Study Drug.................................................40 
8 STATISTICS .......................................................................................................................40 
8.1 
Blinding .................................................................................................................40 
8.2 
Analysis Populations .............................................................................................40 
8.3 
Demographics And Baseline Characteristics .......................................................41 
8.4 
Safety .....................................................................................................................41 
8.4.1 
Adverse Events .........................................................................................41 
8.4.2 
Clinical Laboratory and Vital Signs .........................................................41 
8.5 
Pharmacokinetics ..................................................................................................41 
8.5.1 
PK Linearity and Accumulation Assessment .........................................43 
8.6 
Pharmacodynamics ...............................................................................................43 
8.7 
Sample Size And Power .........................................................................................43 
8.8 
Interim Analyses ....................................................................................................43 
8.9 
Missing Data And Data Imputation ......................................................................43 
9 ACCESS TO SOURCE DOCUMENTS ..................................................................................44 
10 QUALITY CONTROL AND QUALITY ASSURANCE ..........................................................45 
11 ETHICS ...............................................................................................................................45 
11.1 
Declaration of Helsinki .........................................................................................45 
11.2 
Institutional Review Board/Ethics Committee ....................................................45 
11.3 
Informed Consent ..................................................................................................45 
12 DATA HANDLING AND RECORDING ...............................................................................45 
13 PUBLICATION POLICY .....................................................................................................46 
14 PROTOCOL AMENDMENTS AND MODIFICATIONS .......................................................46 
15 REFERENCES ....................................................................................................................47 
APPENDIX A: 
 SCHEDULE OF ASSESSMENTS ................................................................50 


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APPENDIX B: 
 BODY MASS INDEX TABLE (METRIC), FORMULA AND 
CALCULATOR. ...................................................................................................................52 
APPENDIX C: 
DECLARATION OF HELSINKI ..................................................................54 
APPENDIX D: 
HEPATIC ASSESSMENTS..........................................................................59 
The Child-Turcotte-Pugh (CTP) Score ..............................................................................59 
Assessment for Hepatic Encephalopathy .........................................................................59 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
ALT 
alanine transaminase (or serum glutamic-pyruvic transaminase) 
ANC 
absolute neutrophil count 
Anti-HIV AB 
Anti-human immunodeficiency virus antibody 
AST 
aspartate transaminase (or serum glutamic-oxaloacetic transaminase) 
AUC 
area under the time-concentration curve 
AUC0-t 
area under the time-concentration curve from time 0 to the last 
measurable concentration 
AUC0-τ 
area under the time-concentration curve over the dosing interval at 
steady-state 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CAS 
chemical abstracts service 
CBC 
complete blood count 
 
CFR 
Code of Federal Regulations 
Cl 
clearance 
CL/F 
apparent total body clearance after extravascular administration 
Cmax 
maximum concentration 
Cmin 
minimum concentration at steady state 
CRF 
case report form 
CTP 
Child-Turcotte-Pugh 
ECG 
electrocardiogram 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBsAg 
hepatitis B surface antigen 
HERG 
human–ether-a-go-go 
HIV 
human immunodeficiency virus 
HCV 
hepatitis C virus 
ICH 
International Conference on Harmonisation 
IgM AB 
immunoglobulin M antibody 
IM 
intramuscular 
INR 
international normalized ratio 


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IRB 
Institutional Review Board 
IU 
international unit 
IUPAC 
International Union of Pure and Applied Chemistry 
Kel 
apparent first-order terminal elimination constant 
IV 
intravenous 
LFTs 
liver function tests 
ms 
millisecond 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PO 
per orum (by mouth) 
rDNA 
recombinant deoxyribonucleic acid 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
tmax 
time to peak concentration 
t1/2 
apparent elimination half life 
SOC 
standard of care 
TSH 
thyroid stimulating hormone 
UA 
urinalysis 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
Varea/F 
apparent volume of distribution 
WBC 
white blood cell 
 
 
 




Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
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INVESTIGATOR SIGNATURE SHEET 
I have read the attached protocol and agree that it contains all the necessary details for  
performing the study. 
 
I will provide copies of the protocol and of the preclinical information on the test article,  
which was furnished to me by the sponsor, to all members of the study team responsible to  
me who participate in the study.  I will discuss this material with them to assure that they are  
fully informed regarding the test article and the conduct of the study. 
 
Once the protocol has been approved by the IRB/ethics committee, I will not modify this 
protocol without obtaining the prior approval of the sponsor and of the IRB/ethics committee.   
I will submit the protocol modifications and/or any informed consent modifications to the  
sponsor and the IRB/ethics committee, and approval will be obtained before any  
modifications are implemented. 
 
I understand the protocol and will work according to it, the principles of Good Clinical 
Practice (current ICH guidelines), and the Declaration of Helsinki (1964) (Appendix 3)  
including all amendments up to and including the Scotland revision (2000). 
 
 
 
 
 
__________________________________________________________________________ 
Investigator’s Signature  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
(EIG-300 protocol Amendment 3 dated May 10, 2016) 
 
 


Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
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PROTOCOL SUMMARY 
Study Title 
A Phase II, Open Label  Pilot Study of the Safety, Tolerability Pharmacokinetic and 
Pharmacodynamic Activity of EBP-994 Given Orally in Subjects Chronically Infected with 
HDV 
  
 
Sponsor 
Eiger BioPharmaceuticals, Inc. (United States) 
Sigma CRO. (Turkey) 
 
Study Objectives 
The primary objectives of the study are to: 
 
• Evaluate the safety and tolerability of 12 weeks of treatment with a 200 vs. 300 mg 
PO BID dose of EBP-994 in subjects chronically infected with HDV  
• Evaluate the pharmacodynamic (PD) activity of a 200 vs. 300  mg PO BID dose of 
EBP-994 on HDV viral load  
• Evaluate the pharmacokinetic (PK) activity of a 200 vs. 300  mg PO BID dose of 
EBP-994 
• Evaluate the safety, tolerability, PK, and HDV viral load of a treatment up to 48 
weeks with EBP-994 alone and in combination with Norvir® and/or Pegasys® in 
subjects chronically infected with HDV 
 
 
Study Design 
This study is a phase II, randomized, open-label study up to 48 weeks of treatment 
with EBP-994 alone, or in combination with Norvir® and/or Pegasys® in subjects chronically 
infected with HDV genotype 1. The duration of the study for each subject will last 
approximately 11-55 weeks (up to three week screening period, 4-48 week treatment period 
and four week safety follow-up period. The duration of the entire study is anticipated to be 
approximately 45 months (first subject in to last subject out). The investigator is free to 
initiate licensed medications at any time point and decrease the dose of EBP-994 if deemed 
warranted for GI side effects. 
 
This study will explore EBP-994 in four groups of treatments: 
 
Group 1: EBP-994 (up to 600 mg daily dose) monotherapy  
Group 2: EBP-994 (up to 200 mg daily dose) in combination with Norvir® 
Group 3: EBP-994 (up to 600 mg daily dose) in combination with Pegasys® 


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Group 4: EBP-994 (up to 150 mg daily dose) in combination with Norvir® and Pegasys® 
 
Study Population and Number of Subjects 
Up to 75 subjects chronically infected with HDV genotype 1 will be enrolled at a single 
study sites. 
Inclusion Criteria 
A subject may be included in this study if he/she meets all of the following criteria: 
1. Males or females, 18 to 65 years of age who are diagnosed with HDV by PCR 
2. Chronic hepatitis D infection, genotype 1, documented by a positive anti-HDV Ab test 
of at least 6 months duration and detectable HDV RNA by PCR within 3 months to 
study entry 
3. Liver biopsy within the last two (2) years or consent of having a liver biopsy which can 
be done at the Screening Visit 
4. Electrocardiogram (ECG) shows no acute ischemia or clinically significant 
abnormality and a QT/QTc interval <450 milliseconds using Bazett's correction: QTc 
=QT/RR0.5 (ICH Guidance E14 Clinical Evaluation of QT/QTc Interval Prolongation 
and Proarrhythmic Potential for Non-Antiarrhythmic Drugs) 
5. Females of childbearing potential (intact uterus and within one year since the last 
menstrual period) should be non-lactating and have a negative serum pregnancy test. 
In addition, these subjects should agree to use one of the following acceptable birth 
control methods throughout the study: 
a. abstinence 
b. surgical sterilization (bilateral tubal ligation, hysterectomy, bilateral 
oophorectomy) six month minimum 
c. IUD in place for at least three months 
d. barrier methods (condom or diaphragm) with spermicide 
e. surgical sterilization of the partner (vasectomy for six months) 
f. hormonal contraceptives for at least three months prior to the first dose of 
study drug 
6. Willing and able to comply with study procedures and provide written informed 
consent 
 
Exclusion Criteria 
A subject will be excluded from this study if he/she meets any of the following criteria: 
1. Participation in a clinical trial with or use of any investigational agent within 30 days 
of Study Visit 1 
2. Patients co-infected with HIV or HCV (if HCV RNA is positive) 
3. Patients with screening tests positive for anti-HIV Ab 
4. Active jaundice defined by total bilirubin >2.0 and known not to have Gilbert’s 
disease 


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5. INR ≥ 1.5 
6. Eating disorder or alcohol abuse within the past two years, excessive alcohol intake 
(>20 g per day for females (1.5 standard alcohol drinks) or >30 g per day for males 
(2.0 standard alcohol drinks) (a standard drink contains 14 g of alcohol: 12 oz of beer, 
5 oz of wine or 1.5 oz of spirits) (1.0 fluid oz (US) = 29.57 mL) or if in the opinion of 
the investigator, an alcohol use pattern that will interfere with study conduct 
7. Drug abuse within the last six months with the exception of cannabinoids and their 
derivatives 
8. Patients with absolute neutrophil count (ANC) <1500 cells/mm3; platelet count 
<100,000 cells/mm3; hemoglobin <12 g/dL for women and <13 g/dL for men; 
abnormal TSH, T4 or T3 or thyroid function not adequately controlled; or serum 
creatinine concentration ≥1.5 times upper limit of normal (ULN). 
9. History or clinical evidence of any of the following: 
a. variceal bleeding, ascites, hepatic encephalopathy, CTP score >6, 
decompensated liver disease or any other form of non-viral hepatitis 
b. immunologically mediated disease (e.g, rheumatoid arthritis, 
inflammatory bowel disease, severe psoriasis, systemic lupus 
erythematosus) requiring more than intermittent non-steroidal anti-
inflammatory medications for management or that requires frequent or 
prolonged use of corticosteroids (inhaled asthma medications are allowed) 
c. any malignancy within 5 years except for basal cell skin cancer 
d. significant or unstable cardiac disease (e.g, angina, congestive heart 
failure, uncontrolled hypertension, history of arrhythmia) 
e. chronic pulmonary disease (e.g, chronic obstructive pulmonary disease) 
associated with functional impairment 
f. severe or uncontrolled psychiatric disease, including severe depression, 
history of suicidal ideation, suicidal attempts or psychosis requiring 
medication and/or hospitalization 
10. Patients with a body mass index of >30 kg/m2 
11. Concomitant drugs known to prolong the QT interval  
12. Concomitant use of immunosuppressive or immune modulating agents 
13. Patients with any serious condition that, in the opinion of the investigator, would 
preclude evaluation of response or make it unlikely that the contemplated course of 
therapy and follow-up could be completed or increase the risk to the subject of 
participation in the trial 
 
Summary of Dosing Plan/Treatment Plan/Schema 
At the Screening Visit, subjects giving written informed consent will have all required 
evaluations to determine their eligibility to participate in the study. The outpatient Screening 
Visit must occur within 21 days of first Study Visit. 


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Each eligible subject will undergo 8-19 Treatment Study Visits; Screening, Day 1, Day 2, 
Day 3, Day 7, Day 14, Day 28, then every 4 weeks (total treatment duration depends on 
assigned treatment group), followed by a Safety Follow-up Visit, 4 weeks post-treatment. 
Moreover, the investigator is free to initiate licensed medications at any time point and 
decrease the dose of EBP-994 if deemed warranted for GI side effects. 
During the intervals between Study Visits, subjects will be free to carry on their usual 
activities of daily living. Subjects should be instructed to take the study medication at 24 (QD 
dosing), 12 (BID dosing) or 8 (TID dosing) hour intervals ±2 hours. Efforts should be made 
to schedule Study Visits according to the study protocol; however the window for 
consecutive Study Visits will be ±2 days with the exception of Days 2 and 3 for which a visit 
window is not allowed. 
Criteria for Evaluation 
Statistical Plan 
The sample size has not been determined by strict statistical considerations. From a safety, 
pharmacokinetic and pharmacodynamic perspective, no a-priori assumptions are made as to 
the expected treatment effect and associated variability. 
General 
Demographics of subjects will be described.  All reported adverse events will be mapped to 
standard coding terms (MedDRA) and grouped by system organ class and preferred terms.  
The incidence of adverse events will be tabulated by seriousness, severity, and relationship to 
study drug. If an adverse event is reported more than once during the study period, the 
greatest severity and worst-case attribution will be presented in tables. Adverse events will 
also be listed for individual subjects, along with information regarding onset, duration, 
severity, and relationship to study drug. Adverse events that lead to withdrawal from the 
study will be listed and summarized by treatment group separately. Summary tables and 
listings of serious adverse events will also be generated. Pharmacodynamic data will be 
presented in listings and will display viral load data at each period/timepoint collected by 
subject. These data will also be presented graphically. Mean and median levels of the viral 
load will be calculated at each period/timepoint. 
Safety 
Safety will be monitored by assessing vital signs, adverse events, concomitant medications 
and laboratory and ECG results. ECGs will be conducted in triplicate and vital signs assessed 
at each Study Visit.  
The most common side effects seen with lonafarnib (the active ingredient of EBP-994) are 
gastrointestinal (diarrhea, nausea, and vomiting). There were no serious adverse events 
(SAEs) observed in the studies conducted in healthy volunteers. The SAEs reported in at 
least 2% of subjects in the Phase 1 and Phase 2 studies conducted in subjects with solid 
tumors or hematologic malignancies included fever (6%), diarrhea (6%), dehydration (6%), 
febrile neutropenia (4%) and sepsis (4%). 


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As with any anti-viral medication, a possible effect of EBP-994 is viral resistance. Hepatitis 
D viral load levels will be measured through quantitative PCR at all Study Visits. Viral 
mutation analysis and resistance phenotyping will be conducted to assess viral resistance to 
the study medication. The investigator may terminate the subject from the trial if, in his/her 
opinion, there is an unacceptable increase in HDV viral load. Moreover, the investigator is 
free to initiate standard of care (SOC) medications and doses (i.e. Pegasys®) at any time 
point. 
Pharmacokinetics 
Blood samples will be obtained for pharmacokinetics of EBP-994 at Study Visit 1 (Day 1) 
and Study Visit 6 (Day 28). Pharmacokinetic parameters for EBP-994 such as maximum 
concentration (Cmax), area under the time-concentration curve (AUC), time to peak 
concentration (tmax), elimination half life (t1/2), volume of distribution (Varea/F) and clearance 
(CL/F)] will be calculated and tabulated with descriptive statistics. Geometric mean and 
geometric CV% will be provided for AUC and Cmax values. 
Pharmacodynamics 
Mean and median levels of the viral load will be calculated. 
Estimated Start and Completion Dates 
July 2013 through July 2017. 
 
 
 
 
 
 
 
 
 
 
 
 


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1 BACKGROUND 
Hepatitis D virus (HDV) was first described as a novel antigen in the nucleus of hepatocytes 
derived from patients infected with hepatitis B (HBV) and antibodies to this “delta antigen” 
were detected in patients with severe cases of HBV infection.  HDV was subsequently 
identified as the infectious agent causing viral hepatitis in the presence of HBV (1,2).  While 
HDV can replicate autonomously (3), the virus does require co-infection with HBV to 
complete virion assembly and to facilitate transmission.  HDV uses the hepatitis B surface 
antigen (HBsAg) proteins L, M, and S, as its envelope protein which is pivotal for HDV exit 
from host cells and transmission to other hepatocytes (4).  Therefore, HDV can be considered 
a superinfection among patients chronically infected with HBV or as a simultaneous acute 
co-infection with HBV (5). 
The HDV genome is a small circular single-stranded RNA molecule which can be classified 
into eight different genotypes (6).  HDV genotype 1 is the most prevalent globally and is the 
most common in Europe and North America.  The main route of transmission is parenteral 
exposure, like that observed with HBV.  In the United States, the number of cases of HDV is 
projected to be roughly 40,000 to 75,000, or 5% of the estimated 750,000 to 1.5 million 
persons infected with HBV (14). Multiple studies have revealed that chronic HDV infection 
leads to more severe liver disease than HBV mono-infection, is associated with accelerated 
fibrosis progression, as well as a higher risk of developing hepatocellular carcinoma (7,8,9).  
HDV is the only form of chronic viral hepatitis for which there is no established highly 
successful treatment.  Despite multiple direct antiviral agents directed against HBV, these 
have not proven effective against HDV, nor has ribavirin alone, or in combination with 
interferon (10,11,12,13) 
Given the aggressive nature of the hepatitis seen in HDV infection, agents are needed that 
can help mitigate the disease by directly interfering with the virus life-cycle.  An important 
interaction between HDV and HBV proteins has been shown to depend on the presence of 
the last four amino acids of the large delta antigen, comprising a CXXX box motif, where C 
represents cysteine and X denotes any other amino acid.  This amino acid sequence is 
required for the protein to be post-translationally modified by farnesyltransferase (FT), an 
enzyme which covalently attaches a prenyl lipid (farnesyl) to the cysteine of the CXXX box 
as depicted in Figure 1 (15,16) . Prenylation of HDV results in the addition of farnesyl to the 
delta antigen.  Inhibiting the action of FT could result in compromised HDV particle 
production since the unprenylated large delta antigen of HDV cannot associate with HBV 
antigens to form an infective HDV virion.  In addition, the use of FT inhibitors (FTIs) could 
subvert the ability of the virus to develop resistance since the drug targeted locus does not lie 
within the viral genome but is a host function.  Most importantly, host cells display a 
tolerance in the presence of prenylation inhibition by FTIs through the use of alternative 
prenylation pathways while HDV cannot use alternative pathways (17,18). 
 
 
 


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Figure 1 
 
The Mevalonate Pathway 
 
 
Eiger BioPharmaceuticals, Inc. (Eiger BioPharmaceuticals) is developing EBP-994 as an 
investigational new drug for the treatment of hepatitis D virus (HDV) in patients chronically 
infected with HDV. EBP-994 is an orally active tricyclic farnesyltransferase inhibitor (FTI) 
initially developed as lonafarnib (aka SCH 66336) by Schering-Plough, now Merck. It has 
been studied in over 2000 patients within the context of over a dozen clinical studies, 
including three Phase I (pharmacokinetic, metabolic distribution, drug-drug interaction) 
healthy volunteer studies and nine Phase I, II and III studies in patients with advanced 
malignancies in an attempt to inhibit farnesylated ras-mediated cancers. In patients with 
advanced cancers (blast crisis and acute leukemia), EBP-994 has been given for up to 120 
days with the MTD determined to be 200-300 mg PO BID, with TEAEs being diarrhea and 
nausea. 
The drug was generally well tolerated, although insufficient anti-tumor efficacy was 
observed, likely because such malignancies can be driven by additional factors beyond 
farnesylated ras. EBP-994 offers a valuable repurposing opportunity, however, for inhibiting 
the HDV life cycle where a critical dependence on farnesylation of large delta antigen has 
been demonstrated, and thereby treating hepatitis D infections. 
1.1 
Rationale 
The IC50 for EBP-994 (formerly lonafarnib) in the H-ras farnesyl transferase inhibition assay 
is 2.4 nM.  Because HDV particle production is dependent on the farnesylation of HDV large 
delta antigen, EBP-994 is expected to be an inhibitor of the HDV life cycle at the stage of 


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particle production. Indeed, the EC50 for EBP-994 in the HDV virus-like particle (VLP) 
production assay is 34 pM, consistent with the fact that multiple large delta antigen proteins 
are contained in a virus or virus—like particle and the hypothesis that inhibiting the 
farnesylation of only a fraction of the delta antigens can have a trans-dominant effect on 
particle production. These data suggest that EBP-994 can be a potent inhibitor of the HDV 
life cycle in vivo. Combined with EBP-994’s favorable safety and tolerability profile 
demonstrated to date in Phase I through III testing for oncology indications, EBP-994 was 
therefore hypothesized to be a useful novel way of treating hepatitis delta infections. 
Recently, a Phase Ib study of EBP-994 in patient chronically infected with HDV was 
initiated at the National Institutes of Health (NIH). In the first phase of the study, 8 patients 
were randomly assigned to drug (6 patients; 100 mg PO BID) vs. placebo (2 patients) for 28 
days of treatment.  In the second phase, 8 patients will receive either EBP-994 (6 patients; 
200 mg PO BID) or placebo for 28 days of treatment. Data on the first seven patients from 
the first phase of the study is currently available. EBP-994 was well tolerated in all subjects 
with no SAEs. All patients receiving EBP-994 experienced reductions in HDV viral load 
during the treatment period, with rebound observed upon cessation of drug treatment (see 
Figure 2). Three of the 5 patients treated with EBP-994 experienced an approximate 1 log 
drop or greater in HDV viral load during the 28 day treatment period (Note: patients # 3 and 
# 7 received placebo). 
 
Figure 2. Interim analysis of changes in HDV viral load during treatment with 100 mg PO BID 
EBP-994.  Bar indicates period of treatment with EBP-994 (or placebo). 
 
The mean change in viral load from baseline was directly proportional to the mean drug 
levels measured in individual patients. 


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Figure 3.   Average serum EBP-994 concentration vs. average change in HDV viral load 
over days 7-28 of treatment. 
 
These data demonstrate: 1) EBP-994 is well-tolerated in patients with chronic hepatitis D 
infection; 2) a direct antiviral effect of EBP-994 against HDV; 3) a dose dependence of EBP-
994’s anti-HDV efficacy; 4) suboptimal levels of drug appear to be achieved in this patient 
population at the relatively low dose (100 mg PO BID) used in this first phase of the study; 
5) a strong rationale exists for progressing to the planned higher dose of EBP-994.  In 
addition to using the higher doses of EBP-994 that were previously used and tolerated in 
generally sicker patients (i.e with advanced malignancies, including metastatic disease and 
blast crisis), a duration of treatment longer than 28 days is expected to be needed to achieve 
more profound suppression of HDV viral loads (including to undetectability) that will be 
maintained upon cessation of treatment (indicative of cure).  These are exactly the 
interventions to be explored in the current study that aims to determine the safety and 
efficacy of EBP-994 alone, or in combination with Norvir® and/or Pegasys® in chronically 
infected HDV patients for up to 6 months. 
1.2 
Anticipated Risks To Subjects 
Preclinical Safety Summary 


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Toxicokinetic data to support the toxicology program for the development of EBP-994 were 
obtained from three- and six-month toxicity studies in rats (19, 20), three-month and 12-
month toxicity studies in cynomolgus monkeys (21, 22), and an embryo-fetal developmental 
toxicity and toxicokinetic study in rabbits (23). Additionally, a single-dose (SD) oral vs IV 
pharmacokinetic study in monkeys was conducted (24). Data on the distribution of EBP-994 
are available from a single dose tissue distribution study in pigmented rats (25), a pilot whole 
body autoradiography (WBA) study in monkeys (26), and in vitro plasma protein binding 
studies (27, 28). The metabolism of EBP-994 was studied in vitro using liver microsomes, 
hepatocytes, and recombinant human cytochrome P450 (CYP) isozymes (29, 30, 31, 32). 
Additional information about the metabolism of EBP-994 was obtained from profiling in 
rats, monkeys, and humans (33, 34, 35, 36, 37, 38). The routes and extent of excretion of 
EBP-994 were evaluated in rats, monkeys, and humans (26, 33, 34, 35, 36, 37, 39, 40). The 
effects of EBP-994 on enzyme induction and enzyme inhibition were studied in vitro (41, 42) 
and in vivo (19, 21), and the potential for EBP-994 interactions related to transport proteins 
was also assessed (43, 44, 45). 
Pharmacokinetic/toxicokinetic studies in rats, rabbits and monkeys given single and repeated 
oral doses of EBP-994 suggested slow absorption, with mean Tmax = 2-8 hr. The compound 
had good bioavailability, with a mean absolute oral bioavailability of greater than 65% in rats 
and monkeys. In both species, increases in plasma AUC with increasing dose were observed 
but there were also cross-study and cross-species differences in exposure (e.g., sex-
dependence) and accumulation patterns. 
EBP-994 distributed rapidly into tissues, with liver, adrenal gland, pancreas, bile duct, and 
kidney reaching maximum concentrations of radioactivity by 4 hr post-dose; the tissue-to-
plasma ratios of drug-derived radiocarbon in these tissues at 4 hr ranged from 3.90-14.7. 
Plasma protein binding to 3H-EBP-994 was ≥99% in all species over a 0.5-40.0 μg/mL 
concentration range and binding to purified serum proteins (HSA, AAG, HSA-AAG) ranged 
from 94-98%. 
CYP 3A (3A4 and 3A5) is responsible for the oxidative metabolism of EBP-994 (29, 31).  
Studies of CYP inhibition indicate that the CYP3A4 IC50 = 10.2 μg/mL and CYP2C9 IC50= 
16 μg/mL (24), showing that the one-half maximal inhibition is achieved at three to five 
times the mean human plasma Cmax (2.8 μg/mL) at 200 mg BID (46, 47, 48). Preincubation 
of human liver microsomes for 15 min with EBP-994 decreased the IC50 for inhibition of 
CYP3A4, suggesting a metabolism-based inhibition. In vitro inhibition of activity of other 
CYP enzymes (1A2, 2C19, 2D6) by EBP-994, however, does not appear to occur to an 
extent likely to suggest a risk of adverse events in humans. 
In ancillary pharmacology studies in rats, EBP-994 was well tolerated over the oral dose 
range of 30 to 300 mg/kg. It was devoid of gastric ulcerogenicity and adverse effects on CNS 
function, but exhibited moderate inhibition of GI motility at high doses (≥100 mg/kg). 
Clinical findings consistent with a decrease in GI motility have not been observed with EBP-
994. Urine chemistry parameters showed a decrease in sodium and potassium excretion at 
300 and 500 mg/kg and a reduction in creatinine clearance at 500 mg/kg. At doses of 500 
mg/kg orally, rats were moribund and displayed a variety of adverse effects. Repeated oral 


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dosing of EBP-994 to monkeys at 60 mg/kg for 7 days caused diarrhea, emesis, weight loss, 
thrombocytopenia and an elevation of AST. 
Inhibition of the hERG current by EBP-994 occurred at an IC50 of 1.3 μM (representing an 
approximately 59-fold multiple over the mean free Cmax plasma concentration achieved at a 
clinical dose of 200 mg BID). This relatively large safety margin between the IC50 for SCH 
66336 in the hERG assay and the free Cmax at a clinical dose of 200 mg BID, together with 
the absence of effects on isolated Purkinje fibers up to 1.1 μM, is consistent with the absence 
of effects of EBP-994 on QT or QTc interval in vivo in anesthetized guinea pigs (total Cmax 
of 30 μM) and in conscious monkeys (repeated-dose toxicity studies) administered EBP-994 
for three-months and one year at doses up to 60 and 40 mg/kg, respectively. Metabolism 
studies conducted in vitro (30, 31, 32) and in vivo (rat, monkey, human) (33, 34, 35, 36, 37, 
38) provided no evidence for the formation of human-specific EBP-994 metabolites. EBP-
994 was shown to be extensively metabolized following SD administration of 14C-EBP-994 
to rats (PO, IV), monkeys (PO,IV), and humans (PO) (33, 34, 36, 37); only small amounts of 
unchanged EBP-994 were detected in urine, bile or feces. LC-MS analyses indicated that the 
most common metabolic conversions involved oxidation (+O or +16) or dehydrogenation (-
2H or -2) and were associated with changes in the pendant piperidine ring (33, 34, 36, 37). 
Biliary and/or fecal excretion was the major route of elimination for administered drug and 
its metabolites following administration of 14C-EBP-994 to rats; urinary excretion (<1%) 
played a minor role (33, 39, 40). The available data likewise showed excretion patterns in 
monkeys and humans that were similar to those in rat. 
Renal excretion in humans is not a major elimination pathway for EBP-994 and its 
metabolites. Mean urinary recovery of EBP-994 ranged from 0.001 to 0.5% of the dose over 
a 12-hr collection interval (46, 47, 48), and mean urinary radioactivity accounted for only 
~0.7% of the dose following oral administration (37). After administration of 14C-EBP-994 
to bile duct-cannulated rats, 16.5%-55.0% of the administered dose was collected in bile (up 
to 48-hr post-dose) of individual rats (33, 39). Evaluation of enterohepatic circulation by 
intraduodenal (ID) dosing of bile from 14C-EBP-994 PO-dosed donor rats to recipient rats 
suggested that <5% of the EBP-994 dose undergoes enterohepatic circulation (39). 
Thus, the nonclinical pharmacokinetics and metabolism of EBP-994 supported further 
development of the compound. 
Clinical Safety Summary 
There are currently no HDV-specific therapies.  EBP-994 could be the first direct acting anti-
HDV agent by disrupting the HDV life cycle through inhibition of prenylation at the level of 
host cell farnesyl-transferase.  EBP-994 has been dosed in human studies examining PK and 
PD and has exhibited inhibition of farnesyl transferase at levels below the maximally 
tolerated dose (MTD; 300 mg BID).  A risk associated with the use of direct acting antiviral 
agents would be the development of resistance by the virus.  However, because prenylation is 
a host function not coded for by the HDV genome, the risk of resistance development could 
be mitigated.  Viral surveillance will be conducted throughout the conduct of the study to 
assess the risk of viral resistance.  Two doses of EBP-994 alone, or in combination with 
Norvir® and/or Pegasys® will be examined in this proof-of-concept study, 200 vs. 300 mg 


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(PO BID), and the adverse profile will be correlated to the clinical benefit of viral 
suppression.  
Other risks that may be encountered with the treatment of HDV include an increase in liver 
function tests during and after therapy, the risk of a flare in HBV (≥1 log increase in HBV 
viral load) as the HDV viral load goes down, and an increase in HDV viral load after therapy 
is ended.  Flares in liver function tests are not uncommon with the start of treatment of HBV 
disease and necessitate a careful and frequent review of liver function studies. We will follow 
the same approach in this study unless there is a concomitant flare in HBV viral load. A flare 
of HBV viral load while on EBP-994 will be treated by starting specific anti-HBV therapy 
using one of the 5 approved drugs, the selection being made by the Investigator based on the 
subject’s condition and history of prior anti-HBV therapy. A flare in HDV viral load after the 
termination of EBP-994 will be watched closely and interferon therapy may be started as 
determined by the investigator. 
Finally, the known adverse event profile for EBP-994 (and all other prenylation inhibitors in 
clinic) is primarily gastrointestinal, primarily dose related diarrhea as well as nausea and 
vomiting.   
2 STUDY OBJECTIVES 
The primary objectives of the study are to: 
• Evaluate the safety and tolerability of 12 weeks of treatment with either a 200 mg po 
BID dose of EBP-994, or a 300 mg po BID dose of EBP-994, in subjects chronically 
infected with HDV genotype 1 
• Evaluate the pharmacodynamic (PD) activity of a 200 mg po BID dose of EBP-994, 
vs. a 300 mg po BID dose of EBP-994 on HDV viral load 
• Evaluate the pharmacokinetic (PK) profile of a 200 mg po BID dose of EBP-994 vs. a 
300 mg po BID dose of EBP-994 in subjects chronically infected with HDV genotype 
1 
• Evaluate the safety, tolerability, PK, and HDV viral load of a treatment up to 48 
weeks with EBP-994 alone, or in combination with Norvir® and/or Pegasys® in 
subjects chronically infected with HDV 
 
 
3 STUDY DESIGN 
This study is a phase II, randomized, open label study of up to 48 weeks of treatment with 
EBP-994 alone, or in combination with Norvir® and/or Pegasys® in subjects chronically 
infected with HDV genotype 1. The investigator is free to initiate licensed medications at any 
time point and decrease the dose of EBP-994 if deemed warranted for GI side effects. The 
duration of the study for each subject will be approximately 11-55 weeks (up to three week 
screening period, up to 48 week treatment period and four week safety follow-up period). 


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The duration of the entire study is anticipated to be approximately 36 months (first subject in 
to last subject out). Pharmacokinetic sampling will be done at Day 1 and Day 28 of dosing. 
PK sampling will be conducted only on subjects who have consented to participate in the PK 
portion of this study.  Participation in PK sampling is optional for each subject. 
At the Screening Visit, subjects giving written informed consent will have all required 
evaluations to determine their eligibility to participate in the study. The outpatient screening 
visit must occur within 21 days of Study Visit 1. 
Each eligible subject will undergo 8-16 Study Visits; Screening, Day 1, Day 2, Day 3, Day 7, 
Day 14, Day 28, then every 4 weeks (total duration depends on assigned treatment group), 
followed by a Safety Follow-Up Visit, 4 weeks post-treatment. Study drug will consist of 
EBP-994 alone or in combination with either Norvir® and/or Pegasys®, depending on which 
group the subject has been randomized to on the Day 1 visit.  Moreover, the investigator is 
free to initiate licensed medications at any time point and decrease the dose of EBP-994 if 
deemed warranted for GI side effects. 
During the intervals between Study Visits, subjects will be free to carry on their usual 
activities of daily living. Subjects will be instructed to take their study medication at 
appropriate dosing intervals. Efforts should be made to schedule Study Visits according to 
the study protocol; however the window for consecutive Study Visits will be ±2 days with 
the exception of Day 2 and Day 3 for which a visit window is not allowed. 
Safety will be monitored by assessing vital signs, adverse events, concomitant medications, 
laboratory and ECG results. ECGs will be conducted and vital signs assessed at each Study 
Visit. 
As with all antiviral medications, a possible effect of EBP-994 is viral resistance. Hepatitis D 
viral load levels will be measured through quantitative PCR at all Study Visits. Viral 
mutation analysis and resistance phenotyping will be conducted to assess viral resistance to 
the study medication. The investigator may terminate the subject from the trial if, in his/her 
opinion, there is an unacceptable increase in HDV viral load. 
4 ELIGIBILITY CRITERIA 
Up to 75 subjects chronically infected with HDV genotype 1 will be enrolled at a single 
University study site. 
4.1 
Inclusion Criteria 
A subject may be included in this study if he/she meets all of the following criteria: 
1. Males or females, 18 to 65 years of age who are diagnosed with HDV by PCR 
 
2. Chronic hepatitis D infection, genotype 1, documented by a positive anti-HDV Ab 
test at least of 6 months duration and detectable HDV RNA by PCR within 3 months 
to study entry  


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3. Liver biopsy within the last two (2) years (biopsy can be done at the Screening Visit) 
 
4. Positive viral load of  >100,000 copies/mL as measured by quantitative PCR 
 
5. Electrocardiogram (ECG) shows no acute ischemia or clinically significant 
abnormality and a QT/QTc interval <450 milliseconds - using Bazett's correction: 
QTc =QT/RR0.5 (ICH Guidance E14 Clinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs) 
 
6. Females of childbearing potential (intact uterus and within 1 year since the last 
menstrual period) should be non-lactating and have a negative serum pregnancy test. 
In addition, these subjects should agree to use one of the following acceptable birth 
control methods throughout the study: 
a. 
abstinence 
b. 
surgical sterilization (bilateral tubal ligation, hysterectomy, bilateral 
oophorectomy) six months minimum 
c. 
IUD in place for at least six months 
d. 
barrier methods (condom or diaphragm) with spermicide 
e. 
surgical sterilization of the partner (vasectomy for six months) 
f. 
hormonal contraceptives for at least three months prior to the first dose 
of study drug 
 
7.  Willing and able to comply with study procedures and provide written informed 
consent 
4.2 
Exclusion Criteria 
A subject will be excluded from this study if he/she meets any of the following criteria: 
1. Participation in a clinical trial with or use of any investigational agent within 30 days 
of Study Visit 1 
 
2. Patients co-infected with HIV 
 
3. Patients with screening tests positive for HCV, or anti-HIV Ab 
 
4. History of decompensated cirrhosis within the past year. 
 
5. Active jaundice defined by total bilirubin >2.0 excluding Gilbert’s 
 


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6. INR ≥ 1.5 
 
7. Eating disorder or alcohol abuse within the past 2 years, excessive alcohol intake  
(>20 g per day for females (1.5 standard alcohol drinks) or >30 g per day for males 
(2.0 standard alcohol drinks) (a standard drink contains 14 g of alcohol: 12 oz of beer,  
5 oz of wine or 1.5 oz of spirits) (1.0 fluid oz (US) = 29.57 ml), or if in the opinion of  
the investigator, an alcohol use pattern that will interfere with the study conduct 
 
8. Drug abuse within the last six months with the exception of cannabinoids and their 
derivatives 
 
9. Patients with absolute neutrophil count (ANC) <1500 cells/mm3; platelet count 
<100,000 cells/mm3; hemoglobin <12 g/dL for women and <13 g/dL for men; 
abnormal TSH,T4, or T3or thyroid function not adequately controlled; or serum 
creatinine concentration ≥1.5 times upper limit of normal (ULN) 
 
10. History or clinical evidence of any of the following: 
a. variceal bleeding, ascites, hepatic encephalopathy, CTP score >6, 
decompensated liver disease or any other form of non-viral hepatitis 
b. immunologically mediated disease (e.g., rheumatoid arthritis, inflammatory 
bowel disease, severe psoriasis, systemic lupus erythematosus) requiring 
more than intermittent nonsteroidal anti-inflammatory medications for 
management or that requires frequent or prolonged use of corticosteroids 
(inhaled asthma medications are allowed) 
c. any malignancy within 3 years except for basal cell skin cancer 
d. significant or unstable cardiac disease (e.g., angina, congestive heart failure, 
uncontrolled hypertension, history of arrhythmia) 
e. chronic pulmonary disease (e.g., chronic obstructive pulmonary disease) 
associated with functional impairment 
f. severe or uncontrolled psychiatric disease, including severe depression, 
history of suicidal ideation, suicidal attempts or psychosis requiring 
medication and/or hospitalization 
 
11. Patients with a body mass index >30 kg/m2 
 
12. Concomitant drugs known to prolong the QT interval 
 
13. Concomitant use of immunosuppressive or immune modulating agents 
 


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14. Patients with any serious or condition that, in the opinion of the investigator, would 
preclude evaluation of response or make it unlikely that the contemplated course of 
therapy and follow-up could be completed or increase the risk to the subject of 
participation in the trial 
4.3 
Withdrawal Of Subjects 
At any time during the study, a subject may discontinue (i.e., withdraws consent or is no 
longer willing to participate) or a subject may be withdrawn by the Investigator because of a 
safety risk, adverse event, or noncompliance. The reason for early withdrawal shall be noted 
in the appropriate CRF. 
The Sponsor has the option to enroll additional subjects to replace subjects who discontinue 
prematurely. 
4.4 
Study Termination 
Eiger BioPharmaceuticals may terminate the study if new findings indicate that the study 
would be potentially dangerous or detrimental to subjects. Eiger BioPharmaceuticals may 
also terminate the study for administrative reasons unrelated to the purpose of the study. In 
addition, the regulatory agency or the site’s IRB/EC has the authority to stop the study. 
5 STUDY TREATMENT 
5.1 
EBP-994 
The drug to be utilized for this study is EBP-994 (previously developed as lonafarnib by 
Schering-Plough, now Merck). The EBP-994 active pharmaceutical ingredient (API) is 
manufactured by Schering Corporation located in 1011 Morris Avenue Union, NJ 07083. 
Each capsule contains 25 mg, 50 mg or 75 mg of EBP-994. 
5.1.1 Description of EBP-994 
IUPAC Name: 4-(2-4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-
5Hbenzo[5,6]cyclohepta[b]pyridin-11-yl]piperidino-2-oxoethyl)-1-piperidinecarboxamide 
CAS Number: none 
Molecular Formula: C27H31N4O2ClBr2 
Molecular Weight:  638.7 g/mol 


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Figure 4:  EBP-994 
 
 
5.1.2 Description of Study Treatment 
Study Visit 2 (Day 1) marks the initiation of the Treatment Period; all subjects will begin 
dosing with EBP-994 alone or in combination with Norvir® and/or Pegasys®,  and continue 
dosing through Study Visit 7, 8, 9, 10, 11-47 (depending on treatment duration) morning 
dose.  
5.1.2.1 Dosage Form of EBP-994 
EBP-994 is formulated into hard gelatin, white opaque capsule shells. Each capsule contains 
25 mg, 50 mg or 75 mg of EBP-994. The capsules are provided in white opaque high density 
polyethylene (HDPE) bottles with polypropylene twist off caps and desiccant. Each bottle 
contains 30 capsules. EBP-994 is stable if stored at 20°C - 25°C (68°F - 77°F). A “use by” 
date is included on the product label. EBP-994 should be stored at room temperature 20°C - 
25°C (68°F - 77°F) in a locked, limited-access storage area prior to dispensing. 
5.1.2.2 Dosage Form of Ritonavir 
Commercial formulation of ritonavir (Norvir®) is supplied as 100-mg, white, film-coated, 
ovaloid tablets in white, opaque, HDPE bottles with polypropylene twist-off caps.  
Ritonavir should be stored at or below 30 °C (86 °F). 
5.1.2.3 Dosage Form of Pegylated Interferon  
Commercial formulation of Pegasys® is supplied in vials. Each vial contains approximately 
1.2 mL of solution to deliver 1.0 mL of drug product. Subcutaneous (SC) administration of 
1.0 mL delivers 180 µg of drug product (expressed as the amount of interferon alfa-2a). The 
solution is colorless to light yellow. 
 


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5.2 
Administration 
Subjects will be instructed to self-administer EBP-994 at 8, 12 or 24 hour intervals ±2 hours. 
Norvir® at 12 or 24 hour intervals ±2 hours and/or Pegasys® at weekly intervals . If a dosing 
window is missed, the subject should skip the dose completely. Subjects should not “double 
up” at the next scheduled dose period. 
5.3 
Concomitant Medications 
All drugs that are listed as excluded in the Exclusion Criteria should not be initiated during  
the study unless prior approval has been received from the Medical Monitor. Check the 
prescribing information of Norvir® and Pegasys® before initiating any concomitant 
medication. 
5.4 
Measuring Subject Compliance 
Study drug is administered on an out-patient basis. Subjects will be instructed to return all 
study drug containers dispensed at the previous study visit (including empty ones) at each 
Study Visit in order to measure study drug compliance. The study coordinator will verify the 
subject has taken the correct amount of study medication prior to issuing the next supply of 
study medication. 
5.5 
Drug Accountability 
All supplies of study drug will be accounted for by study personnel in accordance with 
current Good Clinical Practices (GCPs). Details of receipt, storage, administration, and return 
or destruction of study drug will be recorded in the study drug accountability record 
according to the standard operating procedure of the investigational site. Copies of the study 
drug accountability record will be provided to the Sponsor. 
6 STUDY PROCEDURES 
Refer to Appendix 1 for Schedule of Events. 
6.1 
Screening; Visit 1 
The outpatient Screening Visit must occur no more than 21 days prior to Study Visit 1. 
Written informed consent must be given before any study related diagnostic or screening 
procedures. At the Screening Visit, subjects will have all required evaluations to determine 
their eligibility to participate in the study as follows: 
1. Written informed consent 
 
2. Medical history 
 


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3. Comprehensive physical examination (performed by a physician) including CTP 
scoring and encephalopathy assessment (see Appendix D) 
 
4. Weight and height (BMI is based on these measures; see Appendix B) 
 
5. Vital signs (BP after being seated for 5 minutes, pulse, respiratory rate and 
temperature) 
 
6. List of concomitant medications 
 
7. Serial 12-Lead ECG (x3) 2-3 minutes apart 
 
8. Liver biopsy (if needed) 
 
9. Laboratory studies (non-fasting): 
a. 
Serum chemistry panel, including liver function tests and albumin  
b. 
Thyroid function tests, T3, T4, TSH 
c. 
Complete blood count (CBC with differential and platelet count) 
d. 
Quantitative PCR for HCV viral load 
e. 
HCV genotype  
f. 
Blood samples (plasma and serum) for viral mutation analysis and 
resistance phenotyping 
g. 
Serologies (HCV, and anti-HIV Ab) 
h. 
INR 
i. 
Urinalysis 
j. 
Urine drug screen for opiates, amphetamines, barbiturates, 
benzodiazepines, cocaine 
k. 
Serum pregnancy test (child bearing females only) 
l. 
Blood sample for monitoring immunologic changes in peripheral 
blood mononuclear cells (PBMC). 
 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria and giving 
written informed consent will return within 21 days after screening for Study Visit 1 when 
randomization one of the treatment groups will occur. 
6.2 
Study Visit 2 (Day 1) – Treatment Period 
This Study Visit marks the beginning of the twenty-four weeks treatment Period in which 
subjects will receive EBP-994 treatments (EBP-994 alone or in combination with Norvir® 
and/or Pegasys®). Subjects will be admitted to the unit on the morning of Day 1 in a fasted 


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state (nothing to eat or drink except water) and will receive a standard breakfast between 45 - 
30 minutes prior to scheduled dosing time. 
The following evaluations and procedures will be performed at Study Visit 1 (see Appendix 
A for summary): 
1. Brief physical examination pre-dose (performed by a physician, nurse practitioner, 
physician’s assistant or nurse). This includes weight and vital signs as well as 
HEENT, heart, lungs, abdomen and lower extremity. 
 
2. Vital signs pre-dose and after the post-dose ECG (BP after being seated for 5 
minutes, pulse, respiratory rate and temperature) 
 
3. Concomitant medications will be recorded 
 
4. Adverse events will be recorded 
 
5. 12-Lead ECG  
 
6. Randomization 
 
Subjects will  be  randomized  to  one  of  the  following  groups:   
Group 1: EBP-994 (up to 600 mg daily dose) monotherapy 
Group 2: EBP-994 (up to 200 mg daily dose) in combination with Norvir® 
Group 3: EBP-994 (up to 200 mg daily dose) in combination with Pegasys® 
Group 4: EBP-994 (up to 200 mg daily dose) in combination with Norvir® and 
Pegasys®  
 
7.  Laboratory studies (Pre-Dose) (non-fasting): 
a. 
Serum chemistry panel, including liver function tests and albumin 
b. 
Complete blood count (CBC with differential and platelet count) 
c. 
Quantitative PCR for HDV viral load 
d. 
Blood samples (plasma and serum) for viral mutation analysis, 
resistance phenotyping, and analysis of drug mechanism and treatment 
response. These analyses include molecular and genetic analysis of 
drug mechanism, viral/host factors influencing treatment response (e.g. 
genotype and subgenotype analysis, quasispecies analysis, 
determination of drug and potential metabolite levels in plasma). 
e. 
Urinalysis 
f. 
Urine pregnancy test (child-bearing females only) 


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g. 
Blood sample for monitoring immunologic changes in peripheral 
blood mononuclear cells (PBMC). 
 
8. Pharmacokinetic blood samples (at the following time points: 0-pre-dose, post dose: 
15 min, 30 min, 60 min, 90 min, 2h, 2.5 h, 3 h, 4 h, ,6 h, 8, 10, 12 h) (for those 
subjects participating in the PK portion of this trial) 
 
9. Dosing Instructions: 
Dosing with EBP-994 alone or in combination with Norvir® and/or Pegasys® should 
occur after the pre-dose vital signs have been taken, the physical examination 
performed, the ECG performed and pre-dose lab samples drawn. EBP-994 capsules 
and/or Norvir® should be taken orally with 240 mL of water. After the morning 
dosing, the post-dose procedures should be conducted in the following order: ECG, 
vital signs, post-dose plasma and serum blood samples. 
 
Subjects will be sent home 3 hours post-dose (except for those participating in the PK 
component of the study) with container(s) of study drug(s) and will be instructed to 
self-administer study drug(s) at appropriate intervals.  Oral study drug should be swallowed 
with 240 mL of water. Subjects will also be given a diary to record the date, time and number 
of capsules they take. 
Subjects should be instructed to bring all container(s) and any unused study medication to the 
study site at the next study visit. Subjects should be instructed NOT to take their morning 
dose of study drug on the morning of the next study visit, Day 2, as pre-dose assessments 
will be conducted. 
6.3 
Study Visit 3 (Day 2) – Treatment Period 
Subjects are not to take their morning dose of study drug at home as pre-dose assessments are 
performed at this Study Visit. 
1. Vital signs pre-dose (BP after being seated for 5 minutes, pulse, respiratory rate and 
temperature) 
 
2. Concomitant medications will be recorded 
 
3. Adverse events will be recorded 
 
4. 12-Lead ECG (x3) 2-3 minutes apart pre-dose and 1 hour post-dose  
 
5. Laboratory studies (pre-dose) (non-fasting): 
a. 
Quantitative PCR for HDV viral load 


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b. 
Pre-dose and 1 hour post-dose blood samples (plasma and serum) for viral 
mutation analysis, resistance phenotyping, and analysis of drug mechanism 
and treatment response. These analyses include molecular and genetic 
analysis of drug mechanism, viral/host factors influencing treatment response 
(e.g. genotype and subgenotype analysis, quasispecies analysis, 
determination of drug and potential metabolite levels in plasma). 
c. 
Blood sample for monitoring immunologic changes in peripheral blood 
mononuclear cells (PBMC). 
6.  Dosing Instructions: 
Dosing with EBP-994 alone or in combination with Norvir® and/or Pegasys® should 
occur after the ECG has been performed and pre-dose lab samples drawn.  The 
subject should receive morning dose of study drug(s). The post-dose ECG should be 
conducted one hour post-dose followed by the post-dose vitals and blood sampling.  
 
The subject should bring the container(s) of study drug(s) dispensed at Study Visit 2 to this 
visit. Study personnel will assess dosing compliance and return container(s) to patient. No 
additional study drug will be dispensed at this visit. Subjects should be instructed to bring all 
container(s) and any unused study medication to the next study visit. Subjects should be 
instructed NOT to take their morning dose of study drug on the morning of the next Study 
Visit, Day 3, as pre-dose assessments will be conducted. Subjects should be sent home three 
hours post-dose. 
6.4 
Study Visit 4 (Day 3) - Treatment Period 
Subjects are not to take their morning dose of study drug at home as pre-dose assessments are 
performed at this Study Visit. 
1. Brief physical examination pre-dose (performed by a physician, nurse practitioner, 
physician’s assistant or nurse). This includes weight as well as HEENT, heart, lungs, 
abdomen and lower extremity.  
 
2. Vital signs 
 
3. Concomitant medications will be recorded 
 
4. Adverse events will be recorded 
 
5. Laboratory studies (Pre-Dose) (non-fasting): 
c. 
Serum chemistry panel, including liver function tests and albumin 
d. 
Complete blood count (CBC with differential and platelet count) 
e. 
Quantitative PCR for HDV viral load 
f. 
Urinalysis 


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g. 
Blood sample for monitoring immunologic changes in peripheral blood 
mononuclear cells (PBMC). 
 
6.  Dosing Instructions: 
Dosing with EBP-994 alone or in combination with Norvir® and/or Pegasys®  should 
occur after the pre-dose vital signs have been taken, the physical examination 
performed, and pre-dose lab samples drawn. The subject should receive morning dose 
of study drug.  
 
The subject should bring the container(s) of study drug(s) dispensed at Study Visit 1 to this 
visit. Study personnel will assess dosing compliance and return container(s) to patient. No 
additional study drug will be dispensed at this visit. Subjects should be instructed to return all 
container(s) and any unused study medication at the next study visit. At each subsequent 
Study Visit, drug accountability will be performed for each subject to ensure that the subject 
is compliant with dosing. Subjects should be instructed NOT to take their morning dose of 
study drug on the morning of the next Study Visit, Day 7, as pre-dose assessments will be 
conducted. Subjects should be sent home three hours post-dose. 
6.5 
Study Visit 5 (Day 7±2 days) - Treatment Period 
Subjects are not to take their morning dose of study drug at home as pre-dose assessments are 
performed at this visit. 
1. Brief physical examination pre-dose (performed by a physician, nurse practitioner, 
physician’s assistant or nurse). This includes weight as well as HEENT, heart, lungs, 
abdomen and lower extremity.  
 
2. Vital signs pre-dose. 
 
3. Concomitant medications will be recorded 
 
4. Adverse events will be recorded 
 
5. Laboratory studies (Pre-Dose) (non-fasting): 
a. Serum chemistry panel, including liver function tests and albumin 
b. Complete blood count (CBC with differential and platelet count) 
c. Quantitative PCR for HDV viral load 
d. Pre-dose and post-dose blood samples (plasma and serum) for viral mutation 
analysis, resistance phenotyping, and analysis of drug mechanism and 
treatment response 
e. Urinalysis 
f.  Blood sample for monitoring immunologic changes in peripheral blood 
mononuclear cells (PBMC). 


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6.  Dosing Instructions 
Dosing with EBP-994 alone or in combination with Norvir® and/or Pegasys® should 
occur after the pre-dose vital signs have been taken, the physical examination 
performed, and pre-dose lab samples drawn. The subject should receive morning dose 
of study drug(s). 
 
The subject should bring the container(s) of study drug(s) dispensed at Study Visit 1 to this 
visit. Study personnel will to assess dosing compliance and return container(s) to patient. A 
new container of study drug will be dispensed at this visit. Subjects should be instructed to 
return all container(s) and any unused study medication at the next Study Visit. At each 
subsequent Study Visit, drug accountability will be performed for each subject to ensure that 
the subject is compliant with dosing. Subjects should be instructed NOT to take their 
morning dose of study drug on the morning of the next Study Visit, Day 14, as pre-dose 
assessments will be conducted. Subjects should be sent home three hours post-dose. 
6.6 
Study Visit 6 (Day 14±2days) - Treatment Period 
Subjects are not to take their morning dose of study drug at home as pre-dose assessments are 
conducted at this visit. 
1. Brief physical examination pre-dose (performed by a physician, nurse practitioner, 
physician’s assistant or nurse). This includes weight and vital signs as well as 
HEENT, heart, lungs, abdomen and lower extremity.  
 
2. Vital signs pre-dose  
 
3. Concomitant medications will be recorded 
 
4. Adverse events will be recorded 
 
5. Laboratory studies (Pre-Dose) (non-fasting): 
a. 
Serum chemistry panel, including liver function tests and albumin 
b. 
Complete blood count (CBC with differential and platelet count) 
c. 
Quantitative PCR for HDV viral load 
d. 
Pre-dose blood samples (plasma and serum) for viral mutation analysis, 
resistance phenotyping, and analysis of drug mechanism and treatment 
response 
e. 
Urinalysis 
f. 
Blood sample for monitoring immunologic changes in peripheral blood 
mononuclear cells (PBMC). 
 
6.  Dosing Instructions: 


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Dosing with EBP-994 alone or in combination with Norvir® and/or Pegasys®  should 
occur after the pre-dose vital signs have been taken, the physical examination 
performed, and pre-dose lab samples drawn.  The subject should receive morning 
dose of study drug(s).  If there is not sufficient drug remaining the subject may take 
the capsules from the container dispensed at this study visit.  EBP-994 and/or Norvir® 
should be taken orally with 240 mL of water. 
 
The container(s) of study drug(s) along with any unused drug dispensed at Study Visit 4 
should be returned at this visit. Study personnel will perform drug accountability on the 
returned container(s) of study drug(s). A new container(s) of drug will be dispensed at this 
visit. Subjects should be instructed to return all container(s) and any unused study medication 
at the next study visit. At each subsequent Study Visit, drug accountability will be performed 
for each subject and reviewed to ensure that subject is compliant with dosing. Subjects 
should be instructed NOT to take their morning dose of study drug on the morning of the 
next Study Visit, Day 28, as pre-dose assessments will be conducted. Subjects should be sent 
home 3 hours post-dose. 
6.7 
Study Visit 7 (Day 28±2days) - Treatment Period 
Subjects are not to take their morning dose of study drug at home as pre-dose assessments are 
conducted at this visit. 
7 Brief physical examination pre-dose (performed by a physician, nurse practitioner, 
physician’s assistant or nurse). This includes weight and vital signs as well as 
HEENT, heart, lungs, abdomen and lower extremity.  
 
8 Vital signs pre-dose and after the post-dose ECG (BP after being seated for 5 
minutes, pulse, respiratory rate and temperature) 
 
9 Concomitant medications will be recorded 
 
10 Adverse events will be recorded 
 
11 12-Lead ECG (x3) 2-3 minutes apart pre-dose and 1 hour post-dose 
 
12 Laboratory studies (Pre-Dose) (non-fasting): 
f. Serum chemistry panel, including liver function tests and albumin 
g. Complete blood count (CBC with differential and platelet count) 
h. Quantitative PCR for HDV viral load 
i. Pre-dose and post-dose blood samples (plasma and serum) for viral mutation 
analysis, resistance phenotyping, and analysis of drug mechanism and 
treatment response 
j. Urinalysis 


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k. Blood sample for monitoring immunologic changes in peripheral blood 
mononuclear cells (PBMC). 
 
13 Pharmacokinetic blood samples (at the following time points: 0-pre-dose, post dose: 
15 min, 30 min, 60 min, 90 min, 2 h, 2.5 h, 3 h, 4 h,  ,6 h, 8, 10, 12 h) (for those 
subjects participating in the PK portion of this trial) 
 
8  Dosing Instructions: 
Dosing with EBP-994 EBP-994 alone or in combination with Norvir® and/or 
Pegasys® should occur after the pre-dose vital signs have been taken, the physical 
examination performed, the pre-dose ECG performed and pre-dose lab samples 
drawn.  The subject should receive morning dose of study drug(s).  If there is not 
sufficient drug remaining the subject may take the capsules from the container 
dispensed at this study visit.  EBP994 alone or in combination with Norvir® should be 
taken orally with 240 mL of water. After dosing the post-dose procedures should be 
conducted in the following order: ECG (one hour post-dose), vital signs (post ECG), 
post-dose plasma and serum blood samples. 
 
The container(s) of study drug(s) along with any unused drug dispensed at Study Visit 5 
should be returned at this visit. Study personnel will perform drug accountability on the 
returned container(s) of study drug(s) to assess dosing compliance. A new container of drug 
will be dispensed at this visit to the subject. Subjects should be instructed to return all 
container(s) and any unused study medication at the next study visit. At each subsequent 
Study Visit, drug accountability will be performed for each subject to ensure that subject is 
compliant with dosing. Subjects should be instructed NOT to take their morning dose of 
study drug on the morning of the next Study Visit, Day 56, as pre-dose assessments will be 
conducted. Subjects should be sent home 3 hours post-dose, except for those participating in 
the PK component of the study. 
If this is the last treatment visit, no new containers of drug(s) will be dispensed and all 
unused study medication will be collected. 
 
6.8 
Study Visit 8 (Week 8 = Day 56±2days) - Treatment Period 
Subjects are not to take their morning dose of study drug at home as pre-dose assessments are 
conducted at this visit. 
1 Brief physical examination pre-dose (performed by a physician, nurse practitioner, 
physician’s assistant or nurse). This includes weight and vital signs as well as 
HEENT, heart, lungs, abdomen and lower extremity. 
 
2 Vital signs pre-dose   
 


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3 Concomitant medications will be recorded 
 
4 Adverse events will be recorded 
 
5 Laboratory studies (Pre-Dose) (non-fasting): 
k. 
Serum chemistry panel, including liver function tests and albumin 
l. 
Complete blood count (CBC with differential and platelet count) 
m. Quantitative PCR for HDV viral load 
n. 
Pre-dose blood samples (plasma and serum) for viral mutation analysis, 
resistance phenotyping, and analysis of drug mechanism and treatment 
response 
o. 
Urinalysis 
p. 
Blood sample for monitoring immunologic changes in peripheral blood 
mononuclear cells (PBMC). 
 
6  Dosing Instructions: 
Dosing with EBP-994 EBP-994 alone or in combination with Norvir® and/or 
Pegasys® should occur after the pre-dose vital signs have been taken, the physical 
examination performed, and pre-dose lab samples drawn. The subject should receive 
morning dose of study drug(s). If there is not sufficient drug remaining the subject 
may take the capsules from the container dispensed at this study visit.  EBP-994 alone 
or in combination with Norvir® should be taken orally with 240 mL of water.  
 
The container(s) of study drug(s) along with any unused drug dispensed at Study Visit 6 
should be returned at this visit. Study personnel will perform drug accountability on the 
returned container(s) of study drug(s) to assess dosing compliance. A new container of drug 
will be dispensed at this visit as well as the diary at the next study visit. At each subsequent 
Study Visit, drug accountability will be performed for each subject to ensure that subject is 
compliant with dosing. Subjects should be instructed NOT to take their morning dose of 
study drug on the morning of the next Study Visit, Day 84, as pre-dose assessments will be 
conducted. Subjects should be sent home 3 hours post-dose. 
If this is the last treatment visit, no new containers of drug(s) will be dispensed and all 
unused study medication will be collected. 
 
6.9 
Study Visit 9-18 (Week 12-48) - Treatment Period 
Subjects are not to take their morning dose of study drug at home as pre-dose assessments are 
conducted at this visit. 


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7 Brief physical examination pre-dose (performed by a physician, nurse practitioner, 
physician’s assistant or nurse). This includes weight and vital signs as well as 
HEENT, heart, lungs, abdomen and lower extremity.  
 
8 Vital signs pre-dose   
 
9 Concomitant medications will be recorded 
 
10 Adverse events will be recorded 
 
11 Laboratory studies (Pre-Dose) (non-fasting): 
p. 
Serum chemistry panel, including liver function tests and albumin 
q. 
Complete blood count (CBC with differential and platelet count) 
r. 
Quantitative PCR for HDV viral load 
s. 
Pre-dose blood samples (plasma and serum) for viral mutation analysis, 
resistance phenotyping, and analysis of drug mechanism and treatment 
response 
t. 
Urinalysis 
u. 
Blood sample for monitoring immunologic changes in peripheral blood 
mononuclear cells (PBMC). 
 
12 Dosing Instructions: 
Dosing with EBP-994 EBP-994 alone or in combination with Norvir® and/or 
Pegasys® should occur after the pre-dose vital signs have been taken, the physical 
examination performed, and pre-dose lab samples drawn.  The subject should receive 
morning dose of study drug.  If there is not sufficient drug remaining the subject may 
take the capsules from the container dispensed at this study visit.  EBP-994 and/or 
Norvir® should be taken orally with 240 mL of water. 
 
The container(s) of study drug(s) along with any unused drug dispensed at Study Visit 7 
should be returned at this visit. Study personnel will perform drug accountability on the 
returned container(s) of study drug(s) to assess dosing compliance. A new container of drug 
will be dispensed at this visit to the subject. Subjects should be instructed to return all 
container(s) and any unused study medication at the next study visit. At each subsequent 
Study Visit, drug accountability will be performed for each subject to ensure that subject is 
compliant with dosing. Subjects should be instructed NOT to take their morning dose of 
study drug on the morning of the next Study Visit, Day 112, as pre-dose assessments will be 
conducted. Subjects should be sent home 3 hours post-dose. 
If this is the last treatment visit, no new containers of drug(s) will be dispensed and all 
unused study medication will be collected. 


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6.10 Study Visit 19 – Four Week Post-Treatment Follow-Up 
Same assessments are taken as in 6.9.  No new containers of drug(s) will be dispensed.  All 
unused study medication will be collected.  No dosing at this visit. 
 
6.11 Supplemental Safety Evaluation Visit(s) 
During the course of the study, if the Investigator has a specific safety concern that may 
merit additional safety evaluation(s), the Medical Monitor should be notified of the intent to 
perform additional Study Visit(s) and/or additional laboratory assessments(s). These visits 
will be considered Unscheduled Visits. 
7 ASSESSMENT OF SAFETY 
7.1 Procedures For Recording Adverse Events 
All adverse events encountered during the clinical study will be recorded on the case report 
form (CRF). An adverse event is defined by the International Conference on Harmonization 
(ICH) as follows: 
o Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a 
causal relationship to this treatment 
o An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including any abnormal laboratory finding for example), symptom, or disease 
temporarily associated with the use of a experimental drug, whether or not 
considered related to the experimental drug 
 
An adverse event is any adverse change from the subject’s baseline condition, including any 
clinical or clinically significant laboratory test value abnormality that occurs during the 
course of the clinical study after the experimental drug has been utilized, whether the adverse 
event is considered related to the treatment or not. 
All adverse events will be followed until resolution.  This may require obtaining clinical 
blood samples for appropriate laboratory tests until their values return to baseline levels or 
performing follow-up physical examinations until resolution of identified abnormalities. 
7.1.1 Routine Reporting of Adverse Events 
Adverse events, whether or not associated with study drug administration, will be recorded 
on the Adverse Event Reporting form of the CRF and will be submitted to the sponsor at 
regularly scheduled intervals. 
The information to be entered in the CRF will include: 


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1. The time of onset of any new adverse event or the worsening of a previously 
observed adverse event 
 
2. The specific type of reaction in standard medical terminology 
 
3. The duration of the adverse event (start and stop dates) 
 
4. The severity/grade of the adverse event 
 
5. As assessment should be made of the relationship of the adverse event to the study 
drug, i.e., according to the definitions in Section 7.1.4. 
 
6. Description of action taken in treating the adverse event and/or change in study drug 
administration or dose 
 
Follow-up assessments should be repeated to document return of any abnormalities to 
normal, or to document other outcome of the adverse event. 
7.1.2 Reporting of Serious Adverse Drug Experiences, including Deaths 
A serious adverse drug experience (SAE), as defined by the International Conference on 
Harmonization and in 21 CFR 312.32 is: 
Any adverse drug experience occurring at any dose that results in any of the 
following outcomes: 
1. Death 
 
2. A life threatening adverse drug experience  
 
3. Inpatient hospitalization or prolongation of existing hospitalization 
 
4. A persistent or significant disability/incapacity 
 
5. Congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 


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convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Serious adverse experiences, including death due to any cause, which occur during this study 
or within 30 days following the last dose of study medication, whether or not related to the 
administration of study drug, must be reported immediately (within 24 hours of learning of 
the event) to the Medical Monitor.  
Contact: 
Eduardo B. Martins, MD, DPhil 
Phone: 650-867-7111  Email: emartins@eigerbio.com  
eigersafety@eigerbio.com 
 
International calls to the United States: dial 00 + 1 before the telephone number 
7.1.3 Severity of Adverse Drug Experiences 
Clinical adverse events will be categorized using the following definitions: 
Mild: discomfort noted, but no disruption of normal daily activity 
Moderate: discomfort noted of sufficient severity to reduce or adversely affect 
normal activity 
Severe: incapacitating, with inability to work or perform normal daily activity 
7.1.4 Relationship of Adverse Events to the Study Drug 
The investigator and/or Medical Monitor should record on the CRF whether the event is best 
described as unrelated, possibly, probably, or definitely related association to the study 
medications, according to the following definitions. 
Unrelated: There is evidence that the adverse event definitely has an etiology 
other than the assigned study drug. 
Possibly Related: The adverse event has a temporal relationship to study drug 
administration.  However, an alternative etiology may be responsible for the 
adverse event.  Information on drug/product withdrawal may be lacking or 
unclear. 
Probably Related: The adverse event has a temporal relationship to study drug 
administration.  The event is unlikely to be related to an alternative etiology.  
There is a reasonable response on withdrawal (dechallenge).  Rechallenge 
information is not required. 
Related: The adverse event has a temporal relationship to study drug 
administration and resolves when the drug is discontinued.  An alternative 
etiology is not apparent. If the subject is rechallenged with the assigned study 
drug, the adverse event recurs. Rechallenge is not necessarily required. 
 


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7.2 
Withdrawal From Study Treatment Due To Adverse Experience 
Subjects withdrawn from receiving additional study drug due to an adverse experience will 
be followed by the Investigator until the outcome is determined; additional reports will be 
provided to the Sponsor or regulatory authorities when requested. Every effort will be made 
to follow the subject for the full study period as per the schedule of Study Visits. 
7.3 
Management Of Toxicity Related To Study Drug 
Safety will be monitored by assessing vital signs, adverse events, concomitant medications 
and laboratory and ECG results. ECGs will be conducted in triplicate and vital signs assessed 
at each Study Visit. During the treatment period, ECGs will be conducted pre and one hour 
post-dose. Vital signs will be taken pre-dose and following the post-dose ECG. 
The most common side effects seen with lonafarnib (the active ingredient of EBP-994) are 
gastrointestinal (diarrhea, nausea, and vomiting).  
There were no serious adverse events (SAEs) observed in the studies conducted in healthy 
volunteers. The SAEs reported in at least 2% of subjects in the Phase 1 and Phase 2 studies 
conducted in subjects with solid tumors or hematologic malignancies included fever (6%), 
diarrhea (6%), dehydration (6%), febrile neutropenia (4%) and sepsis (4%). 
 
As with any anti-viral medication, a possible effect of EBP-994 is viral resistance. Hepatitis 
D viral load levels will be measured through quantitative PCR at all Study Visits. Viral 
mutation analysis and resistance phenotyping will be conducted to assess viral resistance to 
the study medication. The investigator may terminate the subject from the trial if, in his/her 
opinion, there is an unacceptable increase in HDV viral load. Moreover, the investigator is 
free to initiate licensed medications at any time point and decrease the dose of EBP-994 if 
deemed warranted for GI side effects. 
During the conduct of the study, safety laboratory values will be assayed within 48 hours of 
the study visit and the Medical Monitor and Investigator will be informed within 24 hours of 
assay performance of laboratory abnormalities. 
8 STATISTICS 
8.1 Blinding 
This is an open-label study; subjects will not be blinded. 
8.2 Analysis Populations 
The Safety Population comprises all subjects who are enrolled and receive at least one dose 
of study drug, and who have at least one post-dosing safety evaluation. All safety endpoints 
will be analyzed using the Safety Population. 


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The Per-Protocol Population comprises all subjects who complete at least Study Visit 4, as 
specified in the protocol. All pharmacodynamic analysis will be conducted using the Per-
Protocol Population.   
8.3 Demographics And Baseline Characteristics 
Demographic and baseline characteristics will be presented descriptively.  
8.4 Safety  
8.4.1 Adverse Events 
All reported adverse events will be mapped to standard coding terms (MedDRA) and 
grouped by system organ class and preferred terms.  The incidence of adverse events will be 
tabulated by seriousness, severity, and relationship to study drug. If an adverse event is 
reported more than once during the study period, the greatest severity and worst-case 
attribution will be presented in tables. Adverse events will also be listed for individual 
subjects, along with information regarding onset, duration, severity, and relationship to study 
drug. Adverse events that lead to withdrawal from the study will be listed and summarized by 
treatment group separately. Summary tables and listings of serious adverse events will also 
be generated. 
8.4.2 Clinical Laboratory and Vital Signs 
Clinical laboratory data (hematology, blood chemistry, and urinalysis) and vital signs will be 
summarized using descriptive statistics at baseline and each timepoint.  Listings will display 
laboratory data at each period/timepoint collected by subject.   
8.5 Pharmacokinetics 
Blood samples will be obtained for pharmacokinetics of EBP-994 at Study Visit 1 (Day 1) 
and Study Visit 6 (Day 28). 
The following pharmacokinetic parameters will be calculated for EBP-994 on Day 1 using 
non-compartmental analysis, when applicable.  
AUC0-t: 
The area under the plasma concentration versus time curve, from 
time 0 to the last measurable concentration, as calculated by the 
linear trapezoidal method. 
AUCinf: 
The area under the plasma concentration versus time curve from 
time 0 to infinity.  AUCinf is calculated as the sum of AUC0-t plus 
the ratio of the last measurable plasma concentration to the 
elimination rate constant. 
AUC/AUCinf: 
The ratio of AUC0-t to AUCinf. 
Cmax: 
Maximum  measured plasma concentration over the time span 
specified. 


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tmax 
Time of the maximum measured plasma concentration. If the 
maximum value occurs at more than one time point, tmax is 
defined as the first time point with this value. 
kel: 
Apparent first-order terminal elimination rate constant calculated 
from a semi-log plot of the plasma concentration versus time 
curve. The parameter will be calculated by linear least-squares 
regression analysis using the maximum number of points in the 
terminal log-linear phase (e.g. three or more non-zero plasma 
concentrations). 
t½: 
Apparent first-order elimination half-life will be calculated as 
0.693/kel. 
CL/F: 
The apparent total body clearance after extravascular 
administration, calculated as Dose/AUCinf 
Varea/F: 
The apparent total volume of distribution after extravascular 
administration, calculated as Dose/(AUCinf x kel) 
 
No value for kel, AUCinf or t½ will be reported for cases that do not exhibit a terminal log-
linear phase in the concentration versus time profile. 
Other PK parameters may be calculated if deemed appropriate. 
The following pharmacokinetic parameters will be calculated for EBP-994 on Day 28 using 
non-compartmental analysis, when applicable. 
AUC0-τ 
The area under the plasma concentration versus time curve over the 
dosing interval at steady-state, as calculated by the linear trapezoidal 
method. 
Cmax,ss 
Maximum measure plasma concentration over the time span specified. 
Cmin,ss 
Measured plasma concentration at the end of the dosing interval. 
tmax,ss 
Time of the maximum measured plasma concentration.  If the 
maximum  value occurs at more than one time point, tmax is defined as 
the first time point with this value 
Flux 
Percent fluctuation will be calculated as follows: 
(Cmax - Cmin) x 100 
 
 
Cssav 
where Cssav is calculated as the ratio of AUC0-t  to the  dosing interval, 
t. 
Swing 
Percent fluctuation will be calculated as follows: 
(Cmax - Cmin) x 100 
 
 
Cmin 


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where Cssav is calculated as the ratio of AUC0-t  to the  dosing interval, 
t. 
Other PK parameters may be calculated if deemed appropriate. 
Compartmental analysis may be performed , if deemed necessary. 
8.5.1 PK Linearity and Accumulation Assessment 
The pharmacokinetic parameter AUC0-t values will be compared against AUCinf values using 
an analysis of variance (ANOVA) on the ln-transformed values for EBP-994.  The ANOVA 
model will include Day (Day 1 (AUCinf) and Day 28 (AUC0-τ)) as fixed effects.  The 
ANOVA will include calculation of least-squares means (LSM), the difference between day 
LSM and the standard error associated with this difference.  The above statistical analysis 
will be done using the appropriate SAS® procedure. 
Ratio of LSM will be calculated using the exponentiation of the LSM from the analysis on the 
ln-transformed response.  The ratio will be expressed as a percentage relative to AUCinf 
(Day 1). 
Ninety percent confidence interval for the ratio will be derived by exponentiation of the 
confidence interval obtained for the difference between day LSM resulting from the analysis 
on the ln-transformed response.  The confidence interval will be expressed as a percentage 
relative to AUCinf (Day 1).  
Accumulation will be evaluated by comparing the plasma exposure of EBP-994 on Day 28 
(AUC0-τ) to the exposure on Day 1 (AUC0-t). 
8.6 Pharmacodynamics 
Listings will display viral load data at each period/timepoint collected by subject and these 
data will be presented graphically. Mean and median levels of the viral load will be 
calculated at each period/timepoint. 
8.7 Sample Size And Power 
The sample size has not been determined by strict statistical considerations. From a safety, 
pharmacokinetic and pharmacodynamic perspective, no a-priori assumptions are made as to 
the expected treatment effect and associated variability. 
8.8 Interim Analyses 
No interim analyses are planned. 
8.9 Missing Data And Data Imputation 
No missing safety or pharmacodynamic data will be estimated. 


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9 ACCESS TO SOURCE DOCUMENTS 
The investigator will make the source documents for this trial available to the sponsor or its 
representatives, or to the regulatory authority or health authority inspectors. 
Subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties other than those noted below is prohibited. All reports and 
communications relating to subjects in this study will identify each subject only by their  
initials and number. Medical information resulting from a subject’s participation in this study 
may be given to the subject’s personal physician or to the appropriate medical personnel 
responsible for the subject’s welfare. Data generated as a result of this study are to be 
available for inspection on request by government regulatory agency auditors, the Sponsor 
Clinical Monitor (or designee), and the Institutional Review Board/Ethics Committee (IRB, 
EC). 
The information developed in this clinical study will be used by the Sponsor in the clinical 
development of the study medication and therefore may be disclosed by the Sponsor as 
required for disclosure as a public company to other clinical investigators, to other 
pharmaceutical companies, and/or to other government agencies. 
Any information, inventions, or discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports, made or developed by the Investigator(s) as a result of 
conducting this study shall be promptly disclosed to the Sponsor and shall be the sole 
property of the Sponsor.  The Investigator agrees, upon the Sponsor’s request and at the 
Sponsor's expense to execute such documents and to take such other actions, as the Sponsor 
deems necessary or appropriate to obtain patents in the Sponsor’s name covering any of the 
foregoing. 
The investigator will retain all study documents for at least 2 years after the last approval of a 
marketing application in an ICH region (i.e., United States, Europe, or Japan), and until there 
are no pending or contemplated marketing applications in an ICH region.  If no application is 
filed or if the application is not approved for such indication, the investigator will retain all 
study documents for at least 2 years after the investigation is discontinued and regulatory 
authorities have been notified. 
The investigator will notify the sponsor prior to destroying any study records.  Should the 
investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in writing in advance. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all 
of the documents, special arrangements will be made between the investigator and the 
sponsor for storage.  If source documents are required for continued care of the subject, then 
appropriate copies for storage off site will be made. 


Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
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45
10 QUALITY CONTROL AND QUALITY ASSURANCE 
Study monitors will periodically audit, at mutually convenient times during and after the 
study, all CRFs and corresponding office and clinical laboratory records for each subject.  
The monitoring visits provide the sponsor with the opportunity to evaluate the progress of the 
study, to verify the accuracy and completeness of CRFs, to resolve any inconsistencies in the 
study records, and to assure that all protocol requirements, applicable regulations, other 
requirements, and investigator’s obligations are being fulfilled. 
11 ETHICS 
11.1 Declaration of Helsinki 
The study will be conducted in accordance with the Declaration of Helsinki (1964) including 
all amendment up to and including the Scotland revision (2000) as described in Appendix D. 
11.2 Institutional Review Board/Ethics Committee 
The protocol, informed consent form, and any materials (such as advertisements, subject 
information sheets, or descriptions of the study used to obtain informed consent) for this 
study will be reviewed and approved by a duly constituted institutional review board 
(IRB)/ethics committee (EC). 
The investigator will ensure that all aspects of the IRB/EC review are conducted in 
accordance with current institutional, local, and national regulations. A letter documenting 
the IRB/EC approval will be provided to the sponsor prior to initiation of the study.  
Amendments to the protocol will be subject to the same requirements as the original 
protocol. The Investigator will submit all periodic reports and updates that the IRB/EC may 
require, including any final close out reports. The Investigator will inform the IRB/EC of any 
reportable adverse events. 
11.3 Informed Consent 
Each subject will be provided with oral and written information describing the nature and 
duration of the study, in a language they can understand, and must consent in writing to 
participate before undergoing screening. The date of the consent shall be entered by the 
subject. The original signed consent form will be retained with the study center’s records. 
Each subject will also be given a copy of his/her signed consent form. 
12 DATA HANDLING AND RECORDING 
Data for each subject will be recorded on the CRF using indelible black ink. CRFs must be 
completed for every subject who signs an informed consent and has screening procedures 
performed. 


Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
Confidential Information of Eiger BioPharmaceuticals Inc. 
46
The investigator is responsible for the completeness and accuracy of information collected on 
the CRFs for each individual enrolled. The CRFs will be signed and dated by the 
investigator.   
If an entry on a CRF requires change, a single line will be drawn throughout the incorrect 
entry, the correction will be entered, initialed, and dated. White-out, erasures, or obliterations 
on CRFs or on source data are not permitted. 
The sponsor or designee will conduct data processing. Completed CRFs will be reviewed 
carefully for accuracy and completeness. If necessary, the study site will be contacted for 
corrections and/or clarifications. All data will be entered into a study database for analysis 
and reporting. Any data captured electronically (such as laboratory data) will be transferred 
electronically to the database. Upon completion of data entry, the database will receive a 
quality assurance check to ensure acceptable accuracy and completeness. 
13 PUBLICATION POLICY 
The Institution and Investigator shall be permitted to communicate and or/publish data from 
the study in a manner consistent with customary academic standards. However, copies of any 
proposed publication or summaries of any prepared presentation should be submitted to Eiger 
BioPharmaceuticals at least 30 days in advance of the submission of such proposed 
publication or presentation. Eiger BioPharmaceuticals shall have a 30-day period to object to 
the proposed presentation or publication in order to permit Eiger BioPharmaceuticals to 
identify and remove Eiger BioPharmaceuticals confidential information.  
14 PROTOCOL AMENDMENTS AND MODIFICATIONS 
The investigator will ensure that the study is conducted in accordance with the procedures 
and evaluations described in this protocol. The sponsor is responsible for all protocol 
amendments and modifications, except those intended to reduce immediate risk to subjects. 
The sponsor is responsible for submitting protocol amendments to the appropriate 
government regulatory authorities. The investigator is responsible for submitting protocol 
amendments to the appropriate IRB or ethics committee. Approval by the IRB/EC will be 
obtained before changes are implemented. 
 
 


Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
Confidential Information of Eiger BioPharmaceuticals Inc. 
47
15 REFERENCES  
1. Rizzetto M, et al.  Immunoflorescence detection of new antigen-antibody system 
(delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. 
Gut; 1977; 18: 997-1003. 
2. Rizzetto M, et al. Delta agent: association of delta antigen with hepatitis B surface 
antigen and RNA in serum of delta-infected chimpanzees.  Proc. Natl. Acad. Sci. USA; 
1980; 77: 6124- 6128. 
3. Bichko V, et al.  Pathogenesis associated with replication of hepatitis delta virus. Infect 
Agents Dis; 1994; 3: 94. 
4. Bonino F, et al. Hepatitis delta virus: Protein composition of delta antigen and its 
hepatitis B virus-derived envelope.  J Virol; 1986; 58: 945. 
5. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: 
Update and challenges ahead.  Nature Reviews: Gastroenterology and Hepatology; 2010; 
7: 31 – 40. 
6. Makuwa M, et al.  Prevalence and genetic diversity of hepatitis B and delta viruses in 
pregnant women in Gabon: molecular evidence that hepatitis delta virus clade 8 
originates from and is endemic in central Africa.  J. Clin. Microbiol.; 2008; 46: 754 –756. 
7. Rizzetto M.  Hepatitis D: virology, clinical and epidemiological aspects.  Acta 
Gastroenterol. Belg; 2000; 63: 221 – 224. 
8. Fattovich G, et al.  Influence of hepatitis delta virus infection on progression to cirrhosis 
in chronic hepatitis type B.  J. Infect. Dis.; 1987; 155:931 – 935. 
9. Uzunalimoglu O, et al.  Risk factors for hepatocellular carcinoma in Turkey.  Dig. Dis. 
Sci. ; 2001; 46: 1022 – 1028. 
10. Wedemeyer H, et al.  Famciclovir treatment of chronic hepatitis B in heart transplant 
recipients: a prospective trial.  Transplantation; 1999; 68: 1503 – 1511. 
11. Yurdaydin C, et al.  Famciclovir treatment of chronic delta hepatitis.  J. Hepatol.; 2002; 
37(2): 266 – 271. 
12. Lau D, et al.  Lamivudine for chronic delta hepatitis.  Hepatology; 1999; 30: 546 – 549. 
13. Niro GA, et al.  Pegylated interferon alpha-2b as monotherapy or in combination with 
ribavirin in chronic hepatitis delta.  Hepatology; 2006; 44: 713 – 720. 
14. CDC Report; NHANES IV; 2003-2004 
15. Glenn JS, et al.  Identification of a prenylation site in delta virus large antigen.  Science; 
1992; 256: 1331 – 1333. 
16. Otto JC, et al.  The hepatitis delta virus large antigen is farnesylated both in vitro and in 
animal cells.  J. Biol. Chem.; 1996; 271(9): 4567 – 4572. 
17. Bordier BB, et al.  A prenylation inhibitor prevents production of infectious hepatitis 
delta virus particles.  J. Virol.; 2002; 76(20): 10465 – 10472. 
18. Bordier BB, et al.  In vivo antiviral efficacy of prenylation inhibitors against hepatitis 
delta virus.  J. Clin. Invest.; 2003; 112(3): 407 – 414. 
19. SN 96030. Three-month oral (gavage) toxicity study of SCH 66336 in rats. [P-6523]. 
Lafayette (NJ): Schering-Plough Research Institute; 1997 Sep. 


Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
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48
20. SN 96034. A six-month oral (gavage) toxicity and toxicokinetic study of SCH 66336 in 
rats. [S-34851]. Madison (WI): Covance Laboratories Inc.; 2001 Sep. 
21. SN 96612. Three-month oral (gavage) toxicity study of SCH 66336 in cynomolgus 
monkeys. [P-6524]. Lafayette (NJ): Schering-Plough Research Institute; 1997 Sep. 
22. SN 96036. A 52-week oral (gavage) toxicity and toxicokinetic study of SCH 66336 in 
cynomolgus monkeys. [S-34972]. Madison (WI): Covance Laboratories Inc.; 2001 Sep. 
23. SN 96046. Embryo-fetal developmental toxicity and toxicokinetic study of SCH 66336 
administered orally by gavage in rabbits. Lafayette (NJ): Schering-Plough Research 
Institute; 2003 Dec. 
24. SN 02196. SCH 66336: Pharmacokinetics of SCH 66336 following a single oral and 
intravenous dose to male and female cynomolgus monkeys. Worcester (MA): Charles 
River Laboratories. 
25. SN 96558. SCH 66336: Tissue distribution and material balance of 14C-SCH 66336 
following a single oral dose to male and female pigmented rats. [S-37132]. Madison 
(WI): Covance Laboratories Inc.; 2001 Mar. 
26. SN 00039. SCH 66336: Pilot monkey whole body autoradiography study following 
administration of a single oral dose of 14C-SCH 66336 suspension. [S-35100]. 
Kenilworth (NJ): Schering-Plough Research Institute; 2000 Nov. 
27. SN 98139. SCH 66336: In vitro binding of SCH 66336 to rat, monkey, and human 
plasma proteins using ultrafiltration. [S-34263]. Kenilworth (NJ): Schering-Plough 
Research Institute; 2000 Oct. 
28. SN 98276. SCH 66336: In vitro binding of 3H-SCH 66336 to purified human serum 
proteins. Kenilworth (NJ): Schering-Plough Research Institute; 2003 Jan. 
29. SN 98277. SCH 66336: Identification of human liver cytochrome P450 enzymes 
responsible for the metabolism of SCH 66336. [S-35262]. Kenilworth (NJ): Schering-
Plough Research Institute; 2000 Dec. 
30. SN 99118. SCH 66336: In vitro metabolism of SCH 66336 by mouse, rat, monkey and 
human. [S-39037]. Kenilworth (NJ): Schering-Plough Research Institute; 2001 Sep. 
31. SN 01080. SCH 66336: In vitro incubation of SCH 66336 with recombinant CYP3A4 
enzymes and/or microsomes for identification of metabolites. Kenilworth (NJ): Schering-
Plough Research Institute; 2003 Jun. 
32. SN 02596. SCH 66336: Scale-up production of major oxidative metabolites generated 
following CYP3A4-catalyzed reactions. Kenilworth (NJ): Schering-Plough Research 
Institute; 2004 Feb. 
33. SN 98257. SCH 66336: Pilot metabolite profiling and excretion study in Sprague Dawley 
rats following administration of a single oral dose of 14C-SCH 66336 suspension. [S-
35708]. Kenilworth (NJ): Schering-Plough Research Institute; 2001 Oct. 
34. SN 98258. SCH 66336: Pilot monkey metabolite profiling following administration of a 
single oral dose of 14C-SCH 66336 suspension. [S-39414]. Kenilworth (NJ): Schering 
Plough Research Institute; 2001 Oct. 
35. SN 96557. Absorption, metabolism, and excretion of 14C-SCH 66336 following a single 
oral or intravenous dose to male and female rats. Madison (WI): Covance Laboratories, 
Inc. 


Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
Confidential Information of Eiger BioPharmaceuticals Inc. 
49
36. SN 96559. SCH 66336: Absorption, metabolism, and excretion of [14C]-SCH 66336 
following a single oral or intravenous dose to male and female cynomolgus monkeys. 
Kenilworth (NJ): Schering-Plough Research Institute. 
37. Clin Doc 24140280. SCH 66336: The absorption, metabolism, and excretion of 14C-SCH 
66336 following oral administration of 14C-SCH 66336 in healthy volunteers (study 
report for protocol P00260). Kenilworth (NJ): Schering-Plough Research Institute; 2002 
Sep. 
38. P00394. A Phase I study to determine the safety, tolerance, and pharmacokinetics of SCH 
66336 administered in fasting patients with a solid tumor on twice daily oral schedule for  
days. Kenilworth (NJ): Schering-Plough Research Institute; in progress. 
39. SN 97428. SCH 66336: Biliary excretion and enterohepatic circulation of radioactivity 
following a single oral administration of 14C-SCH 66336 suspension to male and 
femalerats. [P-6967]. Kenilworth (NJ): Schering-Plough Research Institute; 2000 Dec. 
40. SN 96533. SCH 66336: Stability of radiolabel following administration of a single oral 
dose of 14C-SCH 66336 to male rats. [S-35705]. Kenilworth (NJ): Schering-Plough 
Research Institute; 2000 Dec. 
41. SN 96638. SCH 66336: Evaluation of SCH 66336 as an inhibitor of human cytochrome 
P-450 3A4. [S-31402]. Lafayette (NJ): Schering-Plough Research Institute; 1999 Dec. 
42. SN 00030. SCH 66336: Characterization of the inhibition spectra of SCH 66336 for five 
human cytochrome P-450 enzymes. [S-34827]. Lafayette (NJ): Schering-Plough 
Research Institute; 2000 Oct. 
43. SN 99074. SCH 66336: Inhibition of the MDR1 mediated transport of the substrate 
rhodamine 123 by SCH 66336. [S-31769]. Lafayette (NJ): Schering-Plough Research 
Institute; 2000 May. 
44. SN 99089. SCH 66336: Inhibition of MDR1 mediated transport of the substrate 
daunorubicin by SCH 66336. [S-35872]. Lafayette (NJ): Schering-Plough Research 
Institute; 2000 Dec. 
45. SN 99075. SCH 66336: Evaluation of SCH 66336 as a substrate for the multidrug 
resistance transporter enzyme MDR1 via ATP hydrolysis assay. [S-35871]. Lafayette 
(NJ): Schering-Plough Research Institute; 2000 Dec. 
46. Clin Doc 1760976. Phase I study to determine the safety of SCH 66336 in patients with a 
solid tumor on twice daily oral schedule for 28 days (study report for protocol I97-211). 
Kenilworth (NJ): Schering-Plough Research Institute; 2001 Aug. 
47. Clin Doc 1715018. SCH 66336: A Phase I study of cyclic two-week oral administration 
of SCH 66336 in patients with advanced cancer (study report for protocol C97-262). 
Kenilworth (NJ): Schering-Plough Research Institute; 2001 Sep. 
48. Clin Doc 1544890. SCH 66336: A Phase I study of cyclic one-week oral administration    
of SCH 66336 in patients with advanced cancer (study report for protocol C97-258). 
Kenilworth (NJ): Schering-Plough Research Institute; 2001 Jun. 


Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
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50
APPENDIX A:  
SCHEDULE OF ASSESSMENTS  
EVENT 
Screening 
Day 
1 
Day 
2 
Day 
3 
Day 
7 
Day 
14 
Day 
28 
Treat 
wk 8 
Treat wk 
12-48 
Follow wk 4 
visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9-18 
19 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Comprehensive physical exam 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
 
 
 
 
 
Height 
X 
X 
 
 
 
 
 
 
 
 
BMI calculation 
X 
X 
 
 
 
 
 
 
 
 
Brief physical exam 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 lead ECG pre/post-dose1 
X 
X 
X 
 
 
 
X 
 
 
X 
Liver biopsy (if needed)2 
X 
 
 
 
 
 
 
 
 
 
Complete blood count 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Chemistry panel 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Thyroid function 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum)  
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine) 
 
X 
 
 
 
 
 
 
 
X 
HBV DNA, HDV RNA 
X 
HDV 
RNA 
HDV 
RNA 
HDV 
RNA 
HDV 
RNA 
HDV 
RNA 
HDV 
RNA 
HDV 
RNA 
HDV 
RNA 
HDV RNA 
Viral mutation analysis3 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
HIV serology 
X 
 
 
 
 
 
 
 
 
 
Urinalysis (pre-dose) 
X 
 
 
X 
X 
 
X 
X 
X 
X 
Urine drug screen4 
X 
 
 
 
 
 
 
 
 
 
PBMC Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCV viral load (quant PCR) 
X 
 
 
 
 
 
 
 
 
 
PK sampling (pre-/post-dose)5 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
INR 
X 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
X 
 
 
X 
 
 
 
 
 
Dispense study drug 
 
X 
 
 
X 
 
X 
X 
X 
 
Study drug accountability 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 


 
Protocol No EIG-300 
 
 
 
 
 
 
 
 
 
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Page 51 
Schedule of Assessments Footnotes 
 
1 = Serial ECG (x3) 2 -3 minutes apart 
2 = See Appendix 4 for CTP scoring and encephalopathy results 
3 = Serum and plasma samples for viral mutation analysis, resistance phenotyping and analysis of drug 
    mechanism and treatment response 
4 = Urine drug screen for opiates, amphetamines, barbiturates, benzodiazapenes, cocaine 
5= Timepoints for optional PK sampling pre-dose (0), 15 min, 30 min, 60 min, 90 min, 2h, 2.5h, 3h, 4h, ,6 
    h, 10h, 12h 
 
 
 
 
 
 
 
 
 
 


Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
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52
APPENDIX B:  
BODY MASS INDEX TABLE (METRIC), FORMULA AND CALCULATOR 
BMI TABLE 
BMI 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
Height 
cms (metres) 
Body Weight 
(kilograms) 
147cm (1.47m)  
41 
44 
45 
48 
50 
52 
54 
56 
59 
61 
63 
65 
67 
69 
72 
73 
76 
150cm (1.50m)  
43 
45 
47 
49 
52 
54 
56 
58 
60 
63 
65 
67 
69 
72 
74 
76 
78 
152cm (1.52m) 
44 
46 
49 
51 
54 
56 
58 
60 
63 
65 
67 
69 
72 
74 
76 
79 
81 
155cm (1.55m) 
45 
48 
50 
53 
55 
57 
60 
62 
65 
67 
69 
72 
74 
77 
79 
82 
84 
157cm (1.57m)  
47 
49 
52 
54 
57 
59 
62 
64 
67 
69 
72 
74 
77 
79 
82 
84 
87 
160cm (1.60m)  
49 
51 
54 
56 
59 
61 
64 
66 
69 
72 
74 
77 
79 
82 
84 
87 
89 
163cm (1.63m) 
50 
53 
55 
58 
61 
64 
66 
68 
71 
74 
77 
79 
82 
84 
87 
89 
93 
165cm (1.65m)  
52 
54 
57 
60 
63 
65 
68 
71 
73 
76 
79 
82 
84 
87 
90 
93 
95 
168cm (1.68m) 
54 
56 
59 
62 
64 
67 
70 
73 
76 
78 
81 
84 
87 
90 
93 
95 
98 
170cm (1.70m) 
55 
57 
61 
64 
66 
69 
72 
75 
78 
81 
84 
87 
90 
93 
96 
98 
101 
172cm (1.72m)  
57 
59 
63 
65 
68 
72 
74 
78 
80 
83 
86 
89 
92 
95 
98 
101 
104 
175cm (1.75m) 
58 
61 
64 
68 
70 
73 
77 
80 
83 
86 
89 
92 
95 
98 
101 
104 
107 
178cm (1.78m) 
60 
63 
66 
69 
73 
76 
79 
82 
85 
88 
92 
95 
98 
101 104 
107 
110 
180cm (1.80m)  
62 
65 
68 
71 
75 
78 
81 
84 
88 
91 
94 
98 
101 
104 107 
110 
113 
183cm (1.83m)  
64 
67 
70 
73 
77 
80 
83 
87 
90 
93 
97 
100 
103 
107 110 
113 
117 
185cm (1.85m)  
65 
68 
72 
75 
79 
83 
86 
89 
93 
96 
99 
103 
107 
110 113 
117 
120 
188cm (1.88m)  
67 
70 
74 
78 
81 
84 
88 
92 
95 
99 
102 
106 
109 
113 116 
120 
123 
191cm (1.91m)  
69 
73 
76 
80 
83 
87 
91 
94 
98 
102 
105 
109 
112 
116 120 
123 
127 
193cm (1.93m)  
71 
74 
78 
82 
86 
89 
93 
97 
100 
104 
108 
112 
115 
119 123 
127 
130 
BMI 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
 


 
Protocol No EIG-300 
 
 
 
 
 
 
 
 
 
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Page 53 
 
Use this BMI chart to calculate your Body Mass Index (BMI). 
 
 
First select your height then select your weight. 
 
Select the nearest value/s to your own if they are not displayed in the chart. 
 
Your BMI will be listed at the top and bottom of the BMI chart. 
 
Source: http://www.whathealth.com/bmi/chart-metric2.html 
 
BMI FORMULA 
 
BMI =  
            Weight in Kilograms              
(Height in centimeters) x (Height in centimeters)  
 
For example a person who weighs 110 kgs and is 190.5 cm tall has a BMI of 30.3. 
 
 
 
 
 
 
 
 
 
 
 
 
110 kgs  
 
 
= 30.3 
 
 
 
 
 
 
 
 
 
 
(190.5 cm) x (190.5 cm)   
BMI CALCULATOR 
For additional information, including a BMI Calculator, please consult  
www.whathealth.com/bmi/chart-metric.html 
 


Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
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54
APPENDIX C: DECLARATION OF HELSINKI 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
 
And amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A: INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other participants in medical 
research involving human subjects.  Medical research involving human subjects includes 
research on identifiable human material or identifiable data. 
 
2. It is the duty of the physician to promote and safeguard the health of the people.  The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
 
3. The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the patient's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the patient." 
 
4. Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
 
5. In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
 
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the 
aetiology and pathogenesis of disease.  Even the best proven prophylactic, diagnostic, 
and therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 


 
Protocol No EIG-300 
 
 
 
 
 
 
 
 
 
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Page 55 
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
 
8. Medical research is subject to ethical standards that promote respect for all human beings 
and protect their health and rights.  Some research populations are vulnerable and need 
special protection.  The particular needs of the economically and medically 
disadvantaged must be recognized.  Special attention is also required for those who 
cannot give or refuse consent for themselves, for those who may be subject to giving 
consent under duress, for those who will not benefit personally from the research and for 
those for whom the research is combined with care. 
 
9. Research Investigators should be aware of the ethical, legal and regulatory requirements 
for research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration. 
 
B: BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
 
10. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
 
11. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation. 
 
12. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
 
13. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol.  This protocol should be  
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
investigator, the sponsor or any other kind of undue influence.  This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed.  The committee has the right to monitor ongoing 
trials.  The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events.  The researcher should also submit to 
the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 


Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
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56
14. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration. 
15. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. The 
responsibility for the human subject must always rest with a medically qualified person 
and never rest on the subject of the research, even though the subject has given consent.  
 
16. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to 
the subject or to others.  This does not preclude the participation of healthy volunteers in 
medical research.  The design of all studies should be publicly available. 
 
17. Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and can 
be satisfactorily managed.  Physicians should cease any investigation if the risks are 
found to outweigh the potential benefits or if there is conclusive proof of positive and 
beneficial results. 
 
18. Medical research involving human subjects should only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the subject.  This is 
especially important when the human subjects are healthy volunteers. 
 
19. Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research. 
 
20. The subjects must be volunteers and informed participants in the research project. 
 
21. The right of research subjects to safeguard their integrity must always be respected.  
Every precaution should be taken to respect the privacy of the subject, the confidentiality 
of the patient's information and to minimize the impact of the study on the subject's 
physical and mental integrity and on the personality of the subject. 
 
22. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail.  The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal.  After ensuring that the subject has understood the information, the physician  
should then obtain the subject's freely-given informed consent, preferably in writing.  If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
 
23. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or 
may consent under duress.  In that case the informed consent should be obtained by a 


 
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well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
24. For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law. 
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
 
25. When a subject deemed legally incompetent, such as a minor child, is able to give assent 
to decisions about participation in research, the investigator must obtain that assent in 
addition to the consent of the legally authorized representative. 
 
26. Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population.  The 
specific reasons for involving research subjects with a condition that renders them unable 
to give informed consent should be stated in the experimental protocol for consideration 
and approval of the review committee.  The protocol should state that consent to remain 
in the research should be obtained as soon as possible from the individual or a legally 
authorized surrogate. 
 
27. Both authors and publishers have ethical obligations.  In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results.  Negative as 
well as positive results should be published or otherwise publicly available.  Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared 
in the publication.  Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication. 
 
C. ADDITIONAL PRICIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
 
28. The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value.  
When medical research is combined with medical care, additional standards apply to 
protect the patients who are research subjects. 
 
29. The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic and therapeutic methods.  This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists. 
 
30. At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by 
the study.   


Protocol No. EIG-300-Amendment 3 dated May 10, 2016 
  
 
 
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58
 
31. The physician should fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship. 
 
32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic 
measures, if in the physician’s judgement it offers hope of saving life, re-establishing 
health or alleviating suffering. Where possible, these measures should be made the object 
of research, designed to evaluate their safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, published. The other relevant guidelines of 
this Declaration should be followed. The physician should fully inform the patient which 
aspects of the care are related to the research. The refusal of a patient to participate in a 
study must never interfere with the patient-physician relationship. 
 
 


 
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APPENDIX D: HEPATIC ASSESSMENTS 
 
The Child-Turcotte-Pugh (CTP) Score 
The score employs five clinical measures of liver disease. Each measure is scored 1-3, with 3 
indicating most severe derangement. Subjects with a total CTP score of 6 or higher are NOT 
eligible to participate in this study. 
 
Measure 
1 point 
2 points 
3 points 
units 
Bilirubin (total) <34 (<2) 
34-50 (2-3) 
>50 (>3) 
μmol/l (mg/dL) 
Serum albumin >35 
28-35 
<28 
mg/L 
INR 
<1.7 
1.71-2.20 
> 2.20 
no unit 
Ascites 
None 
Suppressed with 
medication 
Refractory 
no unit 
Hepatic 
encephalopathy None 
Grade I-II (or 
suppressed with 
medication) 
Grade III-IV (or 
refractory) 
no unit 
http://www.doctorslounge.com/gastroenterology/scores/child.htm 
 
Assessment for Hepatic Encephalopathy 
Subjects with assessments of stage 1-4 are NOT eligible to participate in this study. 
 
West Haven Criteria of Altered Mental Status In Hepatic Encephalopathy 
Stage 
Consciousness 
Intellect and Behavior 
Neurologic Findings 
0 
Normal 
Normal 
Normal examination;  
impaired psychomotor testing 
1 
Mild lack of  
awareness 
Shortened attention span; 
impaired addition or subtraction 
Mild asterixis or 
tremor 
2 
Lethargic 
Disoriented;  
inappropriate behavior 
Obvious asterixis; 
slurred speech 
3 
Somnolent but  
arousable 
Gross disorientation;  
bizarre behavior 
Muscular rigidity and clonus;  
Hyperreflexia 
4 
Coma 
Coma 
Decerebrate posturing 
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/gastro/henceph/table2.htm