Clinical trial NCT02527707
Conditions: Chronic Delta Hepatitis
Sponsor: Eiger BioPharmaceuticals
Start date: 2015-09-01; Completion date: 2017-02-09
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A phase 2, open-label study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of titrating-dose lonafarnib/ritonavir in patients chronically infected with hepatitis delta virus (HDV)

Detailed description:
This is a Phase 2 study of 24 weeks of treatment with a dose-titration regimen of lonafarnib/ritonavir in up to 15 patients chronically infected with HDV: lonafarnib starting at 50 mg twice daily (BID) in combination with ritonavir 100 mg BID and escalating lonafarnib as tolerated.

The duration of the study for each patient is approximately 13 months (up to 4 weeks for screening, 24 weeks of treatment, 4 weeks for the primary follow-up visit, and monthly safety follow-up visits for 5 months thereafter). The 6-month follow-up after the last dose of study drug is designed to allow evaluation of the clinical and virologic course after completion of the 24-week Treatment Period.

Arms: arm 1: Lonafarnib starting at 50 mg BID in combination with ritonavir 100 mg BID and escalating to lonafarnib 75 mg BID and then 100 mg BID as tolerated. The duration of the study for each patient is 6 months of treatment and 6 months follow-up.
Interventions: intervention 1: lonafarnib intervention 2: Ritonavir
Intervention descriptions: intervention 1: antiviral farnesyltransferase inhibitor intervention 2: Cytochromes P450 3A4 inhibitor used to boost lonafarnib

Protocol documents:
Prot_000.pdf: 
Eiger BioPharmaceuticals  |  Confidential and Proprietary  |  Page 1 
CLINICAL STUDY PROTOCOL EIG-LNF-002 
Protocol Title 
A Phase 2, Open-Label Study of the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamic Activity of Titrating-
Dose Lonafarnib in Combination with Ritonavir in Patients 
Chronically Infected with Hepatitis Delta Virus (LOWR-4) 
EudraCT Number 
2015-003077-15 
IND Number 
110,877 
Test Products 
Lonafarnib (also Sarasar, EBP994, SCH 66336) 
Ritonavir (Norvir) 
Sponsor Medical 
Monitor 
Jon Ruckle, MD, CPI 
Principal, Pacific Pharma Group, LLC 
1402 S. Brookside Terrace 
Tacoma, WA 98465-1210 
Clinical Program 
Manager 
Eduardo Martins, MD, DPhil 
SVP, Liver and Infectious Diseases 
Eiger BioPharmaceuticals 
Sponsor 
Eiger BioPharmaceuticals 
350 Cambridge Avenue, Suite 350 
Palo Alto, CA  94306  
USA  
Version 
Amendment 3 
Date Final 
22  December 2015 
CONFIDENTIALITY STATEMENT 
This clinical study is being sponsored by Eiger BioPharmaceuticals, Inc (Eiger Bio). The information contained 
in this document, especially any unpublished data, is the property of Eiger Bio and therefore is provided to you 
in confidence as an Investigator, potential Investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information will not be 
disclosed to others without written authorization from Eiger Bio except to the extent necessary to obtain 
informed consent from persons to whom the drug may be administered.  




Protocol EIG-LNF-002 
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INVESTIGATOR SIGNATURE PAGE 
Protocol Title 
A Phase 2, Open-Label Study of the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamic Activity of Titrating-
Dose Lonafarnib in Combination with Ritonavir in Patients 
Chronically Infected with Hepatitis Delta Virus (LOWR-4) 
Protocol Number 
EIG-LNF-002 
Version 
Amendment 3  
Date Final 
22 December 2015 
 
INVESTIGATOR AGREEMENT 
By my signature below, I attest to the following:  
1. I have received and reviewed the Investigator’s Brochure for lonafarnib provided to me by 
Eiger BioPharmaceuticals or designee.  
2. I have read the attached protocol and the product labeling information for ritonavir.  
3. I agree to conduct the study as outlined in the protocol and in accordance with all 
applicable regulations and guidelines, including the Declaration of Helsinki (version as 
currently endorsed by the European Medicines Evaluation Agency and the United States 
Food and Drug Administration [FDA]); the principles of Good Clinical Practice (GCP) as 
described in the United States Code of Federal Regulations (CFR) – 21 CFR parts 50, 54, 
56, and 312; EU Directive 2005/28/EC; and the ICH document “Guideline for Good 
Clinical Practice, E6 (R1)” dated 10 June 1996. Further, I will conduct the study in 
keeping with local legal and regulatory requirements. 
4. I will initiate this study only with written and dated approval from the appropriate 
Independent Ethics Committee (IEC). I understand that any changes in the protocol must 
be approved in writing by the Sponsor, the IEC, and, in certain cases the FDA or other 
applicable regulatory agencies, before they can be implemented, except where necessary 
to eliminate hazards to patients in compliance with Directive 2001/20/EC. 
5. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
Signed:   
 
 
  
Signature 
 
 Date 
 
Name 
 Institution 


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CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................... 2 
INVESTIGATOR SIGNATURE PAGE ........................................................................................ 3 
PROTOCOL SYNOPSIS ............................................................................................................. 10 
ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................................. 22 
1 
INTRODUCTION AND BACKGROUND ........................................................................ 24 
1.1 Nonclinical Data .................................................................................................................. 24 
1.2 Clinical Data ........................................................................................................................ 25 
1.2.1 Clinical Pharmacokinetics ....................................................................................... 26 
1.2.2 Clinical Efficacy/Pharmacodynamics ...................................................................... 27 
1.2.2.1 Study 12-DK-0016 ............................................................................................. 27 
1.2.2.2 Study EIG-300/LOWR-1 ................................................................................... 28 
1.2.3 Clinical Safety .......................................................................................................... 30 
1.2.3.1 Study 12-DK-0016 ............................................................................................. 30 
1.2.3.2 Study EIG-300/LOWR-1 ................................................................................... 31 
1.3 Potential Risks and Benefits to Human Patients in This Study ........................................... 31 
1.4 Rationale for the Study ........................................................................................................ 32 
2 
STUDY OBJECTIVES ........................................................................................................ 33 
3 
INVESTIGATIONAL PLAN .............................................................................................. 34 
3.1 Overall Study Design ........................................................................................................... 34 
3.2 Rationale for Study Design .................................................................................................. 34 
3.3 Rationale for Use of Lonafarnib in Combination with Ritonavir in HDV .......................... 35 
3.4 Selection of Study Population .............................................................................................. 36 
3.4.1 
Inclusion Criteria ..................................................................................................... 36 
3.4.2 Exclusion Criteria .................................................................................................... 37 
3.4.3 Replacement of Patients in Study ............................................................................ 40 
3.4.4 Early Discontinuation of Study Treatment .............................................................. 40 
3.4.5 Early Withdrawal from Study .................................................................................. 40 
3.4.6 Study Termination by the Sponsor .......................................................................... 40 
3.5 
Investigational Products ....................................................................................................... 41 
3.5.1 Product Identity and Storage .................................................................................... 41 
3.5.2 Study Treatment Distribution .................................................................................. 41 
3.6 Dosage and Titration ............................................................................................................ 41 


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3.6.1 Dosage...................................................................................................................... 41 
3.6.2 Dose Titration .......................................................................................................... 42 
3.6.2.1 Dose Levels ........................................................................................................ 42 
3.6.2.2 Evaluation of Tolerability .................................................................................. 45 
3.6.2.3 Management of Flares........................................................................................ 47 
3.6.3 Missed Doses ........................................................................................................... 48 
3.7 Treatment Adherence and Product Accountability .............................................................. 48 
3.8 Prior and Concomitant Therapies ........................................................................................ 48 
3.8.1 Prior Therapies ......................................................................................................... 48 
3.8.2 Concomitant Therapies During the Treatment Period ............................................. 48 
3.8.2.1 Treatment of Gastrointestinal Symptoms .......................................................... 48 
3.8.2.2 Prohibited Medications ...................................................................................... 49 
3.8.2.3 Medications to be Used with Caution ................................................................ 51 
3.8.2.4 Contraception ..................................................................................................... 52 
3.8.3 Permitted Therapies During the Follow-up Period .................................................. 53 
3.8.4 Randomization and Blinding ................................................................................... 53 
4 
STUDY ASSESSMENTS AND PROCEDURES ............................................................... 54 
4.1 Description of Assessments ................................................................................................. 54 
4.1.1 History, Physical Examination, and Vital Signs ...................................................... 54 
4.1.2 Ophthalmic Examination and Retinal Photography ................................................ 54 
4.1.3 
Liver Biopsy and Fibroscan ..................................................................................... 55 
4.1.4 Electrocardiograms .................................................................................................. 55 
4.1.5 Molecular and Serologic Tests................................................................................. 55 
4.1.6 Pharmacokinetic Sampling ...................................................................................... 56 
4.1.6.1 Pharmacokinetic Sampling Time Points ............................................................ 56 
4.1.6.2 Pharmacokinetic Sample Labeling and Shipping .............................................. 56 
4.1.6.3 Pharmacokinetic Analytical Methods ................................................................ 57 
4.1.7 Routine Clinical Laboratory Tests ........................................................................... 57 
4.1.8 Total Blood Sampling Volume ................................................................................ 58 
4.1.9 Appropriateness of Assessments.............................................................................. 59 
4.2 Description of Study Procedures by Study Visit ................................................................. 59 
4.2.1 Screening Visit(s) (Weeks –4 to –1) ........................................................................ 60 
4.2.2 Treatment Visit – Week 0, Day 1 (±2 Days) ........................................................... 61 
4.2.3 Treatment Visit – Week 1, Day 8 (±2 Days) ........................................................... 61 


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4.2.4 Treatment Visit – Week 2, Day 15 (±2 Days) ......................................................... 63 
4.2.5 Treatment Visits – Weeks 4 and 6, Days 29 and 43 (±2 Days) ............................... 63 
4.2.6 Treatment Visits – Weeks 8, 12, and 16; Days 57, 85, and 113 (±5 Days): 
PK Sampling ............................................................................................................ 64 
4.2.7 Treatment Visit – Week 20; Day 141 (±5 Days) ..................................................... 65 
4.2.8 Treatment Visit – Week 24, Day 169 (±5 Days): End of Treatment Period ........... 65 
4.2.9 Follow-up Visit – Week 28, Day 197 (±5 Days) ..................................................... 66 
4.2.10 Follow-up Visits – Weeks 32, 36, 40, 44, and 48; Days 225, 253, 281, 309, and 337 
(±5 Days) ................................................................................................................. 66 
4.2.11 Unscheduled Visits .................................................................................................. 67 
4.2.12 Early Termination Visit ........................................................................................... 67 
5 
STATISTICAL CONSIDERATIONS................................................................................. 69 
5.1 Analysis Objectives and Endpoints ..................................................................................... 69 
5.2 Determination of Sample Size ............................................................................................. 69 
5.3 Analysis Populations ............................................................................................................ 69 
5.4 Hypothesis Testing............................................................................................................... 69 
5.5 Analysis Plan ....................................................................................................................... 69 
5.5.1 Demographic and Baseline Data .............................................................................. 69 
5.5.2 Safety Analyses ........................................................................................................ 70 
5.5.3 Pharmacodynamics/Efficacy.................................................................................... 71 
5.5.4 Pharmacokinetics ..................................................................................................... 71 
5.5.5 Viral Resistance Analysis ........................................................................................ 72 
6 
SAFETY EVENTS DOCUMENTATION AND REPORTING ......................................... 73 
6.1 
Investigator’s Responsibilities ............................................................................................. 73 
6.2 Monitoring Safety Data During Study ................................................................................. 73 
6.3 Definitions of Types of Adverse Events .............................................................................. 73 
6.3.1 Adverse Events ........................................................................................................ 73 
6.3.2 Suspected Adverse Reactions .................................................................................. 73 
6.3.3 
Life-Threatening Adverse Events ............................................................................ 73 
6.3.4 Serious Adverse Events ........................................................................................... 74 
6.3.5 Unexpected Adverse Event ...................................................................................... 74 
6.4 Adverse Event Classification ............................................................................................... 75 
6.4.1 Severity Grades of Adverse Events and Serious Adverse Events ........................... 75 
6.4.2 Relationship of Adverse Event to Investigational Products .................................... 75 
6.5 Documentation of Adverse Events ...................................................................................... 76 


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6.5.1 Study Drug Action Taken ........................................................................................ 77 
6.5.2 Outcome of Adverse Event ...................................................................................... 77 
6.6 Reporting Serious Adverse Events ...................................................................................... 78 
6.6.1 Reporting to Sponsor ............................................................................................... 78 
6.6.2 Reporting to Regulatory Agencies and Independent Ethics Committee ................. 79 
6.6.3 Emergency Contact .................................................................................................. 79 
6.7 Pregnancy ............................................................................................................................. 79 
6.8 Overdose .............................................................................................................................. 80 
6.8.1 
Lonafarnib Overdose ............................................................................................... 80 
6.8.2 Ritonavir Overdose .................................................................................................. 80 
7 
DATA QUALITY CONTROL AND ASSURANCE ......................................................... 81 
7.1 Overview .............................................................................................................................. 81 
7.2 Study Monitoring ................................................................................................................. 81 
7.3 Data Management ................................................................................................................ 82 
7.4 Quality Assurance Audit ...................................................................................................... 82 
7.5 Data Handling and Recordkeeping ...................................................................................... 82 
7.5.1 Case Report Form Completion ................................................................................ 82 
7.5.2 Data Handling .......................................................................................................... 83 
7.5.3 Study Files and Retention of Study Records ........................................................... 83 
7.6 Drug Accountability............................................................................................................. 83 
8 
ETHICAL AND LEGAL CONSIDERATIONS ................................................................. 84 
8.1 Ethical Conduct and Good Clinical Practice ....................................................................... 84 
8.2 
Independent Ethics Committee ............................................................................................ 84 
8.3 Patient and Data Confidentiality .......................................................................................... 85 
8.4 
Informed Consent................................................................................................................. 85 
8.5 Protocol Amendments .......................................................................................................... 86 
8.6 Delegation of Responsibilities of the Principal Investigator ............................................... 86 
8.7 Coordinating Investigator .................................................................................................... 86 
8.8 Compensation, Insurance, and Indemnity ............................................................................ 87 
8.9 Publication Policy ................................................................................................................ 87 
8.10 Direct Access to Source Data .............................................................................................. 87 
9 
REFERENCES .................................................................................................................... 88 
APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS .................................................. 89 
APPENDIX B 
HEPATIC ASSESSMENTS ........................................................................... 93 


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APPENDIX C 
PROHIBITED CONCOMITANT DRUGS OR DRUGS THAT MAY HAVE 
SIGNIFICANT INTERACTIONS WITH STUDY DRUGS ......................... 93 
APPENDIX D 
SAMPLE PATIENT DIARY—LONAFARNIB/RITONAVIR DOSAGE:  50 
MG BID/100 MG BID .................................................................................. 106 
 
List of Tables 
Table 1 
List of Abbreviations and Acronyms .......................................................................... 22 
Table 2 
Most Frequent Adverse Events in Study 12-DK-0016 ............................................... 30 
Table 3 
Planned Dose Combinations During Study ................................................................ 42 
Table 4 
Grades of Common Expected Adverse Events with Lonafarnib Treatment as Defined 
in the CTCAE (Version 4.03) ..................................................................................... 47 
Table 5 
Drugs Contraindicated with Use of Ritonavir ............................................................ 49 
Table 6 
Serum and Blood Chemistry Laboratory Tests ........................................................... 57 
Table 7 
Blood Sampling Volumes ........................................................................................... 59 
Table 8 
Pharmacokinetic Parameters Derived from Plasma Concentrations for Lonafarnib and 
Ritonavir ..................................................................................................................... 71 
Table 9 
Time Windows for Collection of Pharmacokinetic Samples ...................................... 72 
Table 10 Adverse Event Grades Based on the Common Terminology Criteria for 
Adverse Events ........................................................................................................... 75 
Table 11 Categories for Assessing Relationship of Adverse Events to Investigational Products
..................................................................................................................................... 76 
Table 12 Classifications for Study Drug Action Taken with Regard to an Adverse Event ....... 77 
Table 13 Classifications for Outcome of an Adverse Event ...................................................... 78 
Table 14 Drugs That Are Contraindicated with Use of Ritonavir ............................................. 94 
Table 15 Established and Other Potentially Significant Drug Interactions with Use of Ritonavir
..................................................................................................................................... 97 
 
List of Figures 
Figure 1 
Study 12-DK-0046:  Mean Change in HDV RNA Levels from Baseline During and 
After 4 Weeks of Treatment with Lonafarnib ............................................................. 27 
Figure 2 
Study 12-DK-0016:  Relationship Between Lonafarnib Serum Concentration and 
Change in Log HDV RNA Levels .............................................................................. 28 
Figure 3 
Study EIG-300/LOWR-1:  Change in HDV RNA in Patients at Week 4 .................. 29 


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Figure 4 
Study EIG-300/LOWR-1:  Change in HDV RNA in Patients Treated with Lonafarnib 
and Ritonavir or with Lonafarnib and PEG-IFN-α2a for 8 Weeks ............................. 29 
Figure 5 
Planned Dose-Titration Scheme ................................................................................. 43 
Figure 6 
Dose Down-Titration Scheme..................................................................................... 44 
Figure 7 
Dose Re-Escalation Scheme ....................................................................................... 45 
 


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PROTOCOL SYNOPSIS 
Study Title 
A Phase 2, Open-Label Study of the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamic Activity of Titrating-Dose Lonafarnib in Combination with Ritonavir in 
Patients Chronically Infected with Hepatitis Delta Virus (LOWR-4) 
Sponsor 
Eiger BioPharmaceuticals, Inc. (United States) 
Study Objectives 
The primary objectives of the study are to 
• Evaluate the safety and tolerability of the following dose-titration regimen of 
lonafarnib in combination with ritonavir over the 24-week Treatment Period: 
lonafarnib/ritonavir starting at 50 mg bid/100 mg twice daily (bid) and escalated to 
lonafarnib/ritonavir 75 mg bid/100 mg bid and then to 100 mg bid/100 mg bid as 
tolerated 
• Evaluate the pharmacodynamic activity (change in hepatitis D viral [HDV] load) of 
the dose-titration regimen of lonafarnib in combination with ritonavir over the 
24-week Treatment Period 
 
The secondary objectives of the study are to evaluate the effect of the dose-titration regimen of 
lonafarnib/ritonavir on the following:  
• Pharmacokinetics (PK)  
• Change in alanine aminotransferase (ALT) levels  
• Change in hepatitis B virus (HBV) DNA levels  
 
Exploratory objectives of the study are to evaluate the effects of the dose-titration regimen of 
lonafarnib/ritonavir on immunologic parameters during treatment. 
Study Design 
This is a Phase 2 study of 24 weeks of treatment with a dose-titration regimen of 
lonafarnib/ritonavir in patients chronically infected with HDV: lonafarnib starting at 50 mg bid 
and escalating to 75 mg bid and then 100 mg bid as tolerated in combination with ritonavir 
(100 mg bid). The initial dose of lonafarnib and ritonavir 50 mg bid/100 mg bid will be 
maintained for at least 4 weeks; subsequent dose escalation may occur at an interval of no less 
than 2 weeks after patients have received a particular dose.  
The duration of the study for each patient is approximately 52 weeks (up to 4 weeks for 
screening, 24 weeks of treatment, 4 weeks for the primary follow-up visit, and every 4 weeks 
safety follow-up visits for 20 weeks thereafter). The 24-week follow-up after the last dose of 
study drug is designed to allow evaluation of the clinical and virologic course after completion of 
the 24-week Treatment Period. 


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Study Population and Number of Patients 
Approximately15 patients with chronic HDV infection with detectable HDV RNA by 
quantitative polymerase chain reaction (qPCR) will be enrolled. Patients who discontinue the 
study before Week 12 for reasons other than an adverse event (AE) may be replaced on approval 
of the Sponsor. 
Eligibility Criteria 
Inclusion Criteria 
A patient may be included in this study if he or she meets all of the following criteria: 
1. Willing and able to comply with study procedures and provide written informed consent. 
2. Male or female, 18 to 65 years of age, inclusive. 
3. Has a body mass index (BMI) of ≥18 kg/m2 and has a body weight of ≥45 kg. 
4. Chronic HDV infection documented by a positive HDV antibody (Ab) test of at least 
6 months duration and detectable HDV RNA by qPCR at study entry. 
5. Liver biopsy demonstrating evidence of chronic hepatitis. 
If no liver biopsy is available, the patient must be willing to consent to and have no 
contraindication to liver biopsy. Liver biopsy will be performed during screening.  
6. ALT <10x ULN 
7. Electrocardiogram (ECG) demonstrating no acute ischemia or clinically significant 
abnormality and a QT interval corrected for heart rate (QTc) of <450 ms using Fridericia 
correction (ICH Guidance for Industry E14: Clinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs). 
8. Females who meet the following criteria may be eligible to enter the study:  
a. Of nonchildbearing potential—defined as women who are surgically sterile (have had 
bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), have medically 
documented ovarian failure, or are postmenopausal (amenorrheic for more than 
2 years, age appropriate, and confirmed by follicle-stimulating hormone [FSH] level 
indicating a postmenopausal state).  
b. Of childbearing potential—defined as women who have an intact uterus and ovaries 
and are within 1 year since the last menstrual period who 
– Are not pregnant and have negative serum pregnancy test at screening and a 
negative urine pregnancy test on the Baseline/Day 1 Visit before randomization. 
– Are not lactating or breastfeeding. 
– Agree to use two of the following contraceptive methods until at least 90 days 
after last dose of study drug, of which at least one must be a barrier method:  
 Hormonal contraceptives for at least 3 months before the start of screening 
and for at least 90 days after last dose of study drug  
 Intrauterine device (IUD) in place for at least 3 months before the start of 
screening and until at least 90 days after last dose of study drug. 


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 Double-barrier methods (use of condom [male partner] with either diaphragm 
with spermicide or cervical cap with spermicide) from the start of screening 
until at least 90 days after last dose of study drug. 
 Surgical sterilization of the partner (vasectomy for 1 month before the start of 
screening and, throughout study and for at least 90 days after last dose of 
study drug). 
9. Males with female partners who are of childbearing potential (see above) who meet the 
following criteria may be eligible to enter the study: 
a. Are surgically sterile  
or 
b. Agree to practice two effective forms of birth control from those listed below from 
the start of screening until at least 90 days after their last dose of study drug, at least 
one of which must be a barrier method: 
– Consistently and correctly use a condom 
and 
– Their partner must agree to use a hormonal contraceptive or a nonhormonal 
barrier method (IUD or diaphragm with spermicide or cervical cap with 
spermicide). 
Exclusion Criteria 
A patient will be excluded from this study if he or she meets any of the following criteria: 
     General Criteria 
1. Participation in a clinical trial with or use of any investigational agent within 30 days of 
start of screening. 
2. Pregnant or lactating/breastfeeding. 
3. Previous use of lonafarnib. 
Patients who previously participated in a clinical trial of lonafarnib but are confirmed to 
have received placebo are allowed. 
     Disease-related Criteria 
4. Co-infected with human immunodeficiency virus (HIV) or active infection with hepatitis 
C virus (HCV). 
5. Positive results for HIV or HCV Ab at screening. Patients with a positive HCV Ab at 
screening are allowed if they have completed a curative antiviral regimen and are 
documented to be HCV RNA negative (undetectable) at least 3 months before screening 
and at screening. 
6. Active jaundice defined by total bilirubin level >2.0 mg/dL and known not to have 
Gilbert’s disease. 
7. A CPT score of >6 based on screening laboratory results. 
8. Decompensated liver disease or cirrhosis as defined by the presence of any of the 
following on screening laboratory tests: 
a. Bilirubin level >2.0 mg/dL 


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b. Albumin level <3.0 g/dL
c.
Platelet count <90,000 cells/mm3
d. International normalized ratio (INR) ≥1.5
9. History of bleeding esophageal varices, ascites, or hepatic encephalopathy.
10. Patients with any of the following abnormal laboratory test results at screening:
a.
White blood cell (WBC) count <3,000 cells/mm3
b.
Absolute neutrophil count (ANC) <1500 cells/mm3
c.
Hemoglobin <11 g/dL for women and <12 g/dL for men
d.
Abnormal thyroid-stimulating hormone (TSH), T4, or T3 levels; unless the patient is 
stable on thyroid hormone replacement therapy
11. Significant renal dysfunction, defined as serum creatinine concentration ≥1.5 times the 
ULN or an estimated glomerular filtration rate (eGFR) < 80 mL/min at screening, based 
on the Cockcroft-Gault equation
12. Evidence of another form of viral hepatitis (not including HBV or HCV) or another form 
of liver disease (e.g.,  autoimmune liver disease, primary biliary cirrhosis, primary 
sclerosing cholangitis, Wilson’s disease, alcoholic liver disease, nonalcoholic 
steatohepatitis, hemochromatosis, alpha-1-anti-trypsin deficiency)
13. Evidence of hepatocellular carcinoma
14. Patients with any one of the following:
a.
An eating disorder or alcohol abuse within the past 2 years
b.
Excessive alcohol intake defined as follows:  >20 g/day for females (1.5 standard 
alcohol drinks) or >30 g/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)
15. In the opinion of the Investigator, an alcohol use pattern that will interfere with study 
conduct
16. Drug abuse within the previous 6 months before the screening visit with the exception of 
medically prescribed cannabinoids and their derivatives
17. History or clinical evidence of any of the following:
a.
Immunologically mediated disease (eg, rheumatoid arthritis, inflammatory bowel 
disease, severe psoriasis, systemic lupus erythematosus) that requires more than 
intermittent nonsteroidal anti-inflammatory medications for management or that 
requires use of systemic corticosteroids in prior 6 months (eg, inhaled asthma 
medications are allowed)
b.
History of or evidence of retinal disorder or clinically relevant ophthalmic disorder.
c.
Any malignancy within 5 years of the start of screening. Exceptions are superficial 
dermatologic malignancies (eg, squamous cell or basal cell skin cancer treated with 
curative intent).
d.
Significant or unstable cardiac disease (eg, angina, congestive heart failure, 
uncontrolled hypertension, history of arrhythmia)
e.
Chronic pulmonary disease (eg, chronic obstructive pulmonary disease) associated 
with functional impairment
f.
Pancreatitis 


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g. Severe or uncontrolled psychiatric disease, including severe depression, history of
suicidal ideation, suicidal attempts, or psychosis requiring medication and/or
hospitalization
18. Solid organ transplantation, including liver
Criteria Related to Use of Selected Medications
19. Use of alpha interferon, either interferon alfa-2a or interferon alfa-2b, pegylated interferon
alfa-2a or pegylated interferon alfa-2b within 2 months before the start of screening
20. Concomitant use of any of the following:
a.
Medications or foods that are known moderate or strong inducers or inhibitors of
CYP3A4 or CYP2C19
b. Drugs known to prolong the PR or QT interval otherwise described in protocol (i.e.
Ondansetron).
c.
Receipt of systemic immunosuppressive therapy within the 3 months before start of
screening.
d. Statins, due to inhibition of mevalonate synthesis, which reduces protein prenylation
e.
Medications contraindicated in the prescribing information for ritonavir:
–
Alpha1-adrenoreceptor antagonist:  alfuzosin HCL
–
Analgesics*:  pethidine*, piroxicam*, propoxyphene*
–
Antiarrhythmics: amiodarone, flecainide, propafenone, quinidine, bepridil*,
encainide*
–
Antibiotic*:  fusidic acid*
–
Antifungal: voriconazole
–
Antihistamines*:  astemizole*, terfenadine*
–
Antimycobacterial*:  rifabutin*
–
Ergot derivatives:  dihydroergotamine, ergonovine*, ergotamine,
methylergonovine
–
Gastrointestinal motility agent:  cisapride
–
Herbal products:  St. John’s wort (hypericum perforatum)
–
HMG-CoA reductase inhibitors:  lovastatin, simvastatin
–
Antipsychotics*/Neuroleptic:  clozapine*, pimozide, quetiapine*
–
Phosphodiesterase type 5 (PDE5) enzyme inhibitor: sildenafil [Revatio®] only
when used for the treatment of pulmonary arterial hypertension (PAH), avanafil*,
vardenafil*
–
Sedative/hypnotics:  clorazepate*, diazepam*, estazolam*, flurazepam*, oral
midazolam, triazolam
(Sources:  Prescribing Information for Norvir® [ritonavir] Tablets, 2015. 
*Additional terms from the Summary of Product Characteristics for Norvir®
[ritonavir] tablets, 2014)
f.
History or evidence for any intolerance or hypersensitivity to lonafarnib, ritonavir, or
other substances that are part of the study medication.


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     Other Medical Conditions 
21. Other significant medical condition that may require intervention during the duration of
the study. 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 patient of
participation in the trial.
Investigational Plan 
Study Periods and Visits 
The study will consist of three periods: 
Screening—At the Screening Visit, patients providing written informed consent will 
have required evaluations to determine their eligibility to participate in the study. 
Screening evaluations may occur over more than one visit, depending on the facilities and 
personnel available at the clinical center. All screening procedures must occur within 
4 weeks before the start of dosing (Day −28 through Day −1). 
Treatment—Each eligible patient will undergo a minimum of 10 Treatment Study 
Visits: Week 0 (Day 1), Week 1 (Day 8 ± 2 d), Week 2 (Day 15 ± 2 d), Week 4 
(Day 29 ± 2 d), Week 6 (Day 43 ± 2 d), Week 8 (Day 57 ± 5 d), Week 12 (Day 85 ± 5 d), 
Week 16 (Day 113 ± 5 d), Week 20 (Day 141 ± 5 d), and Week 24 (Day 169 ± 5 d). 
Follow-up—Follow-up visits will occur every 4 weeks for 24 weeks. The first Follow-up 
Visit will be on Week 28 (4 weeks after last dose or if the patient discontinues treatment 
early) and will also include evaluation of lonafarnib level. All Follow-up Visits will 
include evaluations of safety (AEs, concomitant medications, and laboratory values) and 
viral loads (HDV and HBV). Alpha-interferon treatments will be allowed during the last 
20 weeks of the follow-up period (that is, starting 4 weeks after last dose of study 
treatment) if considered by the investigator to be required for patient safety.  
In addition to the planned visits, unscheduled visits may be required if, in the opinion of the 
Investigator, the clinical status of the patient warrants interim evaluation. 
Study Visits should be scheduled according to the study protocol; however, the window for 
Study Visits for Weeks 1 through 6 will be ±2 days of the nominal Study Visit day, and for study 
visits thereafter the window will be ±5 days. 
Study Assessments 
Safety assessments will be performed as shown in the Schedule of Assessment in Appendix A. 
Safety—After consent is obtained, screening assessments will include comprehensive physical 
examination, medical history, height, weight, vital signs, BMI calculation, 12-lead 
electrocardiogram (ECG), ophthalmic examination, retinal photography, concomitant 
medications, assessment of the presence or absence of cirrhosis, liver biopsy (if not done 
previously) and Fibroscan, safety laboratory tests (including hematology, chemistry, and 
coagulation), HDV RNA and HBV DNA analysis, serology (HBV, HCV, HDV, and HIV), 


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serum pregnancy test (females of childbearing potential only), thyroid-stimulating hormone 
(TSH), urinalysis, and urine drug screen. 
During the remainder of the study, safety will be monitored by conducting brief physical 
examinations; assessing vital signs, AEs, concomitant medications, and laboratory and ECG 
results; and reviewing urine pregnancy tests (for women of childbearing potential only). At the 
end of treatment, the ophthalmic examination and retinal photographs will be repeated.  
Peripheral blood mononuclear cell (PBMC) samples will be collected predose and at the end of 
treatment for future analysis.  
Efficacy/Pharmacodynamics—PD activity will be assessed by measurement of HDV viral load 
by quantitative PCR (qPCR). The assay will be performed at Lademannbogen Laboratory, a 
subsidiary of Sonic Healthcare, using the RoboGene HDV RNA Quantification Kit. This assay 
has a limit of quantitation of 500 IU/mL and can detect genotypes 1, 2, 5, 6, 7 and 8.  
Pharmacokinetics—PK sampling will be conducted on all patients. Single blood samples will 
be obtained for trough drug measurements at each study visit starting at Week 2 and through 
Week 16  
Blood samples will be obtained for full PK analysis when patients have maintained a stable dose 
of lonafarnib/ritonavir for at least 2 weeks between Study Weeks 8 and 16 as follows (see 
Section 3.6.2 for dose-titration details). A stable dose is defined as a dose of lonafarnib/ritonavir 
that has been taken for at least 2 weeks and that is likely to be the highest tolerable dose taken by 
the patient during the study, in the opinion of the investigator. Samples for full PK will be taken 
as follows predose (within 30 minutes before the first dose of the day) and 0.5, 1, 2, 3, 4, 6, 8, 10, 
and 12 h postdose.  On the day that full PK is performed, the second dose of study drug may not 
be taken until after the 12 hour sample is obtained.  On the days that PK sampling occurs, 
patients will remain in clinic at least 13 hours.  
If the patient has not been at a stable dose for the 2 weeks before the study visit, PK sampling 
will be performed at a future visit, after the patient has been on a stable dose for at least 2 weeks. 
Investigational Product 
Lonafarnib is formulated in No. 3 and No. 4, hard gelatin, white, opaque capsule shells for oral 
administration. Each No. 4 capsule contains 50 mg of lonafarnib. Each No. 3 capsule contains 
75 mg of lonafarnib.  
Ritonavir is formulated in white, film-coated, ovaloid tablets providing 100 mg of ritonavir per 
tablet. 
Study Drug Administration and Dosage 
Patients will be dispensed lonafarnib capsules and ritonavir tablets in quantities sufficient for a 
2-week study during dose titration and for a 4-week supply once a stable dose is reached.
Lonafarnib and ritonavir will each be dispensed in separate, clearly marked bottles.
All study treatments (lonafarnib/ritonavir) are administered orally. All doses of 
lonafarnib/ritonavir should be administered with food. Patients should be instructed to take the 
study medication at 12-hour intervals ±2 hours. Dose regimens are outlined below; details 
regarding dose titration (both up-titration and down-titration) are provided in Section 3.6. 


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Study Day 
Dose 
Lonafarnib 
Ritonavir 
Days 1–28 
50 mg bid 
100 mg bid 
On or after Day 29a, b 
75 mg bid 
100 mg bid 
On or after Day 43a, b 
100 mg bid 
100 mg bid 
bid = twice daily 
a Patients will be evaluated for tolerability at each dose level as described 
 in Section 3.6.2.2. 
b Only if the patient has been at the previous lonafarnib/ritonavir dosage level for at least 2 weeks. 
Concomitant Medications 
Treatment of Gastrointestinal Symptoms 
Gastrointestinal (GI) symptoms (diarrhea, nausea, dyspepsia, vomiting, and decreased appetite) 
are the most common AEs reported with lonafarnib single-agent therapy. Ritonavir may be 
associated with diarrhea. Occurrence of diarrhea may reduce the absorption of lonafarnib, 
ritonavir, and other medications from the GI tract. Diarrhea may result in loss of fluids and 
dehydration, which can be severe, and require hospitalization for supportive care. Patients 
should receive therapy (antacids, anti-emetics, or anti-diarrheals) for GI symptoms at the 
earliest signs in order to avoid possible severe complications. Electrolytes should be monitored 
in cases of diarrhea and volume depletion. Use of symptomatic treatments for GI toxicity should 
be recorded in the case report form (CRF).  
Ondansetron does not inhibit or induce enzymes in the CYP system. No interaction is expected 
with concomitant administration with lonafarnib.  
Famotidine has not been associated with any clinically significant drug-drug interactions. No 
significant interference with CYP system has been identified; thus, no interaction is expected 
with concomitant administration with lonafarnib. 
Omeprazole inhibits CYP2C19 and P-gp and is completely metabolized, specifically by 
CYP3A4 and CYP2C19. Dose adjustments are typically not required when administering 
omeprazole with other medications metabolized by CYP2C19; however, dose adjustments are 
required for omeprazole when administered to patients with hepatic impairment (refer to the 
Prilosec Product Label for additional information). 
Prohibited Medications 
Use of the following medications is prohibited during the conduct of the study: 
•
Drugs known to prolong the PR or QT interval (unless otherwise described within
protocol as allowed (i.e. Ondansetron)
•
Systemic immunosuppressive therapies
•
Statins, due to inhibition of mevalonate synthesis, which reduces protein prenylation.
Drugs highly dependent on CYP3A4 for clearance are contraindicated with ritonavir (see list 
under Exclusion Criterion 19e above). Appendix C lists all drugs contraindicated with the use of 
ritonavir and also lists drugs that have established or other potentially significant drug 
interactions when used in combination with ritonavir. 


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Medications To Be Used with Caution 
Due to Possible Interaction with Lonafarnib—An in vitro CYP inhibition study conducted 
with lonafarnib suggests that lonafarnib may be a mechanism-based inhibitor of CYP3A4 and 
CYP2C19 enzymes. Any medications that are primarily metabolized by CYP3A4 should be 
avoided. Any medicines that are primarily metabolized by CYP2C19 should be used with 
caution. If at all possible, alternative therapeutic agents that are not CYP3A4 substrates, 
inducers, or inhibitors or are less potent CYP3A4 substrates, inducers, or inhibitors should be 
considered. Concomitant administration of medications that are primarily metabolized by 
CYP3A4 or CYP2C19 may result in large increases in serum levels of these medications that 
may precipitate unwanted toxicities. 
Entecavir, tenofovir, lamivudine, adefovir, and telbivudine do not substantially inhibit or induce 
the enzymes in the CYP system. Therefore, an interaction with lonafarnib is not anticipated due 
to CYP enzymes; however, there is a potential for interaction of lonafarnib with tenofovir due to 
inhibition of P-gp inhibition, breast cancer resistance protein (BCRP), and organic anion-
transporting polypeptide (OATP) 1B1 (see below). 
In vitro tests suggest that lonafarnib may be an inhibitor of efflux pumps p-glycoprotein (P-gp) 
and BCRP and the liver uptake transporter OATP1B1. Therefore, concomitant medications that 
are substrates of P-gp, BCRP, and/or OATP1B1 should be used with caution. Taking 
medications that are substrates of P-gp, BCRP, and/or OATP1B1 may result in unwanted 
increases in serum levels of these medications, especially medications with a narrow therapeutic 
index (eg, digoxin, loperamide, quinidine, talinolol, and vinblastine). 
Because tenofovir is a substrate of P-gp, BCRP, and OATP1B1, concomitant administration of 
lonafarnib and tenofovir may result in increased levels of tenofovir. Therefore, tenofovir should 
be used with caution when co-administered with lonafarnib. 
A source that should be used to check for potential drug-drug interactions is at the following 
website: http://www.Drug-Interactions.com. The website provides a list of drugs known to be 
metabolized by cytochrome P450 enzymes including CYP3A4. Although this list is periodically 
updated, it is not an exhaustive list; therefore, using more than one source is recommended when 
checking for potential interactions. Another source that can be used is by searching the drug 
name and reviewing the product label (Sections 7 and Section 12) at this 
site: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.  
Due to Possible Interaction with Ritonavir—Ritonavir inhibits CYP3A4, P-gp, MRP1, OATP-
C, and BCRP. Ritonavir induces CYP1A2, CYP2C8, CYP2C9, CYP2C19, and MRP1. Ritonavir 
is a substrate of CYP3A4 and CYP2D6. For contraindicated drugs with ritonavir, refer to the list 
under Exclusion Criterion 19e above and Appendix C).  
While patients are receiving ritonavir, the Investigator should review all other medications taken 
by patients and monitor patients for adverse effects due to metabolism interactions of ritonavir 
with concomitant medications. Initiating treatment with ritonavir in patients receiving 
medications primarily metabolized by CYP3A or initiating medications metabolized by CYP3A 
in patients already maintained on ritonavir may result in increased plasma concentrations of 
these medications. Higher plasma concentrations of concomitant medications can precipitate 
adverse effects that can potentially lead to severe, life-threatening, or fatal events. The potential 


Protocol EIG-LNF-002 
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for drug-drug interactions must be considered before initiating therapy or during therapy with 
ritonavir. 
Randomization 
Patients will not be randomized in this open-label, single-arm study. 
Statistical Methods 
The study is designed to evaluate the safety and tolerability of the dose-titration regimen of 
lonafarnib/ritonavir. As such, the sample size is chosen to allow assessment of the safety and 
tolerability of the combination of lonafarnib/ritonavir, recognizing that drug exposures may be 
highly variable and will likely result in an observable range of patient tolerabilities to the same 
administered dose. 
The primary PD/efficacy analysis will compare the change from Baseline (Day 1) to Week 24 
(End of Treatment Visit) in HDV viral load.  
Analysis populations will consist of the following: 
•
Safety population—all patients who receive at least one dose of study drug.
•
Primary PD/efficacy population—patients who receive study drug throughout the
entire 24-week Treatment Period and for whom viral load data are available from
baseline (Week 0) and end-of-treatment (Week 24) study visits.
•
PK population—patients who received at least 2 weeks of study drug at a stable dose
level, and in whom a sufficient number of blood samples were collected, plasma
samples were analyzed, concentration data were analyzed, and PK parameter values
were derived.
Analysis Plan 
Baseline Values—Demographics and baseline characteristics of patients will be summarized. 
Safety—All reported AEs will be mapped to standard coding terms (Medical Dictionary for 
Regulatory Activities [MedDRA]) and grouped by system organ class and preferred terms. 
Treatment-emergent AEs (TEAEs) are defined as those that start or worsen after the start of 
study treatment and up to 28 days after the last dose of study treatment; any AEs that occur after 
that time will be considered posttreatment AEs. TEAEs will be summarized by seriousness, 
severity, and relationship to study drug. If an AE is reported more than once during the study 
period, the greatest severity and worst-case attribution will be presented in tables. AEs will also 
be listed for individual patients, along with information regarding onset, duration, severity, and 
relationship to study drug. AEs that lead to withdrawal from the study will be listed and 
summarized. Summary tables and listings of serious AEs will also be generated.  
Descriptive statistics will be used to summarize clinical laboratory data at each time point and 
the change from baseline in postbaseline measurements. The number of patients above, below, 
and within normal range will be assessed. In addition, ALT, AST, total bilirubin, and AP will be 
summarized by CTCAE grade. Values for vital signs, weight, and ECGs will be summarized and 
listed for each patient. 


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Pharmacodynamics/Efficacy—PD data will be presented by dose level in summary tabulations 
and listings that will display viral load data at each time point collected by patient. These data 
will also be presented graphically. Mean and median levels and change from baseline of the viral 
load will be calculated at each time point. The number of patients with 1 and 1 log reductions 
from baseline will be summarized at each time point. The number of patients with reduction in 
viral load below the limit of quantitation and the limit of detection will be summarized. Missing 
data will not be imputed. 
Pharmacokinetics—The following PK parameters will be derived from plasma concentrations 
for lonafarnib and ritonavir: 
Cmax
Peak plasma concentration as observed. 
Tmax 
Time of the peak plasma concentration. 
AUC0–τ 
Area under the plasma concentration versus time curve during 
the dosing interval calculated by the linear trapezoidal rule. 
Cavg 
Average plasma drug concentration during multiple-dose 
administration. 
Cmin
Minimum plasma concentration. 
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 (eg, three or more 
non-zero plasma concentrations). 
Varea/F 
Apparent total volume of distribution calculated as follows: 
total dose/(total AUC0–∞ × Kel). 
CL/F 
Apparent total body clearance, calculated as follows:  
dose/ AUC0–∞ 
Weight-adjusted CL/F (CL/F/kg) will also be calculated. 
T1/2 
Apparent first-order terminal elimination half-life will be 
calculated as 0.693/Kel. 
A noncompartmental method will be used to derive the PK parameters for lonafarnib and 
ritonavir. Additional PK parameters using noncompartmental methods may also be used if data 
permit. Plasma concentrations of lonafarnib and ritonavir and the generated PK parameters will 
be summarized descriptively by dose level and by patient. The following will be calculated for 
multiple-dose lonafarnib and ritonavir: arithmetic means; coefficients of variation (%CV); 
standard deviations (SD); median, minimum, and maximum values; and number of observations 
PK parameter values will be generated for multiple-dose lonafarnib and ritonavir. 
Other PK analyses for lonafarnib that may be performed include linearity and dose 
proportionality across the different lonafarnib dose levels. These analyses will be conducted for 
patients who receive titrated doses. The relationship between lonafarnib dose and achieved AUC, 
Cmax, and measured viral load (PD) may also be explored by plotting the PK parameters versus 
the dose of lonafarnib and viral log decay. The relationship between lonafarnib dose, lonafarnib 
exposure, and specific AEs may also be explored. 
No formal statistical analyses are planned for PK parameters. 


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Viral Resistance Analysis 
Screening visit and baseline serum samples will be collected from all patients for HDV 
genotypic analysis to determine HDV subtypes (1–8) and to understand natural genetic 
polymorphisms of HDV. 
For resistance surveillance, genotypic analysis of large HDV antigen from patients with virologic 
failure will be conducted. Virologic failure is defined as an increase in serum HDV RNA of at 
least 1.0 log from the nadir value on 2 consecutive visits in patients who stay on lonafarnib 
treatment. In vitro phenotypic analysis may be explored as necessary. 


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ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 1 provides the definitions of the abbreviations and acronyms used in this protocol. 
Table 1 
List of Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
17-OHP
17-hydroxyprogesterone
Ab 
antibody 
AE 
adverse event 
Ag 
antigen 
ALT 
alanine aminotransferase 
AMH 
anti-Müllerian hormone 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the time-concentration curve 
AUC0-t 
Area under the plasma concentration versus time curve during the dosing interval 
calculated by the linear trapezoidal rule 
BCRP 
breast cancer resistance protein 
bid 
twice each day 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Cavg 
average plasma drug concentration during multiple-dose administration 
CFR
Code of Federal Regulations 
CK 
creatine kinase 
CL/F 
apparent total body clearance 
Cmax 
peak plasma concentration as observed 
Cmin 
minimum concentration 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP 
Child-Turcotte-Pugh 
CYP 
cytochrome P450 
DHEA 
dehydroepiandrosterone 
DHEAS 
dehydroepiandrosterone sulfate 
ECG 
electrocardiogram 
Eiger 
Eiger BioPharmaceuticals 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FT 
farnesyltransferase 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HBV 
hepatitis B virus 
HBeAb 
hepatitis B e antibody 
HBsAg 
hepatitis B surface antigen 
HBeAg 
hepatitis B e antigen 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 


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Abbreviation/Acronym 
Definition 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethic Committee 
INR 
international normalized ratio 
IU 
international unit 
IUD 
intrauterine device 
Kel 
apparent first-order terminal elimination constant 
kPa 
kilopascal 
LDH 
lactate dehydrogenase 
LOWR 
Lonafarnib With and Without Ritonavir 
LT 
luteinizing hormone 
MHH 
Medizinische Hochschule Hannover (Hannover Medical School) 
ms 
millisecond 
NIDDK 
United States National Institute of Diabetes and Digestive and Kidney Diseases 
OATP 
organic anion-transporting polypeptide 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD
pharmacodynamics 
PEG-IFN-α2a 
pegylated interferon alfa 2a 
P-gp
P-glycoprotein
PK 
pharmacokinetics 
qd 
once each day 
qPCR 
quantitative polymerase chain reaction 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using Fridericia formula 
qw 
once each week 
SAE 
serious adverse event 
Tmax 
time of the peak plasma concentration 
T1/2 
apparent first-order terminal elimination half-life 
SHBG 
sex hormone binding globulin 
SHIM 
sexual health interest questionnaire 
tid 
three times each day 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
Varea/F 
apparent total volume of distribution 
WBC 
white blood cell 


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1 INTRODUCTION AND BACKGROUND 
Lonafarnib is an orally administered, potent and selective inhibitor of the enzyme 
farnesyltransferase (FT). Farnesylation is important in allowing association of the large hepatitis 
delta virus (HDV) protein and hepatitis B virus (HBV) surface antigens to form an infectious 
HDV particle. This association is critical in the development of HDV infection because HDV 
can propagate only in the presence of HBV. While HDV can replicate autonomously inside the 
hepatocyte, the virus requires co-infection with HBV to complete virion assembly and to 
facilitate transmission. Assembly of the HDV virion depends on prenylation with FT (Bordier 
et al, 2003). Compounds with FT inhibitory activity have been shown to prevent production of 
HDV virions after transfection of Huh7 cells with two different HDV genotypes (Bordier et al, 
2002).  
Worldwide more than 15 million people are co-infected with HDV and HBV. Co-infection 
results in more severe complications compared with infection with HBV alone, and hepatitis D is 
the most aggressive and virulent of the viral hepatitides. HDV is clinically important because, 
although it suppresses HBV replication, it causes severe liver disease with rapid progression to 
cirrhosis and hepatic decompensation when compared with the clinical course associated with 
HBV mono-infection. The prevalence of HDV is increasing in northern and central Europe 
through migration from areas endemic in HDV. Currently, there is no approved therapy for HDV 
infection. 
Lonafarnib has been studied extensively in patients with cancer (more than 1500 patients in 
Phase 1, 2, and 3 studies) because FT also acts on Ras proteins, which play a central role on 
tumor cell growth. Eiger BioPharmaceuticals, Inc, is currently developing lonafarnib for the 
treatment of patients with chronic HDV infection. Based on the known properties of lonafarnib, 
variable absorption in patients, a metabolic pathway that occurs primarily via cytochrome P450 
3A4 (CYP3A4), and the occurrence of dose-dependent gastrointestinal (GI) adverse events 
(AEs), Eiger plans to combine lonafarnib with low-dose ritonavir, a potent CYP3A4 inhibitor, to 
increase systemic concentrations of lonafarnib and to reduce the total administered dose of 
lonafarnib necessary to achieve therapeutic effect. 
1.1 Nonclinical Data 
An extensive nonclinical program has been conducted using lonafarnib; key results are 
summarized below and additional details are provided in the Investigator’s Brochure. 
Pharmacology—Lonafarnib is a potent and selective inhibitor of human FT. Farnesylation of 
large HDV antigen by the human FT is required for the association of the large HDV antigens 
with hepatitis B surface antigen to form an infectious HDV virion (Glenn 1992, Otto 1996). 
Lonafarnib exerts anti-HDV activity by blocking the formation and release of HDV virions. 
Blocking the release of HDV virions by lonafarnib will trap large HDV antigens within HDV 
infected hepatocytes. Since large HDV antigen is a potent trans-dominant inhibitor of HDV 
genome replication, accumulation of large HDV antigens within hepatocytes may further 
suppress HDV genome replication. 


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Using a standard in vitro model of HDV virus-like particle release, Eiger demonstrated that 
lonafarnib is highly potent in inhibiting cellular prenyl transferase. Lonafarnib has half-maximal 
effective concentration (EC50) of approximately 35 pM (2.4 ng/mL), which is 400- to 1000-fold 
lower than the expected Cmax (maximum observed plasma concentration) and trough levels for 
100 and 200 mg of lonafarnib given by mouth twice a day (bid) with food. 
Lonafarnib was tested in a standard model of HBV activity to assess its effect on the anti-HBV 
effects of tenofovir, adefovir, entecavir, lamivudine, and telbivudine. Lonafarnib has no direct 
anti-HBV activity. Lonafarnib has no positive or negative effects on the activity of the approved 
anti-HBV therapies. Lonafarnib appears to be metabolized primarily by CYP450 enzymes. None 
of the standard anti-HBV therapies are metabolized by CYP450 enzymes and all are excreted 
through the urine making it unlikely that there will be metabolic interference due to CYP450 
enzymes between lonafarnib and any of these drugs when given in vivo.  
However, because tenofovir is a substrate of P-glycoprotein (P-gp), breast cancer resistance 
protein (BCRP), and organic anion-transporter polypeptide (OATP) 1B1, concomitant 
administration of lonafarnib and tenofovir may result in increased levels of tenofovir. Therefore, 
tenofovir should be used with caution. 
Toxicity—The in vivo toxicology of lonafarnib has been evaluated in acute studies in mice and 
rats, and in repeat-dose studies for up to 6 months in rats and for 1 year in monkeys. Lonafarnib 
caused mixed induction/inhibition of hepatic drug-metabolizing enzymes in rats and monkeys 
when administered once daily for 3 months in toxicology studies.  
Lonafarnib was well tolerated and had no major end-organ toxicities at repeated doses of 
15 mg/kg up to 6 months in rats and 10 mg/kg up to 1 year in monkeys; these doses resulted in 
systemic exposures that are less than those attained at a clinical dose of 200 mg twice per day 
(bid). At higher doses, representing animal to human exposure multiples less than or similar to 
that seen in humans at 200 mg bid, the key toxicological findings were bone marrow suppression 
and testicular toxicity in rats and monkeys, lymphoid and kidney changes in rats, and diarrhea 
and electroretinographic changes in monkeys.  
Reproductive toxicity has been evaluated in fertility studies in rats, in embryo-fetal development 
studies in rats and rabbits, and in a peri- and postnatal development study in rats. Studies in 
pregnant and lactating rats administered a single oral dose of 30 mg/kg showed that lonafarnib 
crosses the placenta and is secreted into milk.  
The no-effect doses for reproductive effects on fertility (10 mg/kg in rats) and embryo-fetal 
development (15 mg/kg in rats and <10 mg/kg in rabbits) result in systemic exposures less than 
those attained at a clinical dose of 200 mg BID. The no-effect dose for peri- and postnatal 
development in rats was ≥20 mg/kg, the highest dose evaluated. Lonafarnib was not mutagenic 
or clastogenic. 
1.2 Clinical Data 
Lonafarnib has been investigated, alone and in combination with pegylated interferon or 
ritonavir, as a treatment for patients with chronic HDV infections in the following clinical 
studies:  


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•
Protocol 12-DK-0046, conducted under IND 113,137 in the United States National
Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) was a first-in-human, proof-of-principle, two-cohort, randomized,
double-blind, placebo-controlled trial testing lonafarnib 100 or 200 mg bid
administered orally for 28 days to patients with chronic HDV infections (Koh et al,
2015). Eight patients were enrolled in each arm with 6 patients receiving lonafarnib
and 2 patients receiving placebo. This study is completed. All patients underwent
72-hour viral kinetic evaluations at the start of therapy and blood HDV RNA was
measured at each study visit. A total of 14 patients were treated for 4 weeks.
•
Protocol EIG-300, a Phase 2 study performed at a single site in Ankara, Turkey,
under the auspices of Turkish Medicines and Medical Devices Agency, consists of
two parts, LOWR -1 and LOWR-2.
–
LOWR-1: This study is investigating the safety and clinical activity of lonafarnib
alone and in early combinations with ritonavir and pegylated interferon.
Monotherapy lonafarnib treatments include 100 mg 3 times daily [tid] for 4
weeks, 200 mg bid for 12 weeks, and 300 mg bid for 12 week). Combination
treatments include lonafarnib/ritonavir combinations of 100 mg bid/100 mg once
daily (qd) for 8 weeks and lonafarnib/pegylated interferon (PEG-IFN)
combinations of 100 mg bid/180 mcg once a week (qw) for 8 weeks, 200 mg
bid/180 mcg qw for 8 weeks, and 300 mg bid/180 mcg qw for 8 weeks. A total of
21 patients have been treated.
–
LOWR-2: This study is investigating the safety and clinical activity of lonafarnib
in combination with ritonavir. This study is currently ongoing. As of 30 June
2015, a total of 22 patients have been treated.
As of 30 June 2015, a total of 57 patients with chronic HDV infection have been treated with 
lonafarnib, with or without ritonavir, for periods of up to 12 weeks.  
1.2.1 
Clinical Pharmacokinetics 
The pharmacokinetics of lonafarnib are dose-dependent, and plasma concentrations in patients 
and healthy volunteers increase in a greater-than-dose-proportional manner (refer to the 
Investigator’s Brochure for additional information). Lonafarnib was absorbed slowly after twice 
daily oral administration with food, with the mean Cmax (maximum observed plasma 
concentration) occurring between 2.5 and 8 hours postdose. In a single-dose setting, lonafarnib 
absorption was decreased when administered under fed conditions. The relative oral 
bioavailability of lonafarnib under the fed as compared to the fasted condition was 48% and 77% 
based on Cmax and AUC(tf) (area under the concentration-time curve from 0 to time of the final 
quantifiable sample), respectively. However, this food-effect was not observed following 
multiple-dose lonafarnib administration. Based on these findings, lonafarnib should be 
administered with food for both safety/tolerability and exposure reasons.  
Multiple co-administered doses of the P450 inhibitor ketoconazole resulted in a 5-fold increase 
in lonafarnib exposures. Conversely, lonafarnib had no apparent effects on the PK of other co-
administered agents (paclitaxel, carboplatin, docetaxel, gemcitabine), and these agents had no 
apparent effect on the PK of lonafarnib. Lonafarnib is primarily metabolized by CYP3A4, with 
negligible renal elimination (<1%). 


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1.2.2 
Clinical Efficacy/Pharmacodynamics 
1.2.2.1 Study 12-DK-0016 
Study 12-DK-0046 was a Phase 2a study performed by NIDDK (Koh et al, 2015). The study 
enrolled a total of 14 patients, 6 treated with lonafarnib at 100 mg BID and 2 treated with 
placebo (Group 1) and 6 treated at 200 mg BID and 2 on placebo (Group 2) for 28 days. The 
2 placebo patients from Group 1 received lonafarnib 200 mg BID in Group 2. All patients were 
infected with HDV genotype 1.  
From Baseline to Day 28, the mean changes in serum HDV RNA were −0.73,−1.54, and 
−0.13 log10 for patients who received lonafarnib 100 mg BID, lonafarnib 200 mg BID, and 
placebo, respectively (Figure 1). 
Figure 1 Study 12-DK-0046:  Mean Change in HDV RNA Levels from Baseline During 
and After 4 Weeks of Treatment with Lonafarnib 
Half of patients in the 200 mg bid group achieved a decrease from baseline-to-nadir of greater 
than −2 log IU/mL. As shown in Figure 2, lonafarnib serum concentrations correlated with HDV 
RNA change (R2 = 0.78, p < 0.0001).  
After lonafarnib treatment was stopped, viral loads increased back to baseline by 4 weeks 
posttreatment, suggesting that longer treatment with lonafarnib may be required. Treatment with 
lonafarnib for 28 days significantly reduced viral loads in patients chronically infected with 
HDV, and these effects appear dose-dependent. 


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Figure 2 Study 12-DK-0016:  Relationship Between Lonafarnib Serum Concentration 
and Change in Log HDV RNA Levels 
The development of potential HDV resistance to lonafarnib was monitored during treatment by 
sequencing the large HDV antigen coding region at baseline, viral nadir, and at the 24-week 
follow-up. All patients were found to be infected with HDV genotype 1. The most likely place to 
find resistance-conferring mutations would be in the CXXX-box amino acid motif, that is, 
codons 211–214, which is the substrate for prenyltransferases. No evidence of mutations was 
found in that region or anywhere in the large delta antigen coding region. Thus, resistance was 
not observed during 4 weeks treatment with lonafarnib alone and after 24 weeks of follow-up. 
This observation is consistent with the mechanism of action of lonafarnib as inhibiting a host 
enzyme. 
HBV DNA was measured at the same time as HDV RNA. Evidence of virus-virus interactions 
was observed:  a decrease in HDV RNA while on lonafarnib treatment was associated with an 
increase in HBV DNA, and an increase in HDV RNA after treatment cessation was associated 
with a decrease in HBV DNA levels. However, the changes in HBV for a single patient were 
generally 1 log or less. HBV levels were generally unchanged in the patients who were on anti-
HBV treatment during the study. 
1.2.2.2 Study EIG-300/LOWR-1 
In the Phase 2 EIG-300/LOWR-1/EIG-300 study, HDV viral load was evaluated by measuring 
HDV RNA by real-time qPCR in all patients at baseline and periodically thereafter. Interim 
results from 15 patients in Study LOWR-1/EIG-300 who received lonafarnib alone or with 
ritonavir boosting or in combination with PEG IFN indicated that all treatments led to decreased 
viral loads.  
Combination therapy of lonafarnib 100 mg bid with ritonavir or pegylated interferon alfa 2a 
(PEG-IFN-α2a) demonstrated numerically improved anti-HDV activity compared with 
lonafarnib 100 mg tid monotherapy at Week 4 (Figure 3, Yurdaydin 2015). Serum HDV RNA 
declined further from Week 4 to Week 8 in patients on lonafarnib in combination with ritonavir 


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or PEG-IFN-α2a. The mean change in HDV RNA in either combination group was 
approximately −3 log copies/mL from baseline to Week 8 (Figure 4). 
Figure 3 Study EIG-300/LOWR-1:  Change in HDV RNA in Patients at Week 4 
Figure 4 Study EIG-300/LOWR-1:  Change in HDV RNA in Patients Treated with 
Lonafarnib and Ritonavir or with Lonafarnib and PEG-IFN-α2a for 8 Weeks 
Alanine aminotransferase (ALT) levels also decreased in patients who received lonafarnib 100 
mg bid with ritonavir or PEG-IFN-α2a.  
Similar to the observations in Study 12-NK-0046, the mean serum HBV DNA level of all 
patients remained stable and no mutation(s) in the large HDV antigen was detected in patients in 
the 200 mg and 300 mg bid groups during lonafarnib treatment in EIG-300/LOWR-1. 


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1.2.3 
Clinical Safety 
The dose-limiting, significant AEs due to lonafarnib treatment in all patients were primarily GI 
(diarrhea, nausea, vomiting, dyspepsia, and anorexia), as has been reported with many other FT 
inhibitors, with less common and reversible neurological, renal, hematologic, and liver effects. 
Loss of fluids and dehydration due to severe diarrhea can lead to hospitalization; early 
intervention has been effective for the diarrhea. 
1.2.3.1 Study 12-DK-0016 
The most common systemic AEs seen in patients receiving lonafarnib monotherapy in Study 12-
DK-0016 are summarized in Table 2, and included: diarrhea, nausea, dyspepsia, weight loss, 
decreased appetite, and vomiting (Koh et al, 2015).  The frequencies of gastrointestinal AEs 
(nausea, diarrhea, decreased appetite, abdominal bloating, vomiting and weight loss) were 
dose-dependent. 
Table 2 
Most Frequent Adverse Events in Study 12-DK-0016 
Adverse Event 
Placebo 
(N = 4) 
Group 1 
LFN 100 mg bid 
N = 6 
Group 2 
LFN 200 mg bid 
N = 6 
n (%) 
n (%) 
n (%) 
Discontinuation of therapy due to 
Adverse Event 
0 
0 
0 
Serious Adverse Event 
0 
0 
0 
Common Adverse Events 
Nausea 
1 (25%) 
2 (33%) 
6 (100%) 
Diarrhea 
0 
3 (50%) 
6 (100%) 
Decreased appetite 
0 
1 (17%) 
5 (83%) 
Abdominal 
bloating/dyspepsia 
1 (25%) 
1 (17%) 
6 (100%) 
Vomiting 
0 
0 
3 (50%) 
Weight loss >2 kg 
0 
1 (17%) 
6 (100%) 
Headache 
1 (25%) 
1 (17%) 
1 (17%) 
Testicular pain 
0 
1 (17%) 
0 
Lightheadedness 
1 (25%) 
0 
0 
Fatigue 
0 
1 (17%) 
1 (17%) 
From (Koh et al, 2015). 
The side effects of dyspepsia, nausea, and diarrhea were successfully treated with antacids, 
anti-emetics, and anti-diarrheals on an as-needed basis. All AEs resolved rapidly after stopping 
therapy. Lonafarnib 100 mg or 200 mg bid was reasonably well tolerated, and no symptoms 
impaired daily functioning in the study.  
Liver function tests were performed weekly during the 28 days of treatment and for 2 weeks after 
cessation of treatment, and every 4 weeks during the remainder of the follow-up period. The 
28-day treatment with either 100 mg or 200 mg lonafarnib bid appeared to have no adverse effect
on liver enzymes and lowered the ALT and aspartate aminotransferase (AST) levels
from baseline.


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Full ophthalmologic and comprehensive reproductive physiology examinations were performed 
for patients in Study 12-DK-0046. No significant changes were observed in these patients. 
There were no serious AEs (SAEs) in this study. No patients discontinued study drug due 
to AEs. 
1.2.3.2 Study EIG-300/LOWR-1 
Study EIG-300/LOWR-1 tested 100 mg TID, 200 mg BID, and 300 mg BID of lonafarnib alone. 
The study also evaluated lonafarnib 100 mg BID in combination with either 180 mcg Peg-IFN-
α2a QW or ritonavir 100 mg QD. The most common AEs were diarrhea, nausea, vomiting, and 
weight loss. There were no SAEs. 
1.3 Potential Risks and Benefits to Human Patients in This Study 
Collectively, the data from studies in chronic HDV patients treated with lonafarnib as a 
monotherapy or in combination with ritonavir have demonstrated significant reductions in HDV 
viral loads. While these proof-of-principle and early-stage studies are limited in size and scope, 
they provide promising evidence that lonafarnib, especially in combination with ritonavir, may 
offer clinically meaningful benefit to patients with chronic HDV infections. 
The most common, significant AEs due to lonafarnib treatment in all patients were primarily 
vomiting, diarrhea, and anorexia, which were treated as-needed with anti-emetics, antacids, and 
anti-diarrhea medications. Loss of fluids and dehydration due to severe diarrhea can lead to 
hospitalization; early intervention has been effective for treatment of diarrhea. 
Preliminary data indicate that to date two patients (one from the lonafarnib 200 bid group and 
one from the 300 bid group) had posttreatment ALT flares. It is possible that a host-induced flare 
due to “awakening” of hose immune function and/or viral flare may occur during or after 
antiviral treatment. For this reason, patients with decompensated cirrhosis are excluded, and all 
patients will be closely monitored in order to assess the risks of these outcomes during the 
6-month Follow-up Period.
A risk associated with the use of direct-acting antiviral agents is the development of resistance 
by the virus. However, because prenylation is a host function not coded for by the HDV genome, 
preliminary data suggest that the risk of resistance development may be low for lonafarnib. As 
proof of absence of viral resistance with prenylation inhibitors in HDV, population-based 
sequencing of the large delta antigen coding region at baseline, end of therapy, and 24 weeks 
after end of therapy was performed in Study 12-DK-0046. Analysis at these time points revealed 
no changes in viral sequences, thus confirming the absence of viral resistance. 
Ritonavir is an orally bio-available protease inhibitor that has been used in low doses as a PK 
booster (coadministration of 100 mg ritonavir) of second protease inhibitors or other retroviral 
agents. In this study, ritonavir will be used as a pharmacokinetic booster of lonafarnib. The most 
frequently reported adverse drug reactions among patients receiving ritonavir alone or in 
combination with other antiretroviral drugs were GI (including diarrhea, nausea, vomiting, 
abdominal pain), neurological disturbances (including paresthesia and oral paresthesia), rash, and 
fatigue/asthenia nausea, anorexia, diarrhea, vomiting, weight loss, and fatigue (Prescribing 
Information for Norvir® [ritonavir] Tablets, 2015; Summary of Product Characteristics for 
Norvir® [ritonavir] tablets, 2014). 


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While dose-limiting toxicities of lonafarnib are GI AEs, available data suggest that lower doses 
of lonafarnib as planned in this study administered in combination with low-dose ritonavir 
(100 mg bid) will be tolerable. Given that the toxicities appear to be dose-related and respond to 
dose reduction and/or discontinuation, we anticipate that AEs can be readily managed in this 
study with frequent study visits and monitoring. Treatment with the initial dose level for a 
minimum of 4 weeks, escalation in a step-wise fashion, dosing with food, prompt symptomatic 
management of intolerance (eg, GI effects), and monitoring of liver function tests during 
treatment will be implemented to ensure tolerability and minimize risk to the patient. 
1.4 Rationale for the Study 
Chronic HDV infections represent a serious unmet medical need. No therapies are currently 
approved for the treatment of chronic HDV infection. Interferon alpha has been shown to be 
effective in decreasing viral load in approximately 25% of patients after 48–96 weeks of 
treatment, but requires prolonged therapy and is associated with significant rate of relapse after 
treatment discontinuation.  
Lonafarnib monotherapy has been shown to decrease viral load in patients with chronic HDV 
infection in a dose-dependent manner. Given the wide intersubject variability in exposure when 
administered orally as well as the GI toxicities that may be dose-limiting, co-administration of 
lonafarnib with ritonavir, as a PK enhancer, may allow lower lonafarnib doses to be administered 
to the gut and minimize GI adverse effects while resulting in higher systemic levels.  
Currently, it is not known whether initiation of lonafarnib at a lower dose may allow greater 
tolerability over time, and whether the dose of lonafarnib may be titrated upward to allow a 
higher dose to be administered. The previous observation that lonafarnib treatment was not 
associated with viral resistance suggests that dose titration is not likely to be associated with  
development of viral resistance.  
This study will evaluate the effects of dose titration on the tolerability of lonafarnib administered 
in combination with ritonavir and will provide corresponding data of the effects on viral load. 
Taken together, these evaluations will provide insights regarding the most effective and tolerable 
dose combination for use in future, confirmatory studies.  
The results of this study will help determine the optimal regimen(s) of lonafarnib and ritonavir 
that may be further studied as treatment for eradication of chronic HDV infection. 


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2 STUDY OBJECTIVES 
The primary objectives of the study are to 
•
Evaluate the safety and tolerability of the following dose-titration regimen of
lonafarnib in combination with ritonavir over the 24-week Treatment Period:
lonafarnib/ritonavir starting at 50 mg bid/100 mg bid and escalated to
lonafarnib/ritonavir 75 mg bid/100 mg bid and then to 100 mg bid/100 mg bid
as tolerated
•
Evaluate the pharmacodynamic activity (change in HDV viral load) of the dose-
titration regimen of lonafarnib in combination with ritonavir over the 24-week
Treatment Period
The secondary objectives of the study are to evaluate the effect the dose-titration regimen 
of lonafarnib/ritonavir on the following:  
•
Pharmacokinetics
•
Change in ALT levels
•
Change in HBV DNA levels
Exploratory objectives of the study are to evaluate the effects of the dose-titration regimen 
of lonafarnib/ritonavir on immunologic parameters during treatment. 


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3 INVESTIGATIONAL PLAN 
3.1 Overall Study Design 
This is a Phase 2, open-label, single-arm study that will evaluate the dose-titration regimen of 
lonafarnib/ritonavir starting at 50 mg bid/100 mg bid and escalated to 75 mg bid/100 mg bid and 
then to 100 mg bid/100 mg bid as tolerated in patients chronically infected with HDV. The initial 
dose of lonafarnib and ritonavir 50 mg bid/100 mg bid will be maintained for at least 4 weeks; 
subsequent dose escalation may occur at an interval of no less than 2 weeks after the patients 
have received a particular dose. The pharmacokinetic (PD) activity (change in HDV viral load) 
of the lonafarnib/ritonavir dose-titration regimen over the 24-week Treatment Period will be 
evaluated. PK assessments will be performed as will evaluations of ALT and the change in HBV 
DNA levels.  
Approximately 15 evaluable patients with chronic HDV infection with detectable HDV RNA by 
quantitative polymerase chain reaction (qPCR) will be enrolled. The duration of the study for 
each patient is approximately 52 weeks and divided into three periods:  Screening (up to 
4 weeks), Treatment (24 weeks), and Follow-up (4 weeks after last dose of study drugs for the 
primary follow-up visit, and every 4 weeks safety follow-up visits for 20 weeks thereafter). The 
24-week Follow-up Period after the last dose of study drug is designed to allow evaluation of the
clinical and virologic course after completion of the 24-week Treatment Period.
All study treatments (lonafarnib/ritonavir) will be administered orally. All doses of 
lonafarnib/ritonavir should be taken with food. Patients will be instructed to take the study 
medication at 12-hour intervals ±2 hours. 
PK sampling will be conducted on all patients. Single blood samples will be obtained for trough 
drug measurements at each study visit starting at Week 2 and through Week 16. 
Blood samples will be obtained for full PK analysis when patients have maintained a stable dose 
of lonafarnib/ritonavir for at least 2 weeks between Study Weeks 8 and 16 as follows (see 
Section 3.6.2 for dose-titration details). A stable dose is defined as a dose of lonafarnib/ritonavir 
that has been taken for at least 2 weeks and that is likely to be the highest tolerable dose taken by 
the patient during the study. Samples for full PK will be taken as follows predose (within 30 
minutes before the first dose of the day) and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h postdose.  The 
second daily dose of study drug may not be taken until after the 12 hour sample is obtained.  On 
the days that PK sampling occurs, patients will remain in clinic at least 13 hours.  
If the patient has not been at a stable dose for the 2 weeks before the study visit, PK sampling 
will be performed at a future visit, after the patient has been on a stable dose for at least 2 weeks. 
3.2 Rationale for Study Design 
This will be conducted as an open-label study. It is not known whether lonafarnib/ritonavir 
titration will increase tolerability and allow greater systemic exposure that can result in a 
decrease in viral load. The open-label design was chosen to allow flexibility in dosing to 
determine parameters for dose titration for further investigation in a randomized, blinded, 
parallel-group study of lonafarnib/ritonavir. It is anticipated that individual tolerability to 


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lonafarnib may vary and that some, but not all, patients may tolerate escalation to higher doses. 
Safety and tolerability will be assessed by the Investigator before each escalation of the 
lonafarnib dose. The dose of lonafarnib may be decreased or increased as outlined in Section 
3.6.2. The protocol allows for decrease in the dose of lonafarnib at any time for reasons of safety 
and tolerability. Strict guidelines are provided for dose escalation, including minimum 
timeframes at the previous dose, assessment of AEs, and monitoring.  
The primary efficacy evaluation is an objective endpoint, HDV viral load, which will be 
evaluated during the study treatment. It is well accepted that HDV viral load does not change 
appreciably in the absence of effective therapy. 
The duration of treatment (24 weeks) is based on results of previous clinical studies, which have 
tested various doses of lonafarnib with and without ritonavir for up to 3 months. In these studies, 
treatment with lonafarnib with and without ritonavir was associated with decreases in viral load. 
Longer treatment may allow further decreases in viral load and eradication of HDV RNA in 
some patients. The 24-week follow-up period is chosen in order to assess the virologic course 
after 24 weeks of treatment. Based on other studies of antiviral agents, including interferon alpha 
for chronic HDV infection, it is possible that eradication of HDV RNA during or shortly after 
treatment may be associated with relapse. It is also possible that a host-induced flare due to 
“awakening” of host immune function and/or viral flare may occur during or after antiviral 
treatment; patients will be closely monitored and the risks of these outcomes will be assessed 
during the 24-week Follow-up Period. 
Blood sample collection will be performed to assess lonafarnib exposures at steady state, that is, 
once the patient is on a stable dose for at least 2 weeks. This approach will allow an exposure-
response assessment (eg, the relationship of lonafarnib exposure vs. decrease in viral load).  
This clinical trial will be conducted as a single-site study at a facility (Medizinische Hochschule 
Hannover [MHH, Hannover Medical School]) with expert personnel and full capabilities for 
identification, assessment, monitoring, and follow-up of patients with chronic HDV infection.  
3.3 Rationale for Use of Lonafarnib in Combination with Ritonavir in HDV 
Experience from Study EIG-300 (LOWR-1 and 2) suggests that administration of lonafarnib 
with ritonavir may allow higher lonafarnib systemic exposures while limiting the GI exposure to 
the drug, and thereby minimize adverse effects. 
Lonafarnib monotherapy has been shown to decrease viral load in patients with chronic HDV 
infection in a dose-dependent manner. Given the wide intersubject variability in exposure when 
administered orally as well as the GI toxicities that may be dose-limiting, co-administration of 
lonafarnib with ritonavir, as a PK enhancer, may allow lower lonafarnib doses to be administered 
to the gut and minimize GI adverse effects while resulting in higher systemic levels. Currently, it 
is not known whether initiation of lonafarnib at a lower dose may allow greater tolerability over 
time, and whether the dose of lonafarnib may be titrated upward to allow a higher dose to be 
administered. The previous observation that lonafarnib treatment was not associated with viral 
resistance suggests that dose titration is not likely to be associated with development of viral 
resistance.   


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3.4 Selection of Study Population 
The study participants will consist of male or female patients 18 to 65 years old who have 
chronic HDV infection documented by detectable HDV RNA by qPCR who meet the inclusion 
and exclusion criteria specified below. 
3.4.1 
Inclusion Criteria 
A patient may be included in this study if he or she meets all of the following criteria: 
1. Willing and able to comply with study procedures and provide written informed consent.
2. Male or female, 18 to 65 years of age, inclusive.
3. Has a body mass index (BMI) of ≥18 kg/m2 and has a body weight of ≥45 kg.
4. Chronic HDV infection documented by a positive HDV antibody (Ab) test of at least
6 months duration and detectable HDV RNA by qPCR at study entry.
5. Liver biopsy demonstrating evidence of chronic hepatitis.
If no liver biopsy is available, the patient must be willing to consent to and have no
contraindication to liver biopsy. Liver biopsy will be performed during screening.
6. ALT <10x ULN
7. Electrocardiogram (ECG) demonstrating no acute ischemia or clinically significant
abnormality and a QT interval corrected for heart rate (QTc) of <450 ms using Fridericia
correction (ICH Guidance for Industry E14: Clinical Evaluation of QT/QTc Interval
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs).
8. Females who meet the following criteria may be eligible to enter the study:
a.
Of nonchildbearing potential—defined as women who are surgically sterile (have had
bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), have medically
documented ovarian failure, or are postmenopausal (amenorrheic for more than
2 years, age appropriate, and confirmed by FS] level indicating a postmenopausal
state).
b. Of childbearing potential—defined as women who have an intact uterus and ovaries
and are within 1 year since the last menstrual period who
–
Are not pregnant and have negative serum pregnancy test at screening and a
negative urine pregnancy test on the Baseline/Day 1 Visit before randomization.
–
Are not lactating or breastfeeding.
–
Agree to use two of the following contraceptive methods until at least 90 days
after last dose of study drug, of which at least one must be a barrier method:

Hormonal contraceptives for at least 3 months before the start of screening
and for at least 90 days after last dose of study drug

IUD in place for at least 3 months before the start of screening and until at
least 90 days after last dose of study drug.

Double-barrier methods (use of condom [male partner] with either diaphragm
with spermicide or cervical cap with spermicide) from the start of screening
until at least 90 days after last dose of study drug.
9. Surgical sterilization of the partner (vasectomy for 1 month before the start of screening
and maintenance throughout study and at least 90 days after the last dose of study drug).


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Males with female partners who are of childbearing potential (see above) who meet the 
following criteria may be eligible to enter the study: 
a.
Are surgically sterile
or
b. Agree to practice two effective forms of birth control from those listed below from
the start of screening until at least 90 days after their last dose of study drug, at least
one of which must be a barrier method:
–
Consistently and correctly use a condom
and
–
Their partner must agree to use a hormonal contraceptive or a nonhormonal
barrier method (IUD or diaphragm with spermicide or cervical cap with
spermicide).37
3.4.2 
Exclusion Criteria 
A patient will be excluded from this study if he or she meets any of the following criteria: 
     General Criteria 
1. Participation in a clinical trial with or use of any investigational agent within 30 days of
start of screening.
2. Pregnant or lactating/breastfeeding.
3. Previous use of lonafarnib.
Patients who previously participated in a clinical trial of lonafarnib but are confirmed to
have received placebo are allowed.
     Disease-related Criteria 
4. Co-infected with human immunodeficiency virus (HIV) or active infection with hepatitis
C virus (HCV).
5. Positive results for HIV or HCV Ab at screening. Patients with a positive HCV Ab at
screening are allowed if they have completed a curative antiviral regimen and documented
to be HCV RNA negative (undetectable) at least 3 months before screening and at
screening.
6. Active jaundice defined by total bilirubin level >2.0 mg/dL and known not to have
Gilbert’s disease.
7. A CPT score of >6 based on screening laboratory results
8. Decompensated liver disease or cirrhosis as defined by the presence of any of the
following on screening laboratory tests:
a.
Bilirubin level >2.0 mg/dL
b. Albumin level <3.0 g/dL
c.
Platelet count <90,000 cells/mm3
d. International normalized ratio (INR) ≥1.5
9. History of bleeding esophageal varices, ascites, or hepatic encephalopathy.
10. Patients with any of the following abnormal laboratory test results at screening:
a.
White blood cell (WBC) count <3,000 cells/mm3


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b. Absolute neutrophil count (ANC) <1500 cells/mm3
c. Hemoglobin <11 g/dL for women and <12 g/dL for men
d. Abnormal thyroid-stimulating hormone (TSH), T4, or T3 levels; unless the patient is 
stable on thyroid hormone replacement therapy 
11. Significant renal dysfunction, defined as serum creatinine concentration ≥1.5 times the
ULN or an estimated glomerular filtration rate (eGFR) < 80 mL/min at screening, based
on the Cockcroft-Gault equation
12. Evidence of another form of viral hepatitis (not including HBV or HCV) or another form
of liver disease (eg,  autoimmune liver disease, primary biliary cirrhosis, primary
sclerosing cholangitis, Wilson’s disease, alcoholic liver disease, nonalcoholic
steatohepatitis, hemochromatosis, alpha-1-anti-trypsin deficiency)
13. Evidence of hepatocellular carcinoma
14. Patients with any one of the following:
a.
An eating disorder or alcohol abuse within the past 2 years
b. Excessive alcohol intake defined as follows:  >20 g/day for females (1.5 standard
alcohol drinks) or >30 g/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)
15. In the opinion of the Investigator, an alcohol use pattern that will interfere with study
conduct
16. Drug abuse within the previous 6 months before the screening visit with the exception of
medically prescribed cannabinoids and their derivatives
17. History or clinical evidence of any of the following:
a.
Immunologically mediated disease (eg, rheumatoid arthritis, inflammatory bowel
disease, severe psoriasis, systemic lupus erythematosus) that requires more than
intermittent nonsteroidal anti-inflammatory medications for management or that
requires use of systemic corticosteroids in prior 6 months (eg, inhaled asthma
medications are allowed)
b. History of or evidence of retinal disorder or clinically relevant ophthalmic disorder.
c.
Any malignancy within 5 years of the start of screening. Exceptions are superficial
dermatologic malignancies (eg, squamous cell or basal cell skin cancer treated with
curative intent).
d. Significant or unstable cardiac disease (eg, angina, congestive heart failure,
uncontrolled hypertension, history of arrhythmia)
e.
Chronic pulmonary disease (eg, chronic obstructive pulmonary disease) associated
with functional impairment
f.
Pancreatitis
g. Severe or uncontrolled psychiatric disease, including severe depression, history of
suicidal ideation, suicidal attempts, or psychosis requiring medication and/or
hospitalization
18. Solid organ transplantation, including liver
Criteria Related to Use of Selected Medications
19. Use of alpha interferon, either interferon alfa-2a or interferon alfa-2b, pegylated interferon
alfa-2a, or pegylated interferon alfa-2b within 2 months before the start of screening


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20. Concomitant use of any of the following:  
a. Medications or foods that are known moderate or strong inducers or inhibitors of 
CYP3A4 or CYP2C19  
b. Drugs known to prolong the PR or QT interval unless otherwise described in protocol 
(i.e. Ondansetron). 
c. Receipt of systemic immunosuppressive therapy within the 3 months before start of 
screening.  
d. Statins, due to inhibition of mevalonate synthesis, which reduces protein prenylation 
e. Medications contraindicated in the prescribing information for ritonavir: 
– Alpha1-adrenoreceptor antagonist:  alfuzosin HCL 
– Analgesics*:  pethidine*, piroxicam*, propoxyphene* 
– Antiarrhythmics: amiodarone, flecainide, propafenone, quinidine, bepridil*, 
encainide* 
– Antibiotic*:  fusidic acid* 
– Antifungal: voriconazole 
– Antihistamines*:  astemizole*, terfenadine* 
– Antimycobacterial*:  rifabutin* 
– Ergot derivatives:  dihydroergotamine, ergonovine*, ergotamine, 
methylergonovine 
– Gastrointestinal motility agent:  cisapride 
– Herbal products:  St. John’s wort (hypericum perforatum) 
– HMG-CoA reductase inhibitors:  lovastatin, simvastatin 
– Antipsychotics*/Neuroleptic:  clozapine*, pimozide, quetiapine* 
– Phosphodiesterase type 5 (PDE5) enzyme inhibitor: sildenafil [Revatio®] only 
when used for the treatment of pulmonary arterial hypertension (PAH), avanafil*, 
vardenafil* 
– Sedative/hypnotics:  clorazepate*, diazepam*, estazolam*, flurazepam*, oral 
midazolam, triazolam 
(Sources:  Prescribing Information for Norvir® [ritonavir] Tablets, 2015.  
*Additional terms from the Summary of Product Characteristics for Norvir® 
[ritonavir] tablets, 2014) 
f. History or evidence for any intolerance or hypersensitivity to lonafarnib, ritonavir, or 
other substances that are part of the study medication. 
     Other Medical Conditions 
21. Other significant medical condition that may require intervention during the duration of 
the study. 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 patient of 
participation in the trial. 


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3.4.3 
Replacement of Patients in Study 
Patients who discontinue the study before Week 12 for reasons other than an AE may be 
replaced on approval of the Sponsor. 
3.4.4 
Early Discontinuation of Study Treatment 
Study treatment may be discontinued for any of the following reasons: 
• Unacceptable toxicity  
• Patient request or withdrawal of consent 
• Pregnancy 
• Protocol deviation (at the Sponsor’s discretion) 
• Investigator discretion 
• Termination of study by the Sponsor  
 
If early discontinuation of study treatment is being considered, it must be immediately reported  
to the Medical Monitor or designee to discuss the circumstances of the case.  
3.4.5 
Early Withdrawal from Study 
If a patient discontinues study treatment early, every effort should be made to encourage the 
patient to return to the clinic as soon as possible for early termination (ET) assessments (refer to 
the Schedule of Assessments in Appendix A). If a patient discontinues study treatment after 
Week 12 but before Week 24 the ET visit should include the ophthalmic examination. Patients 
who discontinue study drug treatment are encouraged to remain in the study through the 24-week 
follow up period.  For patients terminating study participation during the off-treatment follow-up 
phase additional early termination visits are not required.  The reason for early withdrawal will 
be noted in the appropriate case report form (CRF). 
3.4.6 
Study Termination by the Sponsor 
Eiger BioPharmaceuticals reserves the right to terminate the study at any time. Reasons for 
terminating the study may include but are not limited to the following: 
• Potential health hazard to patients, as indicated by the incidence or severity of AEs in 
this or other studies 
• Unsatisfactory patient enrollment  
• Inaccurate or incomplete data recording 
• Stopping rules and criteria specific to this protocol 
• Administrative reasons 
 
In addition, the regulatory agency or the site’s Independent Ethics Committee (IEC) has the 
authority to stop the study. 


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3.5 Investigational Products 
3.5.1 
Product Identity and Storage 
Lonafarnib—Lonafarnib is a crystalline solid with a melting point of approximately 200°C and 
is nonhygroscopic. Lonafarnib is formulated in No. 3 and No. 4, hard gelatin, white, opaque 
capsule shells for oral administration. Each No. 4 capsule contains 50 mg of lonafarnib. Each 
No. 3 capsule contains 75 mg of lonafarnib. Excipients include povidone, poloxamer 188, 
croscarmellose sodium, silicon dioxide, and magnesium stearate and are considered safe because 
they are well tested and commonly used in marketed products. Lonafarnib capsules are 
formulated in a 1:1 drug:povidine co-precipitate ratio to achieve optimal bioavailability. 
Lonafarnib capsules are provided in white, opaque, high-density polyethylene (HDPE) bottles 
with polypropylene twist-off caps,. Lonafarnib is stable if stored at 15°C–25°C (59°F–77°F). A 
“use by” date is included on the product label. Lonafarnib should be stored at room temperature 
15°C–25°C (59°F–77°F) in a locked, limited-access storage area before dispensing. 
Ritonavir—The formulation of ritonavir (Novir®) marketed in Germany (AbbVie Deutschland 
GmbH &Co, Ludwigshafen, Germany) will be provided by Eiger BioPharmaceuticals during the 
study. Ritonavir will be supplied as 100-mg, white, film-coated, ovaloid tablets debossed with 
the "a" logo and the code NK (Prescribing Information for Norvir® [ritonavir] Tablets, 
2015; Summary of Product Characteristics for Norvir® [ritonavir] tablets, 2014) in white, 
opaque, HDPE bottles with polypropylene twist-off caps.  
Ritonavir should be stored at or below 30°C (86°F). Exposure to temperatures up to 50°C 
(122°F) for 7 days is permitted. Exposure of this product to high humidity outside the original or 
USP-equivalent tight container (60 mL or less) for longer than 2 weeks is not recommended. 
3.5.2 
Study Treatment Distribution 
Patients will be provided appropriate quantities of study drug based on dosage, for a period of 2 
or 4 weeks. Lonafarnib and ritonavir will be supplied in separate, clearly marked bottles. Patients 
will be provided quantities sufficient for a 2-week or 4-week period based on the individual 
patient’s titration schedule.  
3.6 Dosage and Titration  
3.6.1 
Dosage 
All study treatments (lonafarnib/ritonavir) are administered orally. All doses of 
lonafarnib/ritonavir should be taken with food. Patients will be instructed to take the study 
medication at 12-hour intervals ±2 hours.  
Dosages are outlined in Table 3. Ritonavir doses are to remain at 100 mg bid during the 
Treatment Period. The planned combinations of lonafarnib and ritonavir are 50 mg bid/100 mg 
bid, 75 mg bid/100 mg bid, and 100 mg bid/100 mg bid. All dose escalations will be based on 
patient tolerability (see Section 3.6.2.2) and approval of the Investigator. Doses of lonafarnib 
may be reduced and/or discontinued for patient tolerability; the dose of ritonavir will remain at 
100 mg bid, unless lonafarnib is discontinued, in which case ritonavir will be discontinued as 
well Section 3.6.2.1).  


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Table 3 
Planned Dose Combinations During Study 
Study Day 
Dose 
Lonafarnib  
Ritonavir 
Days 1–28 
50 mg bid 
100 mg bid 
On or after Day 29a, b 
75 mg bid 
100 mg bid 
On or after Day 43a, b 
100 mg bid 
100 mg bid 
bid = twice daily 
a Patients will be evaluated for tolerability at each dose level as described 
 in Section 3.6.2.2. 
b Only if the patient has been at the previous lonafarnib/ritonavir dosage level for at least 2 weeks.  
3.6.2 
Dose Titration 
3.6.2.1 Dose Levels 
At each study visit, patients will be evaluated for tolerability by objective criteria (AEs and body 
weight) as outlined in Section 3.6.2.2.  
Patients will be instructed to record doses of drugs taken in a patient diary. The patient diary 
should be brought to the clinic at each study visit during the Treatment Period. 
Planned Titration—Lonafarnib/ritonavir dosages start on Day 1 (baseline, Week 0) at 
50 mg bid/100 mg bid (Figure 5). On or after Day 29, if the lonafarnib/ritonavir dosage of 
50 mg bid/100 mg bid is tolerated and with approval of the Investigator, the dosage of 
lonafarnib/ritonavir may be escalated to 75 mg bid/100 mg bid. On or after Day 43, if the 
lonafarnib/ritonavir dosage of 75 mg bid/100 mg bid is tolerated for at least 2 weeks and with 
approval of the Investigator, the dosage of lonafarnib/ritonavir may be escalated to 
100 mg bid/100 mg bid.  
The goal of dose titration is to determine dosages that are well tolerated for chronic (24 weeks) 
dosing. The treatment duration at the initial tolerated dose of lonafarnib/ should be maintained 
for at least 4 weeks before upward titration; the treatment duration at a particular dosage level for 
any subsequent dose escalation is at least 2 weeks. Therefore, the above treatment intervals 
should be considered as minimum intervals, and longer treatment durations may be used to 
optimize patient tolerability. 
 


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Figure 5 Planned Dose-Titration Scheme 
 
Note:  A stable dose is defined as a dose of lonafarnib/ritonavir that has been taken for at least 2 weeks and that is 
likely to be the highest tolerable dose taken by the patient during the study. 
 
Down Titration—If at any time the current twice daily (bid) lonafarnib dosage is not tolerable, 
the lonafarnib dosage will be reduced to once daily (qd); if the once-daily lonafarnib dosage is 
not tolerable, the lonafarnib/ritonavir will be stopped (Figure 6). Thus, the dosage for a patient 
taking lonafarnib/ritonavir 50 mg bid/100 mg bid will be reduced to lonafarnib/ritonavir 
50 mg qd/100 mg bid; if the patient does not tolerate this regimen, then all study drug treatment 
should be discontinued. For a patient taking lonafarnib/ritonavir 75 mg bid/100 mg bid, the dose 
will be reduced to lonafarnib/ritonavir 75 mg qd/100 mg bid; if the patient does not tolerate this 
regimen, then all study dug treatment should be discontinued. Similarly, for a patient taking 
lonafarnib/ritonavir 100 mg bid/100 mg bid, the dose will be reduced to lonafarnib/ritonavir 
100 mg qd/100 mg bid; if the patient does not tolerate this regimen, then all study drug treatment 
should be discontinued. 
If lonafarnib/ritonavir has been discontinued in a patient for tolerability reasons, it may not be 
restarted; the patient should complete the early termination procedures and should enter the 
Follow-up Period. All follow-up procedures should be conducted according to the Schedule of 
Events (Appendix A). 
 


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Figure 6 Dose Down-Titration Scheme 
 
 
Re-Escalation—At the direction of the Investigator, each patient whose dose has been decreased 
but not discontinued will have the option to re-escalate his or her dose according to the schedule 
shown in Figure 7. The dose level should not be increased until the previous dose has been 
maintained for at least 2 weeks and should be done with the approval of the Investigator. Thus, a 
patient who is taking lonafarnib/ritonavir 50 mg qd/100 mg bid may advance to 
lonafarnib/ritonavir 50 mg bid/100 mg bid; if this is well tolerated for at least 2 weeks, then the 
patient may advance to lonafarnib/ritonavir 75 mg bid/100 mg bid. A patient who has taken 
lonafarnib/ritonavir 75 mg qd/100 mg bid for at least 2 weeks may advance to 
lonafarnib/ritonavir 75 mg bid/100 mg bid; if this is well tolerated for at least 2 weeks, then the 
patient may advance to lonafarnib/ritonavir 100 mg bid/100 mg bid.  
The goal of dose titration is to determine a dosage that is well tolerated for chronic (24 weeks) 
dosing. Therefore, the above treatment intervals should be considered as minimum intervals, and 
longer treatment durations at a particular dose level may be used to optimize patient tolerability. 
Note that ritonavir doses should be maintained at 100 mg bid, unless lonafarnib is discontinued, 
in which case ritonavir should be discontinued as well. 
 


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Figure 7 Dose Re-Escalation Scheme 
 
 
3.6.2.2 Evaluation of Tolerability 
The Investigator will evaluate all AEs and laboratory abnormalities. The intensity (ie, “grade”) 
of an AE will be based on the definitions in the Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.03 (CTCAE 2010), and the guidelines provided in Section 6.4.1. 
Based on findings from previous studies, the following AEs are expected events with lonafarnib 
administration and occur with greater frequency and severity at higher exposures: diarrhea, 
nausea, dyspepsia, vomiting, decrease in appetite, anorexia, fatigue, and weight loss. The criteria 
for assessing the intensity of these AEs from the CTCAE are listed in Table 4.  
The goal is to determine a dosage suitable for chronic dosing of lonafarnib/ritonavir. The 
following guidelines will apply to management of AEs, patient tolerability, and lonafarnib dose 
adjustments: 
• If a patient experiences any study-drug-related AE that is Grade 3 or above (as 
defined in Section 6.4.1), the patient’s lonafarnib dose must be decreased according 
to the dose down-titration scheme (Figure 6).  If a patient experiences unintentional 
weight loss of at least 3 kg or 5% from baseline weight, whichever is greater, the 
Investigator should assess for factors contributing to weight loss and encourage 
optimum nutrition. The lonafarnib dose may be decreased according to the dose 
down-titration scheme at the Investigator’s discretion. If a patient experiences 
unintentional study-drug related weight loss of at least 6 kg or 10% from baseline 
weight, whichever is greater, and this is considered to be study drug related, then the 
patient’s lonafarnib dose must be decreased according to the dose down-titration 
scheme.  In this instance, “weight loss” should be entered as an AE and outcome 
captured as “resulted in dose reduction.” 
• If a patient develops a study-drug-related Grade 1 or 2 AE (as defined in Section 
6.4.1), the Investigator will exercise medical judgement regarding the need to adjust 


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the lonafarnib dose.  If a patient experiences unintentional weight loss of at least 3 kg 
or 5% from baseline weight, whichever is greater, the Investigator should assess for 
factors contributing to weight loss and encourage optimum nutrition.  The Lonafarnib 
dose may be decreased according to the dose down-titration scheme at the 
Investigator’s discretion.  If a patient experiences unintentional study-drug related 
weight loss of at least 6 kg or 10% from baseline weight, whichever is greater, and 
this is considered to be study drug related, then the patient’s Lonafarnib dose must be 
decreased according to the dose down-titration scheme.  In this instance, “weight 
loss” should be entered as an AE and outcome captured as “resulted in dose 
reduction.” 
 
Ritonavir doses should be maintained at 100 mg bid, unless lonafarnib is discontinued, in which 
case ritonavir should be discontinued as well. 


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Table 4 
Grades of Common Expected Adverse Events with Lonafarnib Treatment as 
Defined in the CTCAE (Version 4.03) 
Adverse 
Event 
Grade 
1 
2 
3 
4 
5 
Diarrhea 
Increase of <4 
stools per day 
over baseline; 
mild increase 
in ostomy 
output 
compared to 
baseline 
Increase of 4–6 
stools per day over 
baseline; moderate 
increase in ostomy 
output compared to 
baseline 
Increase of ≥7 stools 
per day over baseline; 
incontinence; 
hospitalization 
indicated; severe 
increase in ostomy 
output compared to 
baseline; limiting self 
care ADL 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Nausea  
Loss of 
appetite 
without 
alteration in 
eating habits 
Oral intake 
decreased without 
significant weight 
loss, dehydration or 
malnutrition  
Inadequate oral caloric 
or fluid intake; tube 
feeding; TPN or 
hospitalization 
indicated 
— 
— 
Dyspepsia 
Mild 
symptoms; 
intervention 
not 
indicated 
Moderate 
symptoms; medical 
intervention 
indicated 
Severe symptoms; 
surgical 
intervention indicated 
— 
— 
Vomiting 
1–2 episodes 
(separated by 
5 minutes) in 
24 hours 
3–5 episodes 
(separated by 
5 minutes) in 
24 hours 
≥6 episodes (separated 
by 5 minutes) in 
24 hours; tube feeding, 
TPN or hospitalization 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Anorexia 
Loss of 
appetite 
without 
alteration in 
eating habits 
Oral intake altered 
without significant 
weight loss or 
malnutrition; oral 
nutritional 
supplements 
indicated  
Associated with 
significant weight loss 
or malnutrition (eg, 
inadequate oral caloric 
and/or fluid intake); 
tube feeding or TPN 
indicated  
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Fatigue 
Fatigue 
relieved by 
rest 
Fatigue not relieved 
by rest; limiting 
instrumental ADL 
Fatigue not relieved by 
rest; limiting self care 
ADL 
— 
— 
Weight 
loss 
5% to <10% 
from baseline; 
intervention 
not indicated 
10% to <20% from 
baseline; nutritional 
support indicated 
≥20% from baseline; 
tube feeding or TPN 
indicated 
— 
— 
ADL = activities of daily living; TPN = total parenteral nutrition 
 
3.6.2.3 Management of Flares 
Patients should be followed closely for the possibility of hepatic flare, as defined by an increase 
in ALT of ≥10x the ULN. A flare may be associated with an increase in viral replication (“viral 


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flare”) or with a decrease in viral replication (“hepatic flare”). An unscheduled visit may be used 
to evaluate the patient. 
For patients who are not on concurrent nucleos(t)ide therapy, consideration should be given to 
initiation of nucleos(t)ide therapy to address HBV reactivation/flare. 
3.6.3 
Missed Doses 
Patients will be instructed to self-administer lonafarnib and ritonavir at 12-hour intervals 
±2 hours. If a dosing window is missed, the patient should skip the dose completely. Patients 
should not “double up” at the next scheduled dose period. 
3.7 Treatment Adherence and Product Accountability 
Patients will receive instructions regarding how to self-administer all study drugs. Patients will 
also be instructed to bring their patient diary and to return study drug bottles when they come to 
the clinic for each study visit during the Treatment Period. Adherence with the prescribed 
regimen for each study drug will be measured using bottle and capsule/tablet counts. 
Patients will be instructed to record all study drug administrations in the patient diary. A sample 
patient diary is included in Appendix D. 
3.8 Prior and Concomitant Therapies 
All prior medications taken within 28 days before baseline (Day 1) and all concomitant 
medications taken during the study will be recorded in the CRF. All prior treatments 
administered for HDV and HBV infections will be recorded on the CRF. 
3.8.1 
Prior Therapies 
Patients are prohibited from using systemic immunosuppressive therapy within the 3 months 
before start of screening and from using alpha interferon, either interferon alfa-2a or interferon 
alfa-2b, or pegylated interferon alfa-2a or alfa-2b within 2 months before the start of screening.  
Patients are prohibited from participating in a clinical trial with or receiving an investigational 
product within 30 days before the start of screening. 
3.8.2 
Concomitant Therapies During the Treatment Period 
3.8.2.1 Treatment of Gastrointestinal Symptoms 
Gastrointestinal (GI) symptoms (diarrhea, nausea, dyspepsia, vomiting, and decreased appetite) 
are the most common AEs reported with lonafarnib single-agent therapy. Ritonavir may be 
associated with diarrhea. Occurrence of diarrhea may reduce the absorption of lonafarnib, 
ritonavir, and other medications from the GI tract. Diarrhea may result in loss of fluids and 
dehydration, which can be severe, and require hospitalization for supportive care. Patients 
should receive therapy (antacids, anti-emetics, or anti-diarrheals) for GI symptoms at the 
earliest signs in order to avoid possible severe complications. Electrolytes should be monitored 
in cases of diarrhea and volume depletion. Use of symptomatic treatments for GI toxicity should 
be recorded in the CRF.  


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Ondansetron does not inhibit or induce enzymes in the CYP system. No interaction is expected 
with concomitant administration with lonafarnib.  
Famotidine has not been associated with any clinically significant drug-drug interactions. No 
significant interference with CYP system has been identified; thus, no interaction is expected 
with concomitant administration with lonafarnib. 
Omeprazole inhibits CYP2C19 and P-glycoprotein (P-gp) and is completely metabolized, 
specifically by CYP3A4 and CYP2C19. Dose adjustments are typically not required when 
administering omeprazole with other medications metabolized by CYP2C19; however, dose 
adjustments are required for omeprazole when administered to patients with hepatic impairment 
(refer to the Prilosec Product Label for additional information). 
3.8.2.2 Prohibited Medications 
Use of the following medications is prohibited during the conduct of the study:   
• Drugs known to prolong the PR or QT interval 
• Use of ondansetron for symptomatic treatment of nausea is allowed; prudent medical 
judgment should be applied as to the dose and duration of its use.  
• Systemic immunosuppressive therapies 
• Statins, due to inhibition of mevalonate synthesis, which reduces protein prenylation. 
Use of any prescription, nonprescription or natural medications (herbal medicines) is excluded 
unless use of such medication is medically necessary; as drug-drug interactions with lonafarnib 
and ritonavir and other drugs have not been fully explored; all concomitant medications should 
be appropriately monitored for possible interactions throughout the course of the study. 
Drugs highly dependent on CYP3A4 for clearance are contraindicated with ritonavir (Table 
5). Appendix C lists all drugs contraindicated with the use of ritonavir and also lists drugs that 
have established or other potentially significant drug interactions when used in combination with 
ritonavir. 
Table 5 
Drugs Contraindicated with Use of Ritonavir 
Class 
Drug 
Clinical Outcome/Rationale 
Alpha1- adrenoreceptor 
antagonist 
Alfuzosin HCL 
Potential for hypotension. 
Increased plasma concentrations 
of alfuzosin which may lead to 
severe hypotension 
Analgesics* 
Pethidine*, piroxicam*, 
propoxyphene* 
Increased plasma concentrations 
of norpethidine, piroxicam and 
propoxyphene. Thereby, 
increasing the risk of serious 
respiratory depression or 
haematologic abnormalities, or 
other serious adverse effects from 
these agents. 
Antiarrhythmics 
Amiodarone, bepridil*, 
encainide*, flecainide, 
propafenone, quinidine 
Potential for cardiac arrhythmias. 
Increased plasma concentrations 
of amiodarone, bepridil, 
encainide, flecainide, 


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Class 
Drug 
Clinical Outcome/Rationale 
propafenone, quinidine. Thereby, 
increasing the risk of arrhythmias 
or other serious adverse effects 
from these agents. 
Antibiotic* 
Fusidic acid* 
Increased plasma concentrations 
of fusidic acid and ritonavir. 
Antifungal 
Voriconazole 
Co-administration of 
voriconazole with ritonavir 400 
mg every 12 hours significantly 
decreases voriconazole plasma 
concentrations and may lead to 
loss of antifungal response. 
Voriconazole is contraindicated 
with ritonavir doses of 400 mg 
every 12 hours or greater  
Antihistamines* 
Astemizole*, terfenadine* 
Increased plasma concentrations 
of astemizole and terfenadine. 
Thereby, increasing the risk of 
serious arrhythmias from these 
agents. 
Antimycobacterial* 
Rifabutin* 
Concomitant use of ritonavir 
dosed as an antiretroviral agent 
(600 mg twice daily) and 
rifabutin due to an increase of 
rifabutin serum concentrations 
and risk of adverse reactions 
including uveitis). 
Recommendations regarding use 
of ritonavir dosed as a 
pharmacokinetic enhancer with 
rifabutin are noted in section 4.5 
of the Summary of Product 
Characteristics 
Antipsychotics*/Neuroleptics 
Clozapine*, pimozide 
Potential for cardiac arrhythmias. 
Increased plasma concentrations 
of clozapine and pimozide. 
Thereby, increasing the risk of 
serious haematologic 
abnormalities, or other serious 
adverse effects from these agents. 
 
Quetiapine* 
Increased plasma concentrations 
of quetiapine which may lead to 
coma. The concomitant 
administration with quetiapine is 
contraindicated 
Ergot Derivatives 
Dihydroergotamine, ergonovine, 
ergotamine, methylergonovine 
Potential for acute ergot toxicity 
characterized by vasospasm and 
ischemia of the extremities and 
other tissues including the central 
nervous system. 


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Class 
Drug 
Clinical Outcome/Rationale 
Gastrointestinal Motility Agent 
Cisapride 
Increased plasma concentrations 
of cisapride. Potential for cardiac 
arrhythmias. 
Herbal Products 
St. John's Wort (hypericum 
perforatum) 
Co-administration of NORVIR 
with St. John’s Wort may result 
in decreased ritonavir plasma 
concentrations and may lead to 
loss of virologic response and 
possible resistance to NORVIR or 
to the class of protease inhibitors. 
HMG-CoA Reductase Inhibitors: 
Lovastatin, simvastatin 
Increased plasma concentrations 
of lovastatin and simvastatin; 
thereby, increasing the risk of 
myopathy including 
rhabdomyolysis 
PDE5 enzyme inhibitor 
Avanafil* 
Increased plasma concentrations 
of avanafil  
 
Sildenafil (Revatio®) only when 
used for the treatment of 
pulmonary arterial hypertension 
(PAH) 
A safe and effective dose has not 
been established when used with 
ritonavir. There is an increased 
potential for sildenafil- associated 
adverse events, including visual 
abnormalities, hypotension, 
prolonged erection, and syncope. 
 
Vardenafil* 
Increased plasma concentrations 
of vardenafil  
Sedative/hypnotics 
Clorazepate*, diazepam*, 
estazolam*, flurazepam*, oral 
midazolam, triazolam 
Prolonged or increased sedation 
or respiratory depression. 
Thereby, increasing the risk of 
extreme sedation and respiratory 
depression from these agents 
Sources:  Prescribing Information for Norvir® [ritonavir] Tablets, 2015. *Additional terms from the Summary of 
Product Characteristics for Norvir® [ritonavir] tablets, 2014 
 
3.8.2.3 Medications to be Used with Caution 
3.8.2.3.1 Due to Possible Interaction with Lonafarnib 
An in vitro CYP inhibition study conducted with lonafarnib suggests that lonafarnib may be a 
mechanism-based inhibitor of CYP3A4 and CYP2C19 enzymes. Any medications that are 
primarily metabolized by CYP3A4 should be avoided. Any medications that are primarily 
metabolized by CYP2C19 should be used with caution. If at all possible, alternative therapeutic 
agents that are not CYP3A4 substrates, inducers, or inhibitors or are less potent CYP3A4 
substrates, inducers, or inhibitors should be considered. Concomitant administration of 
medications that are primarily metabolized by CYP3A4 or CYP2C19 may result in large 
increases in serum levels of these medications that may precipitate unwanted toxicities. 
Entecavir, tenofovir, lamivudine, adefovir, and telbivudine do not substantially inhibit or induce 
the enzymes in the CYP system. Therefore an interaction with lonafarnib is not anticipated due 


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to CYP enzymes; however, there is a potential for interaction of lonafarnib with tenofovir due to 
inhibition of P-gp, BCRP, and OATP1B1 inhibition (see below). 
In vitro tests suggest that lonafarnib may be an inhibitor of efflux pumps P-gp and BCRP and the 
liver uptake transporter OATP1B1. Therefore, concomitant medications that are substrates of 
P-gp, BCRP, and/or OATP1B1should be used with caution. Taking medications that are 
substrates of P-gp, BCRP, and/or OATP1B1 may result in unwanted increases in serum levels of 
these medications, especially medications with a narrow therapeutic index (eg, digoxin, 
loperamide, quinidine, talinolol, vinblastine). 
Because tenofovir is a substrate of P-gp, BCRP, and OATP1B1, concomitant administration of 
lonafarnib and tenofovir may result in increased levels of tenofovir. Therefore, tenofovir should 
be used with caution when co-administered with lonafarnib. 
A source that should be used to check for potential drug-drug interactions is at the following 
website: http://www.Drug-Interactions.com. The website provides a list of drugs known to be 
metabolized by cytochrome P450 enzymes including CYP3A4. Although this list is periodically 
updated, it is not an exhaustive list; therefore, using more than one source is recommended when 
checking for potential interactions. Another source that can be used is by searching the drug 
name and reviewing the product label (Sections 7 and Section 12) at this 
site: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. 
3.8.2.3.2 Due to Possible Interaction with Ritonavir 
Ritonavir inhibits CYP3A4, P-gp, MRP1, OATP-C, and BCRP. Ritonavir induces CYP1A2, 
CYP2C8, CYP2C9, CYP2C19, and MRP1. Ritonavir is a substrate of CYP3A4 and CYP2D6. 
Drugs highly dependent on CYP3A4 for clearance are contraindicated with ritonavir (refer to 
Table 5 and Appendix C). 
While patients are receiving ritonavir, the Investigator should review all other medications taken 
by patients and monitor patients for adverse effects due to metabolism interactions of ritonavir 
with concomitant medications. Initiating treatment with ritonavir in patients receiving 
medications primarily metabolized by CYP3A or initiating medications metabolized by CYP3A 
in patients already maintained on ritonavir may result in increased plasma concentrations of 
these medications. Higher plasma concentrations of concomitant medications can precipitate 
adverse effects that can, potentially lead to severe, life-threatening or fatal events. The potential 
for drug-drug interactions must be considered before initiating therapy or during therapy with 
ritonavir.  
3.8.2.4 Contraception 
Female patients of childbearing potential and male patients with partners of childbearing 
potential must agree to use adequate methods of contraception during the study and for 1 month 
after end of study treatment. Adequate methods of contraception for patients or partner include 
the following:  
• For females, two of the following contraceptive methods, with at least one being a 
barrier method 
– Hormonal contraceptives for at least 3 months before the start of screening and 
for at least 90 days after last dose of study drug  


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– Intrauterine device (IUD) in place for at least 3 months before the start of 
screening and until 90 days after last dose of study drug. 
– Double-barrier methods (use of condom [male partner] with either diaphragm 
with spermicide or cervical cap with spermicide) from the start of screening until 
90 days after last dose of study drug. 
– Surgical sterilization of the partner (vasectomy for 1 month before the start of 
screening and maintenance until at least 90 days after the last dose of study drug. 
• For males 
– Surgical sterilization (vasectomy for 1 month before the start of screening and 
maintenance throughout and for at least 90 days after the last dose of study drug). 
or 
– Two effective forms of birth control from those listed below from the start of 
screening until 90 days after their last dose of study drug, with at least one being a 
barrier method: 
 Consistently and correctly use a condom 
and 
 Their partner must agree to use a hormonal contraceptive or a nonhormonal 
barrier method (IUD or diaphragm with spermicide or cervical cap with 
spermicide) 
 
Male patients must also refrain from sperm donation for 90 days after receiving the last dose of 
study drug. 
3.8.3 
Permitted Therapies During the Follow-up Period 
Alpha interferon and pegylated interferon alfa-2a treatments are allowed during the last 20 weeks 
of the Follow-up Period (that is, starting 4 weeks after last dose of study treatment), if, in the 
opinion of the investigator, they are required for patient safety. Note that for patients who 
experience an HBV reactivation/flare, treatment with nucleos(t)ide therapy should be considered 
in those who are not currently receiving this therapy (see Section 3.6.2.3). 
3.8.4 
Randomization and Blinding 
This is a nonrandomized, open-label study. 


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4 STUDY ASSESSMENTS AND PROCEDURES 
4.1 Description of Assessments  
Written informed consent must be obtained before initiating any study-mandated procedures. See 
Section 8.4 for additional information regarding informed consent 
Study procedures are defined as liver biopsy (if required) and Fibroscan; medical history; 
physical examinations; ophthalmic examinations and retinal photographs; vital sign, height, 
weight, and ECG assessments; and blood draws for molecular (DNA/RNA) analyses and 
serologic tests, PK evaluations, and clinical laboratory tests (blood chemistry and hematology). 
During the study, procedures and observations will be monitored to confirm that study 
requirements are being followed as outlined in the Schedule of Assessments in Appendix A. 
After patients complete the treatment period (through Week 24), they will be followed for every 
4 weeks Follow-Up Visits through Week 48. 
4.1.1 
History, Physical Examination, and Vital Signs 
Medical history, including details regarding illnesses and allergies, date(s) of onset, and whether 
conditions are currently ongoing, and medication history will be collected on all patients during 
screening. The medical history will be updated at the Day 1 Visit and will then serve as the 
baseline for other clinical assessments. 
A comprehensive physical examination will be performed at screening, including all body 
systems pertinent to the patient and CTP scoring and encephalopathy assessment 
(see Appendix B). If clinically significant abnormalities are observed before Day 1, they should 
be reported in the patient’s medical history. If clinically significant abnormalities are observed 
after Day 1, the Investigator should decide if they are new adverse events. 
Brief, directed physical examinations will be performed during the remainder of the study 
performed by a physician, nurse practitioner, physician’s assistant, or nurse). This includes 
weight and vital signs as well as HEENT (head, eyes, ears, nose, and throat), heart, lungs, 
abdomen, and lower extremity.  
Vital signs will be followed throughout the study and will include resting heart rate, blood 
pressure, respiratory rate, and body temperature. Blood pressure and heart rate should be 
measured after 5 minutes in a sitting position. 
Weight will be followed throughout the study and should be measured with inner clothing (ie, 
without heavy outer wear such as jackets and coats) and without shoes. 
4.1.2 
Ophthalmic Examination and Retinal Photography 
Ophthalmic examinations will be performed during the study and will include visual acuity 
examination, dilatation, and slit lamp examination. On slit lamp examination, orbit, eyelids, 
lashes, lacrimal glands, conjunctiva, cornea, sclera, anterior chamber, and iris will examined. On 
the dilated fundus examination, lens, vitreous, optic disc, and retina will examined. 
 Retinal photography will also be performed predose and at the end of treatment. 


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Any visual symptoms that occur during the study (such as impairment in night vision) should be 
assessed, and if indicated, a repeat ophthalmic examination should be performed. 
4.1.3 
Liver Biopsy and Fibroscan  
Each patient must have documentation of a liver biopsy demonstrating evidence of chronic 
hepatitis. If no liver biopsy was performed or no documentation of a biopsy is available, the 
patient must be willing to have a liver biopsy performed within the screening period. To avoid 
unnecessary biopsies for ineligible patients, it is recommended that the liver biopsy be performed 
after the patient successfully completes all other screening assessments. 
A Fibroscan is to be performed at baseline (Day 1) and at the end of treatment (Week 24 Visit). 
Patients must fast for at least 3 hours before the Fibroscan is performed. 
4.1.4 
Electrocardiograms 
All ECGs for this study will be 12-lead, serial ECGs performed in triplicate (×3) 2 to 3 minutes 
apart. Three interpretable ECGS recordings (ie, without artifacts) should be obtained at each time 
point. The average of the three readings will be used to determine ECG intervals. (Single ECG 
recordings may be obtained at unscheduled time points as indicated.) 
Patients should rest in a supine position for ≥5 minutes before the ECG recording is made. When 
ECG recordings coincide with PK draws, the EGCs should be obtained before the PK draw is 
performed. ECGs must be read by the Investigator or a qualified designee, and the results 
recorded in the CRF. On-treatment ECGs should be compared to the patient’s baseline as part of 
routine safety monitoring. All clinically relevant abnormalities will be reported as AEs. 
ECG printouts will be maintained with the source documentation. 
4.1.5 
Molecular and Serologic Tests 
Serologic testing for HBV, HCV, HDV, and HIV will be performed during screening evaluation 
of entry criteria.  
Throughout the study, serum and plasma samples will be obtained for HDV/HBV molecular and 
serologic tests.  
• HDV RNA viral load will be quantified using the RoboGene® HDV RNA 
Quantification Kit, which uses real-time qPCR of HDV RNA in human serum 
samples. The assay is designed to detect genotypes 1, 2, 5, 6, 7, and 8 of HDV, 
applying probes and primers specific for a subsequence of the hepatitis delta antigen. 
The assay has a lower limit of quantitation of 500 U/mL based on calibrated standards 
using a reference HDV genotype 1 positive serum. 
• HBV DNA will be analyzed using COBAS® AmpliPrep/COBAS® TaqMan® HBV 
Test. This is a nucleic acid amplification test for the quantification of Hepatitis B 
Virus (HBV) DNA in human plasma and serum. The COBAS® AmpliPrep/COBAS® 
TaqMan® HBV Test is based on two major processes: (1) specimen preparation to 
isolate HBV DNA and (2) simultaneous PCR amplification of target DNA and 
detection of cleaved dual-labeled oligonucleotide detection probe specific to the 


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target. The assay can quantitate HBV DNA levels with an upper limit of 
quantification of 1.7 × 108 IU/mL and a lower limit of detection of 20 IU/mL. 
• In addition to HBV DNA levels, hepatitis B surface antigen (HBsAg), hepatitis B e 
antigen (HBeAg), and hepatitis B e antibody (HBeAb) levels will be followed during 
the study because these may be important to indicate seroconversion or disease 
course. 
 
4.1.6 
Pharmacokinetic Sampling 
4.1.6.1 Pharmacokinetic Sampling Time Points 
PK sampling will be conducted on all patients.  Sampling times and windows are presented in 
Table 9. 
Single blood samples will be obtained for trough drug measurements at each study visit starting 
at Week 2 and through Week 16. 
Blood samples will be obtained for full PK analysis when patients have maintained a stable dose 
of lonafarnib/ritonavir for at least 2 weeks between Study Weeks 8 and 16 as follows (see 
Section 3.6.2 for dose-titration details). A stable dose is defined as a dose of lonafarnib/ritonavir 
that has been taken for at least 2 weeks and that is likely to be the highest tolerable dose taken by 
the patient during the study. Samples for full PK will be taken as follows predose (within 30 
minutes before the first dose of the day) and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h postdose.  The 
second daily dose of study drug may not be taken until after the 12 hour sample is obtained.  On 
the days that PK sampling occurs, patients will remain in clinic at least 13 hours.  
If the patient has not been at a stable dose for the 2 weeks before the study visit, PK sampling 
will be performed at a future visit, after the patient has been on a stable dose for at least 2 weeks. 
4.1.6.2 Pharmacokinetic Sample Labeling and Shipping 
Plasma samples for PK analysis must be labeled with unique identification numbers. Additional 
labeling information is provided in the laboratory manual. Labels must remain intact and 
indelible throughout processing and frozen storage. 
Pharmacokinetic samples are to be shipped in insulated containers filled with dry ice to the 
following address: 
The Doctors Laboratory 
60 Whitfield Street 
London, UK 
W1T 4EU 
 
Details for shipment to the analytical laboratory are included in the laboratory manual.  
Unused PK samples will be stored until directed by the Sponsor that they may be destroyed. 


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4.1.6.3 Pharmacokinetic Analytical Methods 
Plasma concentrations for lonafarnib and ritonavir will be determined using validated analytical 
methods for each of the analytes.  
The validated range can be truncated when less than 5 calibrants appear to be below the expected 
maximum plasma concentration observed (Cmax), provided that this new calibration curve range 
is validated before use. 
Where possible, all samples from each patient will be analyzed on the same standard curve. 
Quality control samples will be distributed through each batch of study samples assayed. 
Samples with drug concentrations greater than the upper limit of quantitation (ULQ) of the assay 
range will be diluted with the appropriate drug-free biological fluid and re-assayed; those that are 
below the lower limit of this range will be reported as below the limit of quantitation (BLQ).  
Unacceptable values attributable to bioanalytical reasons will be determined according to the 
standard operating procedures (SOPs) of the bioanalytical facility. Such re-assayed samples will 
be termed “repeats”. The method of re-assay and the acceptance criteria for selecting which 
value to report for the re-assayed samples will also follow the SOPs of the bioanalytical facility. 
All cases of re-assay will be detailed in the final bioanalytical report. With the written consent of 
the patient, remaining plasma samples may be stored for possible future analyses by the Sponsor 
if deemed necessary (eg, for determination of active metabolite concentrations, HDV and HBV 
analyses, and host DNA analyses of polymorphisms that may impact drug response).  
4.1.7 
Routine Clinical Laboratory Tests 
Serum and blood chemistry laboratory tests are listed in Table 6. 
Table 6 
Serum and Blood Chemistry Laboratory Tests 
Test Category 
Hematology 
Clinical Chemistry 
Hemoglobin 
Alanine aminotransferase (ALT) 
Hematocrit 
Albumin 
Erythrocyte count (red blood cell) 
Alkaline phosphatase 
Mean corpuscular volume 
Amylase 
Mean corpuscular hemoglobin 
Aspartate aminotransferase (AST) 
Mean corpuscular hemoglobin concentration 
Bicarbonate 
Leukocytes (white blood cell) 
Bilirubin (direct, indirect, and total) 
Neutrophils, segmented 
Blood urea nitrogen (BUN) 
Neutrophils, juvenile (bands) 
Calcium 
Lymphocytes 
Chloride 
Monocytes 
Cholesterol 
Eosinophils 
Creatine kinase (CK) 
Basophils 
Creatinine 
Platelets 
Gamma-glutamyl transferase (GGT) 
Cell morphology 
Globulin 
 
Glucose, nonfasting 
   
Lactate dehydrogenase (LDH) 
Coagulation 
Magnesium 
Prothrombin time  
Phosphorus 
INR 
Potassium 


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Test Category 
Sodium 
Urinalysis 
Triglycerides 
Specific gravity 
Total protein 
Protein 
Uric acid 
Ketones 
Bilirubin 
Urobilinogen 
Quantitative Polymerase Chain Reaction 
Blood 
Hepatitis B virus 
Nitrite 
Hepatitis C virus a 
Microscopic examination of sediment 
Hepatitis D virus 
Other Tests 
Viral Serology 
Blood ethanol test b 
Hepatitis B e serology 
Urine drug screen b 
Hepatitis B surface antigen (HBsAg) 
Pregnancy test c 
Hepatitis C virus serology a 
Peripheral blood mononuclear cell (PBMC) 
Hepatitis D virus serology 
Triiodothyronine (T3) 
Human immunodeficiency virus serology 
Thyroxine (T4) 
Thyroid stimulating hormone (TSH) 
Reproductive Serology - Males 
Reproductive Serology - Females 
Inhibin B 
Luteinizing hormone  
Luteinizing hormone (LH) 
Follicle-stimulating hormone (FSH) 
Follicle-stimulating hormone (FSH) 
Estradiol 
Free and total testosterone 
Progesterone 
Anti-Müllerian hormone (AMH) 
Dehydroepiandrosterone  (DHEA) 
Dehydroepiandrosterone sulfate (DHEAS) 
Androstenedione 
Testosterone 
Free testosterone 
Sex hormone binding globulin (SHBG) 
17-Hydroxyprogesterone (17-OHP)
a Patients with a positive HCV Ab result at screening must have completed a curative antiviral regimen and 
documented to be HCV RNA negative (undetectable) at least 3 months before screening and at screening. 
b  Blood alcohol test and urine drug screen for cannabinoids, opiates, amphetamines, barbiturates, benzodiazepenes, 
cocaine at screening. 
c  Serum pregnancy test at screening, and urine pregnancy test during remainder of the study; if urine pregnancy test 
result is positive, confirm immediately with serum pregnancy test. 
4.1.8 
Total Blood Sampling Volume 
During the study, blood samples for hematology, chemistry, serology, and viral load analyses 
will be collected via venipuncture. Some plasma samples will be stored for possible future 
analytical analyses by the Sponsor (eg, for generation of active metabolite concentrations) for 
patients who have provided written informed consent for this procedure.  
Blood sampling volumes to be collected during the study are listed in Table 7. 


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Table 7 
Blood Sampling Volumes 
Test Group 
Volume per Draw 
(mL) 
Total Volume for 
Study (mL) 
Biochemistry, HepB serology, HIV1&2 antibodies, 
Hepatitis B surface antigen, Hepatitis C Virus antibody, 
T3, T4, TSH, Serum pregnancy test 
5 
90 
Hepatitis C Virus PCR 
4 
4 
Blood alcohol 
2 
2 
Hematology 
2 
36 
Coagulation 
2.7 
24.3 
Hepatitis B Virus PCR 
4 
72 
Hepatitis D Virus PCR, Hepatitis D antibodies 
5 
90 
HBV genotyping, HDV genotyping 
5 
95 
Reproductive Serology 
7.5 
105 
PK samples 
7.5 
112.5 
PBMC 
45 
360 
Total for study 
 
990.8 
a Volume for PK draw = 10 mL. 
 
4.1.9 
Appropriateness of Assessments 
The assessments planned are standard, well-established procedures for a study of this type and 
duration and are designed to provide the data required to address the objectives of the study. 
4.2 Description of Study Procedures by Study Visit 
The results of all procedures listed below will be documented in the patient’s medical record and 
recorded on the patient’s case report forms (CRFs). See Appendix A for a schedule of study 
evaluations and procedures. 
Study visits will occur during three periods:  
Screening—At the Screening Visit, patients providing written informed consent will 
have required evaluations to determine their eligibility to participate in the study. 
Screening evaluations may occur over more than one visit, depending on the facilities and 
personnel available at the clinical center. All screening procedures must occur within 
4 weeks before the start of dosing (Day −28 through Day −1). 
Treatment—Each eligible patient will undergo a minimum of 10 Treatment Study 
Visits: Week 0 (Day 1), Week 1 (Day 8 ± 2 d), Week 2 (Day 15 ± 2 d), Week 4 
(Day 29 ± 2 d), Week 6 (Day 43 ± 2 d), Week 8 (Day 57 ± 5 d), Week 12 (Day 85 ± 5 d), 
Week 16 (Day 113 ± 5 d), Week 20 (Day 141 ± 5 d), and Week 24 (Day 169 ± 5 d). 
Follow-up—Follow-up visits will occur every 4 weeks for 24 weeks. The first Follow-up 
Visit will be on Week 28 (4 weeks after last dose or if the patient discontinues treatment 
early) and will also include evaluation of lonafarnib level. All Follow-up Visits will 
include evaluations of safety (adverse events, concomitant medications, and laboratory 
values) and viral loads (HDV and HBV). Alpha-interferon treatments will be allowed 


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during the last 20 weeks of the follow-up period (that is, starting 4 weeks after last dose 
of study treatment).  
 
In addition to the planned visits, unscheduled visits may be required if, in the opinion of the 
Investigator, the clinical status of the patient warrants interim evaluation. 
Study Visits should be scheduled according to the study protocol; however, the window for 
Study Visits for Weeks 1 through 6 will be ±2 days of the nominal Study Visit day, and for study 
visits thereafter the window will be ±5 days. 
4.2.1 
Screening Visit(s) (Weeks –4 to –1) 
Written informed consent must be given before any study-related diagnostic or screening 
procedures are performed. At the Screening Visit, patients will have all required evaluations to 
determine their eligibility to participate in the study.  
The Screening Period is defined as the time between the date of the first Screening procedure and 
Day −1 and may last up to 28 days. Screening procedures may be conducted over multiple days 
within the Screening period if convenient. 
The following procedures will be performed during Screening: 
• Obtain signed informed consent. 
• Determine eligibility based on inclusion/exclusion criteria. 
• Obtain medical history, review systems. 
• Query use of concomitant medications. 
• Conduct comprehensive physical examination, including measurements of height and 
weight (≥45 kg), calculate BMI (≥18 kg/m2), and assess CTP score and 
encephalopathy (see Appendix B). 
• Conduct genital examination. 
• Conduct ophthalmic examination and obtain retinal photographs. 
• Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should 
rest in a supine position for ≥5 minutes before the ECG recording is made. 
• Measure vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature). Blood pressure and heart rate should be measured after 5 minutes in a 
sitting position 
• Conduct liver biopsy (if patient lacks documentation of a liver biopsy demonstrating 
evidence of chronic hepatitis). 
• Obtain blood samples for  
– Clinical laboratory assessments, including hematology, serum chemistries, 
serologic tests (HBsAg, HBeAg and HBeAb, HCV Ab, HDV Ab, and HIV Ab), 
prothrombin time and INR, Triiodothyronine (T3) and thyroxine (T4), and serum 
pregnancy test for women of childbearing capacity.  
– Quantitative PCR (HBV DNA, HDV RNA, HCV RNA [if positive HCV Ab]) 
• Obtain urine sample for urinalysis and drug screen. 


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Patients meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the first treatment visit (Week 0, Day 1) assessments and randomization. 
4.2.2 
Treatment Visit – Week 0, Day 1 (±2 Days) 
Day 1 procedures that must be performed before administration of first study treatment are listed 
below.  
Before First Study Treatment: 
• Review and confirm inclusion eligibility. 
• Update medical history as necessary. 
• Review concomitant medications. 
• Conduct brief physical examination and calculate BMI. 
• Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should 
rest in a supine position for ≥5 minutes before the ECG recording is made. 
• Measure vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature) and weight. Blood pressure and heart rate should be measured after 
5 minutes in a sitting position. 
• Conduct Fibroscan (patients must fast for at least 3 hours before the Fibroscan is 
performed). 
• Obtain blood samples for  
– Clinical laboratory assessments, including hematology, serum chemistries, 
serologic tests (HDV, HBsAg, HBeAg, HBeAb, and reproductive). 
– PBMC analysis. 
– Quantitative PCR (HBV DNA, HDV RNA). 
– Genotypic analysis of sequences of large HDV antigen.  
• Obtain urine sample for pregnancy test for women of childbearing capacity. 
• Obtain urine sample for urinalysis. 
• Inquire about AEs. 
 
Start of Study Treatment: 
• Instruct patients how to administer study drug; provide patient information sheet and 
patient diary. 
• Dispense 2-week supply of study drugs. Start dosing on Day 1. 
4.2.3 
Treatment Visit – Week 1, Day 8 (±2 Days) 
All Day 8 procedures must be performed before administration of study treatment.  
• Review concomitant medications. 
• Conduct brief physical examination. 


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•
Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should
rest in a supine position for ≥5 minutes before the ECG recording is made.
•
Measure vital signs (heart rate, blood pressure, respiratory rate, and body
temperature) and weight. Blood pressure and heart rate should be measured after
5 minutes in a sitting position.
•
Obtain blood samples for
–
Clinical laboratory assessments, including hematology, serum chemistries,
serologic tests (HBsAg).
–
Quantitative PCR (HBV DNA, HDV RNA).
–
Genotypic analysis of sequences of large HDV antigen (analyzed only in case of
viral load rebound).
•
Inquire about AEs.
•
Review patient diary and review instructions on administration of study drugs.
•
Review bottles of study drugs for drug accountability; return bottles to patient.


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4.2.4 
Treatment Visit – Week 2, Day 15 (±2 Days) 
All Day 15 procedures must be performed before administration of study treatment.  
• Review concomitant medications. 
• Conduct brief physical examination. 
• Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should 
rest in a supine position for ≥5 minutes before the ECG recording is made. 
• Measure vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature) and weight. Blood pressure and heart rate should be measured after 
5 minutes in a sitting position. 
• Obtain blood samples for  
– Clinical laboratory assessments, including hematology, serum chemistries, 
serologic tests (HDV, HBsAg).  
– PBMC analysis. 
– Quantitative PCR (HBV DNA, HDV RNA). 
– Genotypic analysis of sequences of large HDV antigen (analyzed only in case of 
viral load rebound). 
– Trough PK measurement 
• Obtain urine sample for urinalysis. 
• Inquire about AEs. 
• Review patient diary and remind patients how to administer study drugs. 
• Review returned bottles of study drugs for drug accountability. 
• Dispense 2-week supply of study drugs.  
4.2.5 
Treatment Visits – Weeks 4 and 6, Days 29 and 43 (±2 Days) 
All Day 29 and 43 procedures must be performed before administration of study treatment.  
• Review concomitant medications. 
• Conduct brief physical examination. 
• Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should 
rest in a supine position for ≥5 minutes before the ECG recording is made. 
• Measure vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature) and weight. Blood pressure and heart rate should be measured after 
5 minutes in a sitting position. 
• Obtain blood samples for  
– Clinical laboratory assessments, including hematology, serum chemistries, 
serologic tests (HDV, HBsAg and reproductive). 
– PBMC analysis (Week 4 only). 
– Quantitative PCR (HBV DNA, HDV RNA). 
– Genotypic analysis of sequences of large HDV antigen. 
– Trough PK measurement 


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• Obtain urine sample for pregnancy test for women of childbearing capacity. 
• Obtain urine sample for urinalysis. 
• Inquire about AEs. 
• Evaluate patients for dose escalation. 
• Review patient diary and remind patients how to administer study drugs. 
• Review returned bottles of study drugs for drug accountability. 
• Dispense 2-week supply of study drugs.  
4.2.6 
Treatment Visits – Weeks 8, 12, and 16; Days 57, 85, and 113 (±5 Days): 
PK Sampling 
All Day 57, 85, and 113 procedures except postdose PK blood sample collection must be 
performed before administration of study treatment. 
• Review concomitant medications. 
• Conduct brief physical examination. 
• Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should 
rest in a supine position for ≥5 minutes before the ECG recording is made. 
• Measure vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature) and weight. Blood pressure and heart rate should be measured after 
5 minutes in a sitting position. 
• Obtain blood samples for  
– Clinical laboratory assessments, including hematology, serum chemistries, 
serologic tests (HDV, HBsAg, reproductive).  
– PBMC analysis (Week 12 only ). 
– Quantitative PCR (HBV DNA, HDV RNA). 
– Genotypic analysis of sequences of large HDV antigen (analyzed only in case of 
viral load rebound). 
• Obtain urine sample for pregnancy test for women of childbearing capacity.  
• Obtain urine sample for urinalysis. 
• Obtain blood samples for either trough or full PK analysis. If the patient has been on 
a stable dose for the previous 2 weeks, samples for full PK analysis should be 
obtained at the following time points: within 30 minute before the first dose of drug, 
and 0.5, 1, 2, 3, 4, 6, 8,10 and 12 hours. The second daily dose of drug should not be 
taken until after the 12 hour time point. If the patient has not been at a stable dose for 
the 2 weeks before the study visit, obtain a single trough sample, and conduct full PK 
sampling at a future visit, after the patient has been on a stable dose for at least 2 
weeks. 
• Inquire about AEs. 
• Review patient diary and remind patients how to administer study drugs. 
• Review returned bottles of study drugs for drug accountability. 
• Dispense 4-week supply of study drugs.  


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4.2.7 
Treatment Visit – Week 20; Day 141 (±5 Days) 
All Day 141 procedures must be performed before administration of study treatment.  
• Review concomitant medications. 
• Conduct brief physical examination. 
• Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should 
rest in a supine position for ≥5 minutes before the ECG recording is made. 
• Measure vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature) and weight. Blood pressure and heart rate should be measured after 
5 minutes in a sitting position. 
• Obtain blood samples for  
– Clinical laboratory assessments, including hematology, serum chemistries, 
serologic tests (HDV, HBsAg, reproductive).  
– Quantitative PCR (HBV DNA, HDV RNA). 
– Genotypic analysis of sequences of large HDV antigen (analyzed only in case of 
viral load rebound). 
• Obtain urine sample for pregnancy test for women of childbearing capacity. 
• Obtain urine sample for urinalysis. 
• Inquire about AEs. 
• Review patient diary and remind patients how to administer study drugs. 
• Review returned bottles of study drugs for drug accountability. 
• Dispense 4-week supply of study drugs.  
4.2.8 
Treatment Visit – Week 24, Day 169 (±5 Days): End of Treatment Period 
All Day 169 procedures must be performed before administration of study treatment.  
• Review concomitant medications. 
• Conduct brief physical examination. 
• Conduct genital examination. 
• Conduct ophthalmic examination and obtain retinal photographs. 
• Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should 
rest in a supine position for ≥5 minutes before the ECG recording is made. 
• Measure vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature) and weight. Blood pressure and heart rate should be measured after 
5 minutes in a sitting position. 
• Conduct Fibroscan (patients must fast for at least 3 hours before the Fibroscan is 
performed). 
• Obtain blood samples for  
– Clinical laboratory assessments, including hematology, serum chemistries, 
serologic tests (HDV, HBsAg, HBeAb, HBeAg, reproductive), prothrombin time 
and INR.  


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– PBMC analysis. 
– Quantitative PCR (HBV DNA, HDV RNA). 
– Genotypic analysis of sequences of large HDV antigen (analyzed only in case of 
viral load rebound). 
• Obtain urine sample for pregnancy test for women of childbearing capacity. 
• Obtain urine sample for urinalysis. 
• Inquire about AEs. 
• Collect and review patient diary. 
• Review returned bottles of study drugs for drug accountability. 
4.2.9 
Follow-up Visit – Week 28, Day 197 (±5 Days) 
• Review concomitant medications. 
• Conduct brief physical examination. 
• Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should 
rest in a supine position for ≥5 minutes before the ECG recording is made. 
• Measure vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature) and weight. Blood pressure and heart rate should be measured after 
5 minutes in a sitting position. 
• Obtain blood samples for  
– Clinical laboratory assessments, including hematology, serum chemistries, 
serologic tests (HDV, HBsAg, reproductive), prothrombin time and INR.  
– Quantitative PCR (HBV DNA, HDV RNA). 
– Genotypic analysis of sequences of large HDV antigen (analyzed only in case of 
viral load rebound). 
– PBMC analysis 
• Obtain urine sample for pregnancy test for women of childbearing capacity. 
• Obtain urine sample for urinalysis. 
• Inquire about AEs. 
4.2.10 
Follow-up Visits – Weeks 32, 36, 40, 44, and 48; Days 225, 253, 281, 309, and 337 
(±5 Days) 
• Review concomitant medications. 
• Conduct brief physical examination. 
• Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should 
rest in a supine position for ≥5 minutes before the ECG recording is made. 
• Measure vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature) and weight. Blood pressure and heart rate should be measured after 
5 minutes in a sitting position. 
• Obtain blood samples for  


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– Clinical laboratory assessments, including hematology, serum chemistries, 
serologic tests (HDV, HBsAg, reproductive), prothrombin time and INR.  
– Quantitative PCR (HBV DNA, HDV RNA). 
– Genotypic analysis of sequences of large HDV antigen (analyzed only in case of 
viral load rebound). 
– PBMC analysis (Weeks 36 & 48 only) 
• Obtain urine sample for pregnancy test for women of childbearing capacity. 
• Obtain urine sample for urinalysis. 
• Inquire about AEs. 
4.2.11 
Unscheduled Visits 
Unscheduled visits may occur as needed, for example, to assess a viral or hepatic flare, during 
the study. The following procedures should be performed during an unscheduled visit:  
• Review concomitant medications. 
• Conduct brief physical examination. 
• Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should 
rest in a supine position for ≥5 minutes before the ECG recording is made. 
• Measure vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature) and weight. Blood pressure and heart rate should be measured after 
5 minutes in a sitting position. 
• Obtain blood samples for  
– Clinical laboratory assessments, including hematology, serum chemistries, 
serologic tests (HDV, HBsAg, reproductive), prothrombin time and INR.  
– Quantitative PCR (HBV DNA, HDV RNA). 
– Genotypic analysis of sequences of large HDV antigen (analyzed only in case of 
viral load rebound). 
• Obtain urine sample for pregnancy test for women of childbearing capacity.  
• Obtain urine sample for urinalysis. 
• Inquire about AEs. 
• Review returned bottles of study drugs for drug accountability if patient is on study 
treatment. 
• Review patient diary if unscheduled visit occurs during the Treatment Period. 
 
4.2.12 
Early Termination Visit  
The following procedures should be performed if the patient discontinues treatment early:  
• Review concomitant medications. 
• Conduct brief physical examination. 
• Conduct genital examination. 


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• Record ECGs (12-lead, serial ECGs in triplicate 2 to 3 minutes apart). Patients should 
rest in a supine position for ≥5 minutes before the ECG recording is made. 
• Measure vital signs (heart rate, blood pressure, respiratory rate, and body 
temperature) and weight. Blood pressure and heart rate should be measured after 
5 minutes in a sitting position. 
• Obtain blood samples for  
– Clinical laboratory assessments, including hematology, serum chemistries, 
serologic tests (HDV, HBsAg, reproductive), prothrombin time and INR.  
– PBMC analysis. 
– Quantitative PCR (HBV DNA, HDV RNA). 
– Genotypic analysis of sequences of large HDV antigen (analyzed only in case of 
viral load rebound). 
• Obtain urine sample for pregnancy test for women of childbearing capacity.  
• Obtain urine sample for urinalysis. 
• Inquire about AEs. 
• Collect and review patient diary if visit occurs during the Treatment Period. 
• Opthalmic exam if patient discontinues treatment between weeks 12-24.  
 
 


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5 STATISTICAL CONSIDERATIONS 
5.1 Analysis Objectives and Endpoints 
The purpose of this study is to evaluate the safety and tolerability of the dose-titration regimen of 
lonafarnib in combination with ritonavir over the 24-week treatment period. In addition, the PD 
activity (ie, change in HDV viral load) of the lonafarnib/ritonavir dose-titration regimen over the 
24-week Treatment Period will be evaluated. 
Secondary evaluations will include the effect the lonafarnib/ritonavir dose-titration regimen on 
PK characteristics, ALT levels, and HBV DNA levels. Exploratory evaluations will include the 
effects of the lonafarnib/ritonavir dose-titration regimen on immunologic parameters during 
treatment. 
5.2 Determination of Sample Size 
A sample size of 15 was  chosen to allow assessment of the safety and tolerability of the 
combination of lonafarnib/ritonavir, recognizing that drug exposures may be highly variable and 
will likely result in an observable range of patient tolerability to the same administered dose.  In 
this study of approximately 15 patients, the probability of at least one patient experiencing an 
event with a true incidence rate of 1/100 is 14%, and the probability of at least one patient 
experiencing an event with a true incidence rate of 5/100 is 54%. 
5.3 Analysis Populations 
The safety population will consist of all patients who receive at least one dose of study drug.  
The primary PD/efficacy population will consist of patients who receive study drug throughout 
the entire 24 week treatment period and for whom viral load data are available from baseline and 
end-of-treatment (Week 24) study visits.  
The PK population will include patients who received at least 2 weeks of study drug at a stable 
dose level, and in whom a sufficient number of blood samples were collected, plasma samples 
were analyzed, concentration data were analyzed, and PK parameter values were derived.  
5.4 Hypothesis Testing 
No hypothesis will be tested during this clinical trial.  
5.5 Analysis Plan 
5.5.1 
Demographic and Baseline Data 
Descriptive statistics will be used to summarize demographic and baseline patient characteristics. 
Continuous-scaled variables (eg, age) will be summarized with means, medians, standard 
deviations, quartiles, and minimum and maximum values. Categorical variables (eg, sex) will be 
summarized using patient counts and percentages.  
Baseline medical histories and pre-existing conditions will be summarized by treatment group 
based on mapping to system organ classes and preferred terms in the Medical Dictionary for 
Regulatory Activities (MedDRA). 


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Medications taken after informed consent is signed and before randomization will be 
summarized by treatment group, based on mapping to drug classes and generic terms in the 
WHO Drug Dictionary. 
5.5.2 
Safety Analyses 
A primary goal of this study is to evaluate the tolerability of the lonafarnib/ritonavir dose-
titration regimen. The safety endpoints are as follows: 
• Treatment-emergent AEs 
• Treatment-emergent SAEs 
• Treatment-emergent treatment-related AEs 
• Treatment-emergent treatment-related SAEs and deaths 
• AEs leading to early discontinuation of study treatment 
• AEs leading to dose reduction 
• Treatment-emergent changes in clinical laboratory findings and ECGs 
 
AEs will be mapped to system organ classes and preferred terms in MedDRA. Treatment-
emergent AEs (TEAEs) are defined as those that start or worsen after the start of study treatment 
and up to 28 days after the last dose of study treatment; any AEs that occur after that time will be 
considered posttreatment AEs. TEAEs will be summarized by dose level, system organ class, 
and preferred term, and also by event severity and by the event’s relationship to study treatment. 
At each level of summation, patients will be counted only once, under the greatest severity and 
strongest study-drug relationship (as reported by the Investigator). If an AE is reported more than 
once during the study period, the greatest severity and worst-case attribution will be presented in 
tables. AEs will also be listed for individual patients, along with information regarding onset, 
duration, severity, and relationship to study drug. SAEs and AEs that lead to withdrawal from the 
study will be listed by individual patients. Events with missing severity will be classified as 
Grade 3; events with missing attribution will be classified as related to study drug. 
Clinical laboratory data will be summarized at each measurement time point and for each 
patient’s final postbaseline measurement in the following ways: (1) with descriptive statistics 
(mean, standard deviation, median, and range) for each measurement time point and (2) with 
descriptive statistics for the change from baseline in the measurements at each postbaseline time 
point. All clinical laboratory values collected during the study will be listed, with values outside 
the normal ranges flagged for clinical evaluation. Grade 3 and 4 laboratory results will be listed 
and summarized. In addition, ALT, AST, total bilirubin and AP will be summarized by 
CTCAE grade.  
Actual values for vital signs and changes from baseline will be summarized and listed for each 
patient. No inferential statistics are planned for safety data. Actual values for ECG intervals and 
changes from baseline will be summarized by study visit using descriptive statistics. Clinical 
interpretation of ECG results will be listed. 
Concomitant medications will be summarized based on mapping to drug classes and generic 
terms in the World Health Organization Drug Dictionary Enhanced (WHO-DD Enhanced).  


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5.5.3 
Pharmacodynamics/Efficacy 
Pharmacodynamic data will be presented by dose level in summary tabulations and listings that 
will display viral load data at each period/time point collected by patient. These data will also be 
presented graphically. Mean and median levels and change from baseline of the viral load will be 
calculated at each time point. For analysis of change from baseline, baseline will be defined as 
the geometric mean of the HDV RNA titer obtained at the Screening and Day 1 (pretreatment) 
visits. The number of patients with 1 and 1 log reductions from baseline will be summarized at 
each time point. The number of patients with reduction in viral load below the limit of 
quantitation and the limit of detection will be summarized. 
Results below the level of detection will be imputed as half the lower limit of detection 
(500 IU/mL). 
Missing data will not be imputed. All summaries and figures will show the number of non-
missing data at each visit. 
5.5.4 
Pharmacokinetics 
The PK parameters listed in Table 8 will be derived from plasma concentrations for lonafarnib 
and ritonavir. 
 
Table 8 
Pharmacokinetic Parameters Derived from Plasma Concentrations for 
Lonafarnib and Ritonavir 
PK Parameter 
Definition 
Cmax 
Peak plasma concentration as observed. 
Tmax 
Time of the peak plasma concentration. 
AUC0–τ 
Area under the plasma concentration versus time curve during the dosing interval calculated 
by the linear trapezoidal rule. 
Cavg 
Average plasma drug concentration during multiple-dose administration. 
Cmin 
Minimum plasma concentration. 
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 (eg, three or more non-zero plasma concentrations). 
Varea/F 
Apparent total volume of distribution calculated as follows: total dose/(total AUC0–∞ × Kel). 
CL/F 
Apparent total body clearance, calculated as follows:  
dose/ AUC0–∞ 
Weight-adjusted CL/F (CL/F/kg) will also be calculated. 
T1/2 
Apparent first-order terminal elimination half-life will be calculated as 0.693/Kel. 
 
 
Protocol-scheduled times will be used in the PK analyses unless actual collection times deviate 
significantly. Deviations will be considered significant if the time between scheduled and actual 
times is more than the reporting standards listed in Table 9. 
 


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Table 9 
Time Windows for Collection of Pharmacokinetic Samples 
Nominal Time 
Reporting Standards 
Predose 
Within 30 minutes before first dose 
0.0–2.0 hours 
≤ ±1 minute 
>2.0–8.0 hours 
≤ ±2 minutes 
>8.0-12 hours 
≤ ±5 minutes 
 
A noncompartmental method will be used to derive the PK parameters for lonafarnib and 
ritonavir. Additional PK parameters using noncompartmental methods may also be used if data 
permit. Plasma concentrations of lonafarnib and ritonavir and the generated PK parameters will 
be summarized descriptively by dose level and by patient. The following will be calculated for 
multiple-dose lonafarnib and ritonavir: arithmetic means; coefficients of variation (%CV); 
standard deviations (SD); median, minimum, and maximum values; and number of observations 
PK parameter values will be generated for multiple-dose lonafarnib and ritonavir. 
Other PK analyses for lonafarnib that may be performed include linearity and dose 
proportionality across the different lonafarnib dose levels. These analyses will be conducted for 
patients who receive titrated doses. The relationship between lonafarnib dose and achieved AUC, 
Cmax, and measured viral load (PD) may also be explored by plotting the PK parameters versus 
the dose of lonafarnib and viral log decay. The relationship between lonafarnib dose, lonafarnib 
exposure, and specific AEs may also be explored. 
No other formal statistical analyses are planned for PK parameters. 
5.5.5 
Viral Resistance Analysis 
Screening visit and baseline serum samples will be collected from all patients for HDV 
genotypic analysis to determine HDV subtypes (1–8) and to understand natural genetic 
polymorphisms of HDV. 
For resistance surveillance, genotypic analysis of large HDV antigen from patients with virologic 
failure will be conducted. Virologic failure is defined as an increase in serum HDV RNA of at 
least 1.0 log from the nadir value on 2 consecutive visits in patients who stay on lonafarnib 
treatment. In vitro phenotypic analysis may be explored as necessary. 


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6 SAFETY EVENTS DOCUMENTATION AND REPORTING 
6.1 Investigator’s Responsibilities 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for providing appropriate medical care. In addition, the Investigators are responsible for 
alerting Eiger BioPharmaceuticals or its designee to any event that seems unusual, even if the 
event may be considered an unanticipated benefit to the patient, and for reporting the event on 
the appropriate case report form (CRF) or safety report form. 
A serious adverse event (SAE) should be reported to Eiger BioPharmaceuticals or its designee 
within 24 hours after becoming aware of its occurrence. Investigators must report all SAEs to 
their governing IEC as required by local regulations and guidelines. The Investigator is 
responsible for reporting the relationship to study drug for each adverse event (AE). 
By exercising appropriate health-care options, the Investigator remains responsible for managing 
AEs that are serious or that cause the patients to withdraw before completing the study. 
Frequency of follow-up of any particular AE is left to the discretion of the Investigator. Duration 
of follow-up and requirements for immediate SAE reporting (within 24 hours of the event) are 
described below. 
6.2 Monitoring Safety Data During Study 
Safety results collected during the study (eg, AEs, laboratory test results, physical findings, 
ECGs) will be monitored on an ongoing basis by the Medical Monitor and Investigator. 
6.3 Definitions of Types of Adverse Events 
6.3.1 
Adverse Events 
An AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE (also referred to as an adverse experience) can be 
any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about causality. 
An AE can arise with any use of the drug (eg, off-label use, use in combination with another 
drug) and with any route of administration, formulation, or dose, including an overdose. 
6.3.2 
Suspected Adverse Reactions 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. For the purposes of investigational new drug (IND) or Investigational Medicinal 
Product (IMP) safety reporting, ‘‘reasonable possibility’’ means there is evidence to suggest a 
causal relationship between the drug and the AE. Suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any AE caused by a drug. 
6.3.3 
Life-Threatening Adverse Events 
An AE or suspected adverse reaction is considered ‘‘life-threatening’’ if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death. It does not 


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include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
6.3.4 
Serious Adverse Events 
An AE or suspected adverse reaction is considered ‘‘serious’’ if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
•
Death
•
A life-threatening AE (see Section 6.3.3)
•
Inpatient hospitalization or prolongation of existing hospitalization
•
A persistent or significant incapacity or substantial disruption of the ability to conduct
normal life functions
•
A congenital anomaly/birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, they 
may jeopardize the patient 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 department or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
6.3.5 
Unexpected Adverse Event 
An AE or suspected adverse reaction is considered ‘‘unexpected’’ if it meets any of the 
following criteria: 
•
It is not listed in the Investigator’s Brochure or is not listed at the specificity or
severity that has been observed.
•
If an Investigator Brochure is not required or available, it is not consistent with the
risk information described in the general investigational plan or elsewhere in the
current application, as amended.
•
If it is not listed in the Summary of Product Characteristics for Norvir® [ritonavir]
tablets, (2014)
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the Investigator Brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the Investigator’s Brochure listed only cerebral vascular accidents.  
‘‘Unexpected,’’ as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the Investigator’s Brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation. 


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6.4 Adverse Event Classification 
6.4.1 
Severity Grades of Adverse Events and Serious Adverse Events 
The seriousness of an AE should not be confused with its intensity (severity). To describe the 
maximum intensity of the AE on the AE CRF, the Investigator will use the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 
(CTCAE 2010). For events not listed in the CTCAE, the definitions from the CTCAE provided 
in Table 10 should be used to evaluate the grade of severity for the AE. 
Table 10 Adverse Event Grades Based on the Common Terminology Criteria for 
Adverse Events 
Grade 
Description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (eg, preparing meals, shopping for groceries or clothes, using 
the telephone, and managing money) 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities of daily living (eg, bathing, 
dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden) 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
Source:  National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 
(CTCAE 2010) 
6.4.2 
Relationship of Adverse Event to Investigational Products 
The Investigator’s assessment of causality must be provided for all AEs (serious and nonserious). 
An Investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE. To describe the 
relationship of the AE to study drug on the AE CRF, the Investigator will use the terms and 
definitions provided in Table 11. For a particular AE, the Investigator will assess both the 
relationship to lonafarnib and the relationship to ritonavir.  


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Table 11 Categories for Assessing Relationship of Adverse Events to Investigational 
Products 
Assessment of 
Causality 
Definition 
Not related 
No relationship between the event and the administration of study drug or another 
cause of the event is most plausible, the experience does not follow a clear temporal 
association with study drug administration, or the event is related to other etiologies 
such as concomitant medications or patient’s clinical state 
Possibly related 
An event that follows a plausible temporal sequence from administration of the study 
drug and follows a known or expected response pattern to the suspected study drug 
but that might have been produced by a number of other factors 
Definitely related 
An event that follows a plausible temporal sequence from administration of the study 
drug and without significant alternative etiology. In addition, the relationship may be 
supported by improvement on study drug discontinuation and/or a positive 
rechallenge  
 
6.5 Documentation of Adverse Events 
Patients will be evaluated and questioned generally to identify AEs during the study. Any events 
occurring before administration of the first dose of study drug will be recorded on the Medical 
History CRF. Events occurring after administration of the first dose of study drug will be 
recorded on the AE CRF. Adverse events that occur up to and including 28 days after 
administration of the last dose of study drug will be considered treatment-emergent AEs. Any 
AEs reported more than 28 days after the last dose of study drug will be considered 
posttreatment AEs. 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the AE CRF for that visit. Any clinically relevant deterioration in laboratory 
assessments or other clinical findings will be considered an AE and must be recorded on the AE 
CRF. In addition, an abnormal test finding will be classified as an AE if one or more of the 
following criteria are met: 
• The test finding is accompanied by clinical symptoms. 
• The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention, including significant additional concomitant drug treatment or other 
therapy. Note: Simply repeating a test finding, in the absence of any of the other 
listed criteria, does not constitute an AE. 
• The test finding leads to a change in study drug dosing or discontinuation of patient 
participation in the clinical research study. 
• The test finding is considered an AE by the Investigator. 
 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified. However, if an observed or reported sign or symptom is not 
considered a component of a specific disease or syndrome by the Investigator, it should be 
recorded as a separate AE. Laboratory data are to be collected as stipulated in this protocol. 


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Clinical syndromes associated with laboratory abnormalities are to be recorded as appropriate 
(eg, diabetes mellitus rather than hyperglycemia). 
For SAEs, an SAE Form must also be completed with as much information as possible and 
submitted in the time frame described in Section 6.6.1. When new significant information is 
obtained as well as when the outcome of an event is known, the Investigator should record the 
information on a new SAE Form. If the patient was hospitalized, then a copy of the discharge 
summary and any other relevant hospital records (eg, admission report, laboratory test results) 
must be included as part of the patient medical file.  
All AEs considered to be related (definitely or probably related, see Section 6.4.2) to study drug 
and all SAEs will be followed until resolved or until a stable status has been achieved. 
6.5.1 
Study Drug Action Taken 
The action taken for each study drug should be classified according to the categories shown 
in Table 12. 
 
Table 12 Classifications for Study Drug Action Taken with Regard to an Adverse Event 
Action 
Definition 
Drug interrupted  
Study drug administration interrupted in response to an AE. 
Drug withdrawn  
Study drug administration permanently discontinued in response to an AE 
Dose not changed  
Study drug dose not changed in response to the AE. 
Dose reduced  
Study drug dose reduced in response to an AE. 
Not applicable  
Action taken regarding study drug administration does not apply. “Not applicable” 
should be used in circumstances such as when the investigational treatment had been 
completed before the AE began and no opportunity to decide whether to continue, 
interrupt or withdraw treatment is possible. 
Unknown  
Action taken is unknown (eg,, a patient hospitalized at a hospital not under the case of 
the Investigator and the Investigator has no knowledge whether study drugs were 
continued or not). 
 
6.5.2 
Outcome of Adverse Event 
The outcome should be classified according to the categories shown in Table 13. All AEs 
considered to be related (definitely or probably related, see Section 6.4.2) to study drug and all 
SAEs will be followed until resolved or until a stable status has been achieved. 
 


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Table 13 Classifications for Outcome of an Adverse Event 
Outcome 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms. 
Recovered/resolved with sequelae 
Resolution of an AE with residual signs or symptoms. 
Not recovered/not resolved 
(continuing) 
Either incomplete improvement or no improvement of an AE, such that it 
remains ongoing. 
Fatal 
Outcome of an AE is death. “Fatal” should be used when death is at least 
possibly related to the AE. 
Unknown 
Outcome of an AE is not known. e.g. a patient lost to followup 
6.6 Reporting Serious Adverse Events 
6.6.1 
Reporting to Sponsor 
All SAEs that occur during the study must be reported by the Investigator to the Sponsor and to 
the Medical Monitor within 24 hours via eCRF, facsimile (ie, fax) or email. The SAE Form 
should be submitted within 1 working day from the point in time when the Investigator becomes 
aware of the SAE. In addition, all SAEs that occur up to and including 1 month (28 days) after 
administration of the last dose of study drug must be reported to the Sponsor within 1 working 
day from when the Investigator becomes aware of the SAE. Any SAEs reported more than 1 
month (28 days) after the last dose of study drug will be considered posttreatment SAEs. 
Investigators must report to the Sponsor any SAE, whether or not considered drug related, 
including those listed in the protocol or Investigator Brochure. The report must include an 
assessment of causality.  
For all SAEs, the Investigator is obligated to obtain and provide information to the Sponsor in 
accordance with the timeframes for reporting specified above. In addition, an Investigator may 
be requested by the Sponsor to obtain specific additional follow-up information in an expedited 
fashion. This information may be more detailed than that captured on the AE CRF. In general, 
this information will include a description of the AE in sufficient detail to allow for a complete 
medical assessment of the case and independent determination of possible causality. Information 
on other possible causes of the AE, such as concomitant medications and illnesses must be 
provided. In the case of a patient death, a summary of available autopsy findings must be 
submitted as soon as possible to the Sponsor or its designated representative. 
SAE reporting contact information: 
Eduardo Martins, MD, DPhil 
SVP, Liver and Infectious Diseases 
Eiger BioPharmaceuticals, Inc. 
350 Cambridge Avenue, Suite 350 
Palo Alto, CA 94306 USA 
Telephone: +1-650-867-7111 
Fax:  +1-650-618-1608 
email address:  eigersafety@eigerbio.com 


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Alternate: 
Shelly Xiong, PhD 
Vice President, Regulatory Affairs 
Eiger BioPharmaceuticals, Inc. 
350 Cambridge Avenue, Suite 350 
Palo Alto, CA 94306  USA 
Telephone: +1-408-230-1668 
Fax: +1-650-618-1608 
email address: eigersafety@eigerbio.com 
6.6.2 
Reporting to Regulatory Agencies and Independent Ethics Committee 
If there is a suspected, unexpected, serious adverse reaction (SUSAR), the Sponsor or designee 
will notify the appropriate regulatory agency(ies) and all appropriate parties on an expedited 
basis. 
It is the responsibility of the Investigator to promptly notify the IEC of all SUSARs involving 
risk to patients. 
6.6.3 
Emergency Contact 
In a medical emergency (ie, an event that requires immediate attention regarding the treatment of 
a patient, operation of the clinical study, and/or the use of investigational product), study site 
personnel will apply appropriate medical intervention according to current standards of care and 
contact the Medical Monitor : 
Frank Tschubar, MD 
Cato Europe GmbH 
Hertzstrasse 7 
50859 Cologne, 
Germany 
Telephone: +49-2234-37944-10 
Fax: +49-2234-37944-25 
Email: f.tschubar@cato-europe.com 
6.7 Pregnancy 
The patient will be instructed to notify the Investigator if the patient or the patient’s partner 
becomes pregnant during the study. The Investigator must notify the Sponsor or designee within 
24 hours via fax or e-mail and must complete the Pregnancy Notification Form and submit it to 
the Sponsor within 1 working day of being notified. The Investigator should obtain informed 
consent from the patient or the patient’s partner allowing the Investigator to obtain information 
regarding the pregnancy and its outcome, and record the informed consent in the patient’s source 
documents. If the patient or the patient’s partner provides informed consent, the Investigator 
should follow the pregnancy until outcome. A final Pregnancy Notification Form should be 
completed when the outcome of the pregnancy is known. 


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6.8 Overdose 
6.8.1 
Lonafarnib Overdose 
A small number of cancer patients in clinical trials have received an overdose of lonafarnib as a 
single agent or in combination therapy. The highest dosage was 800 mg/day. The resulting AEs 
(anorexia, fatigue, diarrhea, vomiting, dehydration, and AST and ALT elevation) were expected 
and known to be associated with lonafarnib when administered at the recommended dose. Given 
the limited experience with overdoses with this drug, it is recommended that general supportive 
measures and close monitoring of blood counts, electrolytes, and renal function be employed. It 
is unknown if lonafarnib binds to activated charcoal. As lonafarnib is absorbed slowly, induction 
of emesis or administration of activated charcoal may limit absorption of drug from the GI tract. 
There is no evidence of abuse potential based on the nonclinical pharmacology of lonafarnib.  
6.8.2 
Ritonavir Overdose 
Human Experience—According to the prescribing information for ritonavir (Prescribing 
Information for Norvir® [ritonavir] Tablets, 2015; Summary of Product Characteristics for 
Norvir® [ritonavir] tablets, 2014), human experience of acute overdose with ritonavir is limited. 
One patient in clinical trials took ritonavir 1500 mg per day for 2 days. The patient reported 
paresthesias which resolved after the dose was decreased. A postmarketing case of renal failure 
with eosinophilia has been reported with ritonavir overdose. The approximate lethal dose was 
found to be greater than 20 times the related human dose in rats and 10 times the related human 
dose in mice. 
Management—According to the prescribing information for ritonavir (Prescribing Information 
for Norvir® [ritonavir] Tablets, 2015; Summary of Product Characteristics for Norvir® [ritonavir] 
tablets, 2014), treatment of overdose with ritonavir consists of general supportive measures 
including monitoring of vital signs and observation of the clinical status of the patient. There is 
no specific antidote for overdose with ritonavir. If indicated, elimination of unabsorbed drug 
should be achieved by gastric lavage; usual precautions should be observed to maintain the 
airway. Administration of activated charcoal may also be used to aid in removal of unabsorbed 
drug. Since ritonavir is extensively metabolized by the liver and is highly protein bound, dialysis 
is unlikely to be beneficial in significant removal of the drug. A Certified Poison Control Center 
should be consulted for up-to-date information on the management of overdose with ritonavir. 


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7 DATA QUALITY CONTROL AND ASSURANCE 
7.1 Overview 
The Sponsor is responsible for implementing and maintaining quality assurance (QA) and quality 
control (QC) systems with written standard operating procedures (SOPs). Accurate, consistent, 
and reliable data will be ensured through the use of standard Good Clinical Practices (GCPs). 
Local monitors and representatives of the Sponsor will monitor the study for compliance with 
appropriate regulations, International Conference on Harmonisation (ICH) and GCP guidelines, 
and requirements of individual countries. 
The Investigator at each investigational site is responsible for the quality of all study data from 
that site. This includes but is not limited to adherence to the study protocol and study procedure 
manual, review of the results of all study evaluations to ensure quality, and accurate data entry. 
A list of individuals who will have key positions in this study will be saved in the Trial Master 
File. This list will include names, titles, and roles of selected individuals from the Sponsor and 
the contract research organization (CRO) that will contribute to this study. 
Quality control will be applied to each stage of data handling. The following steps will be taken 
to ensure the accuracy, consistency, completeness, and reliability of the data: 
•
Investigator meeting
•
Site initiation visit
•
Routine site monitoring
•
Ongoing site communication and training
•
Data management quality control checks
•
Continuous data acquisition and cleaning
•
Internal review of data
In addition, the Sponsor’s or its designee’s Clinical QA Department may conduct periodic audits 
of the study processes, including but not limited to study site, site visits, vendors, and clinical 
database. When audits are conducted, the Sponsor’s representatives and authorized regulatory 
representatives must be allowed access to all study-related documents, including medical history 
and concomitant medication documentation. If the site is informed of an inspection by any 
regulatory authority, the Investigator should notify the Sponsor immediately. 
7.2 Study Monitoring 
The Sponsor has engaged the services of a CRO to perform all monitoring functions for this 
clinical study. Monitors will work in accordance with Sponsor’s and CRO’s SOPs and have the 
same rights and responsibilities as monitors from the Sponsor organization. Monitors will 
establish and maintain regular contact between the Investigator or a designee and the Sponsor. 
Monitors will evaluate the competence of each study site, informing the Sponsor about any 
problems relating to facilities, technical equipment, or medical staff. During the study, 
monitors will  


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•
Check that written informed consent has been correctly obtained from each patient in
the study
•
Data are recorded correctly and completely on the CRFs
•
Compare entries in CRFs with corresponding source data and inform the Investigator
or a designee of any errors or omissions
•
Review adherence to the protocol and to regulatory requirements at the study site and
discuss and deviations noted with the Investigator or a designee.
Monitors will arrange for the study site to receive an adequate supply of investigational products 
and ensure that appropriate storage conditions are maintained. 
Monitoring visits will be conducted according to the US CFR Title 21 parts 50, 56, and 312; 
EU_Directive 2005/28/EC; and International Conference on Harmonisation (ICH) Guideline for 
GCP. The monitor will submit written reports to the Sponsor following each contact with the 
Investigator or a designee, regardless of whether it is by phone or in person. 
7.3 Data Management 
Study data will be handled according to the relevant SOPs of the data management and 
biostatistics departments of the Sponsor or CRO. 
7.4 Quality Assurance Audit 
Study sites, the study database, and study documentation may be subject to a QA audit during the 
study by the Sponsor or its designee on behalf of the Sponsor. In addition, inspections may be 
conducted by regulatory agencies at their discretion. 
7.5 Data Handling and Recordkeeping 
7.5.1 
Case Report Form Completion 
Case report forms will be completed for each patient enrolled in the study. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
patient’s CRF. Source documentation supporting the CRF data should indicate the patient’s 
participation in the study and should document the dates and details of study procedures, AEs, 
and patient status. Study monitors will discuss instances of missing or uninterpretable data with 
the Investigator for resolution. Any changes to study data will be made to the CRF according to 
SOP specifications. 
For patients who discontinue treatment or withdraw from the study, the CRFs will be completed 
as much as possible, and the reason for the discontinuation or withdrawal clearly and concisely 
specified on the appropriate CRF. 
If electronic CRFs (eCRFs) are used, data will be entered into the CRF by site personnel using a 
secure, validated web-based electronic data capture (EDC) application. Any data not entered by 
the site will be entered into an eCRF by trained data entry staff using a secure, validated, web-
based EDC application. The Sponsor will have access to all data on entry in the EDC application. 


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7.5.2 
Data Handling 
If data are transformed during processing, records will be maintained so that it will be possible to 
compare the original data and observations with the processed data. 
An unambiguous patient identification code will be used that allows identification of all the data 
reported for each patient. 
7.5.3 
Study Files and Retention of Study Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. Essential study documents 
(protocol and protocol amendments, completed CRFs, signed ICFs, relevant correspondence, and 
all other supporting documentation) must be maintained until at least 15 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 15 years after the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or the hospital, 
institution, or private practice in which the study is being conducted. Patient identification codes 
(patient names and corresponding study numbers) will be retained for this same period of time. 
These documents may be transferred to another responsible party, acceptable to the Sponsor, 
who agrees to abide by the retention policies. Written notification of transfer must be submitted 
to the Sponsor. The Investigator or designee must contact the Sponsor before disposing of any 
study records. 
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 10 years. Samples may be retained for future determination of active metabolite 
concentrations, HDV and HBV analyses, and host DNA analyses of polymorphisms that may 
impact drug response (refer to Section 8.4 for information regarding written informed consent for 
permission to retain the samples).  
7.6 Drug Accountability 
It is the responsibility of the Investigator to maintain drug accountability at the study site and 
ensure that a current record of investigational product disposition is maintained. It is the 
responsibility of the Investigator to ensure that the investigational product is used only in 
accordance with the approved protocol. This includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), patient dispensing records, and returned or 
destroyed study product. Dispensing records will document quantities received from Eiger 
BioPharmaceuticals and quantities dispensed to patients, including lot number, date dispensed, 
patient identifier number, patient initials, and the initials of the person dispensing the drug. At 
the end of the study, after final drug inventory reconciliation by the monitor, the study site will 
dispose of and/or destroy all unused investigational medicinal product supplies, including empty 
containers, according to standard procedures. 
In this study, drug accountability will be ascertained through assessment of the study drug both 
dispensed and returned at each study visit during the Treatment Period, as well as review of the 
patient diary. Patients will be instructed to bring any bottles of study drug and the patient diary to 
each study visit during the Treatment Period. 


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8 ETHICAL AND LEGAL CONSIDERATIONS 
8.1 Ethical Conduct and Good Clinical Practice 
This study will be conducted in compliance with GCP as described in the ICH document 
“Guidance for Industry—E6 Good Clinical Practice:  Consolidated Guidance,” dated June 1996. 
These practices are consistent with the principles stated in the Declaration of Helsinki (version as 
currently endorsed by the European Medicines Evaluation Agency and the US FDA). The study 
will also be performed in keeping with local legal and regulatory requirements of the country in 
which the research is conducted, whichever affords the greater protection to the study subject. 
For studies conducted under a United States Investigational New Drug (IND) application, the 
Investigator will ensure that the basic principles of “Good Clinical Practice,” as outlined in the 
US Code of Federal Regulations (CFR) Title 21, Part 312 Subpart D “Responsibilities of 
Sponsors and Investigators”, Part 50 “Protection of Human Subjects”, and Part 56 “Institutional 
Review Boards” are adhered to. For studies conducted in the EU the GCP requirements are 
outlined in Directive 2005/28/EC. These standards are consistent with the requirements of the 
European Community Directive 2001/20/EC. 
Since this is a “covered” clinical trial, the Investigator will ensure that 21 CFR, Part 54 
“Financial Disclosure by Clinical Investigators”, is adhered to. A “covered” clinical trial is any 
“study of a drug or device in humans submitted in a marketing application or reclassification 
petition subject to this part that the applicant or FDA relies on to establish that the product is 
effective (including studies that show equivalence to an effective product) or that make a 
significant contribution to the demonstration of safety.” This requires that Investigators and all 
subinvestigators must provide documentation of their financial interest or arrangements with 
Eiger BioPharmaceuticals, or proprietary interests in the drug being studied. This documentation 
must be provided before participation of the Investigator and any subinvestigator. The 
Investigator and subinvestigator agree to notify Eiger BioPharmaceuticals of any change 
reportable interests during the study and for one year following completion of the study. Study 
completion is defined as the date that the last subject has completed the protocol defined 
activities. 
8.2 Independent Ethics Committee 
All IECs will meet all FDA requirements governing Investigational Review Boards (21 CFR Part 
56 “Institutional Review Boards”) and the EU requirements outlined in Directive 2001/20/EC. 
The protocol and informed consent forms that will be used must be approved by the IEC before 
the study is initiated; documentation of this approval (ie, a copy of the document showing IEC 
approval including the chairperson's signature and the date of approval) must be provided to the 
Sponsor or its designee and made available during an inspection by regulatory agency inspectors. 
Other Investigator responsibilities relative to the IEC’s requirements include the following: 
•
Submit to the IEC/IRB and to the Sponsor or its designee for review any
advertisements that will be used to recruit patients or any other relevant materials
intended or directed to patients
•
During the conduct of the study, submit timely and accurate progress reports to the
IEC/IRB, if required, and request re-review of the study at least once a year


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•
Report, in writing, to the IEC/IRB any SAEs that occur during the study or SAEs
reported in other studies using pirfenidone, per local IEC/IRB regulations
•
Inform the IEC/IRB of any changes in the protocol and obtain documented IEC/IRB
approval of the changes
•
Provide the IEC/IRB with any other information it requests before or during the
conduct of the study
•
Maintain a file of study-related information, including all correspondence with the
IEC/IRB
8.3 Patient and Data Confidentiality 
Patient Data--The Investigator must ensure that the patient’s confidentiality is maintained. All 
CRFs, study drug accountability records, study reports, and communications will identify the 
patient by the assigned patient number. Patients should not be identified by name, social security 
number, or medical record number on any documents or materials (samples, slides) sent to Eiger 
BioPharmaceuticals or its representatives (eg, data management organization) or during verbal 
communications. The Investigator will maintain a list of patient identification numbers and 
names to enable identification of patient records. Only the patient’s identification number and 
initials will be recorded in the CRFs, and if a patient’s name appears on any other document, it 
must be obliterated on copies provided to the Sponsor.  
The patients will be informed in writing that representatives of the Sponsor, IEC, or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. The patient’s confidentiality will be maintained and 
will not be made publicly available to the extent permitted by the applicable laws and 
regulations. If results of the study are published, subject identity will remain confidential. 
Other Study Information—All information regarding the investigational product supplied by 
the Sponsor to the Investigator is privileged and confidential information. The Investigator 
agrees to use this information to accomplish the study and will not use it for other purposes 
without consent from the Sponsor. It is understood that there is an obligation to provide the 
Sponsor with complete data obtained during the study. The information obtained from the 
clinical study will be used toward the development of the investigational product and may be 
disclosed to regulatory authority(ies), other Investigators, corporate partners, or consultants as 
required. 
8.4 Informed Consent 
The Investigator or designee is responsible for the content of the informed consent form (ICF), 
but the content must be approved by the IEC/IRB and the Sponsor or designee. The content of 
the ICF must comply with FDA regulations (21 CFR Part 50.25), Directive 2001/20/EC, and the 
ICH document “Guidance for Industry—E6 Good Clinical Practice:  Consolidated Guidance,” 
dated June 1996. It should also include any additional information required by local laws relating 
to institutional review. The content of the ICF must not be altered without the prior agreement of 
the relevant IEC and the Sponsor.  


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The ICF will be used to explain the risks and benefits of study participation in simple terms 
before the patient will be entered into the study. The ICF will contain a statement that the 
consent is freely given, that the patient is aware of the risks and benefits of entering the study, 
and that the patient is free to withdraw from the study at any time. The ICF must include 
information about the possible retention of biological samples at the conclusion of this study; 
with the patient’s permission, samples may be retained for future determination of active 
metabolite concentrations, HDV and HBV analyses and host DNA analyses of polymorphisms 
that may impact drug response. 
The Investigator is responsible for obtaining written informed consent from each patient 
participating in the study. If there are amendments to the ICF, patients should be re-consented in 
a timely fashion. Informed consent must be obtained from the patient before any screening 
activity or treatment is undertaken that is not part of routine care. This includes, but is not limited 
to, the performance of diagnostic or therapeutic procedures and the administration of the first 
dose of the study drug. Before a patient’s participation in the study, the written ICF should be 
signed and personally dated by the patient or by the patient’s legally acceptable representative, 
and by the person who conducted the informed consent discussion.  
The ICF must be written in a language understandable to the patient or to his or her 
representative. The Investigator is responsible for keeping the original signed and dated ICF in a 
secure place. A signed and dated copy of the ICF must be given to the person signing the 
document. This document should not be displayed or made accessible to any third party except 
for Eiger BioPharmaceuticals or regulatory agency representative.  
If a patient permanently revokes informed consent, recording of study data will stop. 
8.5 Protocol Amendments 
Protocol amendments should be approved by the Sponsor and the IEC before implementation, 
except when necessary to eliminate immediate hazards to the patients or when the changes 
involve only logistical or administrative aspects of the study (eg, change of monitor, telephone 
numbers). In this case, the Sponsor will amend and implement the protocol change and 
subsequently notify the regulatory authorities and/or the IEC, as appropriate. 
8.6 Delegation of Responsibilities of the Principal Investigator 
The Investigator should ensure that all persons involved in the conduct of the study are informed 
about the protocol, protocol amendments, study procedures, and any study-related duties. The 
Principal Investigator (PI) is also responsible for ensuring that the study is being conducted by 
qualified personnel. Documentation of these qualifications must be retained with the Regulatory 
Binder.  
Any study-related responsibilities that are delegated to a subinvestigator or other person should 
be clearly documented in the Delegation of Authority Log. The designee should be appropriately 
trained and where necessary certified or licensed to perform the task. 
8.7 Coordinating Investigator 
The Principal Investigator will be responsible for signing the final clinical study report and 
assuring that the study has been executed according to the protocol. 


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8.8 Compensation, Insurance, and Indemnity 
Information regarding compensation, insurance, and indemnity will be provided to the 
Investigator in a separate document. 
8.9 Publication Policy 
The data generated by this study are considered confidential information and the property of 
Sponsor and shall not be published or disclosed without the prior written consent of Sponsor. 
8.10 Direct Access to Source Data 
The Investigator/institution and study site will permit study-related monitoring, audits, IEC 
review, and regulatory inspections as requested by regulatory authorities and the Sponsor or its 
designee, including direct access to source data/documents (eg, original medical records, 
laboratory reports, hospital documents, progress reports, and signed ICFs) in addition to CRFs..  
The Investigator or a designee will prepare and maintain adequate and accurate source 
documents to support all observations and other pertinent data recorded on the CRFs for patient 
enrolled in the study. 


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9 REFERENCES 
Bordier BB, Marion PL, Ohashi K, Kay MA, Greenberg HB, Casey JL, et al. 2002. 
A prenylation inhibitor prevents production of infectious hepatitis delta virus particles. 
J Virol 76(20):10465-72. 
Bordier BB, Ohkanda J, Liu P, Lee SY, Salazar FH, Marion PL, et al. 2003. In vivo antiviral 
efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest 
112(3):407-14. 
CTCAE. 2010. Common Terminology Criteria for Adverse Events, version 4.03, dated 14 June 
2010. US Department of Health and Human Services, National Institutes of Health, 
National Cancer Institute. Accessed at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 
Glenn J, Watson JA, Havel CM, White JM. 1992. Identification of a prenylation site in delta 
virus large antigen. Science, 256, 1331-1333. 
Koh C, Canini L, Dahari H, Zhao X, Uprichard S, Haynes-Williams V, et al. 2015. Oral 
prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept 
randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect Dis. 
Published online 16 July 2015. DOI: http://dx.doi.org/10.1016/S1473-3099(15)00074-2. 
Otto JC, PJ Casey. 1996. The hepatitis delta virus large antigen is farnesylated both in vitro and 
in animal cells. J Biol Chem, 271, 4569-4572. 
Prescribing Information for Norvir® (ritonavir) Tablets. 2015. AbbVie Inc. Rev 03/15.  
Summary of Product Characteristics for Norvir® [ritonavir] tablets 100 mg and oral solution 
80 mg/mL [EMEA/H/C/000127]. 2014. AbbVie Ltd. Last updated 05 Dec 2014. 
Yurdaydin C, Idilman R, Choong I, Kalkan C, Keskin O, Karakaya MF, et al. 2015. Optimizing 
the prenylation inhibitor lonafarnib using ritonavir boosting in patients with chronic delta 
hepatitis. J Hepatology. Suppl 2, vol 62: S252. European Association for the Study of the 
Liver 50th Annual Meeting 2015, Abstract 0118, oral presentation.  
 


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APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS 
Activity 
Study Week 
Study Period 
Screening 
Treatment a 
Follow-up 
ET b 
−4 to −1 
0 
1 
2 
4, 6 
8, 12, 16 
20 
24 
(EOT) 
28  
32, 36, 40, 44, 48,  
or Unscheduled Visit 
— 
Study Day 
−28 to −1 
1  
(±2) 
8 
(±2) 
15 
(±2) 
29, 43 
(±2) 
57, 85, 113 
(±5) 
141 
(±5) 
169  
(±5) 
197 
(±5) 
225, 253,  
281, 309, 337 (±5) 
— 
Visit Number 
1 
2 
3 
4 
5, 6 
7, 8, 9 
10 
11 
12 
13, 14, 15, 16, 17 
— 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X c 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
Comprehensive physical examination d 
X 
 
 
 
 
 
 
 
 
 
 
Brief physical examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Genital examination 
X 
 
 
 
 
 
 
X 
 
 
X 
Concomitant medications e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
BMI calculation g 
X 
X 
 
 
 
 
 
 
 
 
 
Ophthalmic examination h  
X 
 
 
 
 
 
 
X 
 
 
X h 
Retinal photography 
X 
 
 
 
 
 
 
X 
 
 
 
Vital signs i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG j  
X 
X 
X 
X  
X 
X  
X 
X 
X 
X 
X 
Liver biopsy (if needed) k 
X 
 
 
 
 
 
 
 
 
 
 
Fibroscan l 
 
X 
 
 
 
 
 
X 
 
 
 
Hematology m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry panel n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prothrombin time and INR 
X 
 
 
 
 
 
 
X 
X 
X 
X 
T3, T4, TSH 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum) o 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine) p 
 
X p 
 
 
X p 
X p 
X p 
X p 
X p 
X p 
X p 
Reproductive serology (includes FSH) q 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
HBV DNA analysis  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Activity 
Study Week 
Study Period 
Screening 
Treatment a 
Follow-up 
ET b 
−4 to −1 
0 
1 
2 
4, 6 
8, 12, 16 
20 
24 
(EOT) 
28  
32, 36, 40, 44, 48,  
or Unscheduled Visit 
— 
Study Day 
−28 to −1 
1  
(±2) 
8 
(±2) 
15 
(±2) 
29, 43 
(±2) 
57, 85, 113 
(±5) 
141 
(±5) 
169  
(±5) 
197 
(±5) 
225, 253,  
281, 309, 337 (±5) 
— 
Visit Number 
1 
2 
3 
4 
5, 6 
7, 8, 9 
10 
11 
12 
13, 14, 15, 16, 17 
— 
HBeAg, HBeAb 
X 
X 
 
 
 
 
 
X 
 
 
 
HBsAg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCV serology r 
X 
 
 
 
 
 
 
 
 
 
 
HDV serology s 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
HDV viral load (qPCR) t 
X 
X 
X 
X 
X 
X t 
X 
X 
X 
X 
X 
Large HDV Ag genotype u 
 
X 
Xu 
Xu 
Xu 
Xu 
Xu 
Xu 
Xu 
Xu 
Xu 
HIV serology 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis (predose) v 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug screen w 
X 
 
 
 
 
 
 
 
 
 
 
Blood alcohol test 
X 
 
 
 
 
 
 
 
 
 
 
PBMC collection x 
 
X 
 
X 
X 
X  
 
X 
X 
X 
 
PK sampling y  
 
 
 
X 
X 
X y 
(Collect full 
PK once at 
either Wk  
8, 12, or 16) 
 
 
 
 
 
Evaluate for dose escalation  
 
 
 
 
X 
 
 
 
 
 
 
Dispense study drug z 
 
X 
 
X 
X 
X 
X 
 
 
 
 
Study drug administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study drug accountability z 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Provide patient diary/patient 
information sheet 
 
X 
 
 
 
 
 
 
 
 
 
Review patient diary 
 
 
X 
X 
X 
X 
X 
X 
 
 
X aa 
Collect patient diary 
 
 
 
 
 
 
 
X 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMI = body mass index, ECG = electrocardiogram, EOT = end of treatment, ET = early termination, HBV = hepatitis B virus, HDV = hepatitis D virus, 
PBMC = peripheral blood mononuclear cell, qPCR = quantitative polymerase chain reaction,  
a Complete all assessments before the first dose of the day is administered.  


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b Early termination visit: Patients who withdraw from treatment early during the Treatment Period should return as soon as possible to undergo these 
assessments; patients who withdraw early during the Follow-Up Period should undergo the assessments planned at the next scheduled study visit.  
c  Inclusion criteria:  Review and confirm inclusion eligibility.  
d Conduct comprehensive physical examination, including measurement of height and weight, calculate BMI, and assess CTP score and encephalopathy 
(see Appendix B) 
e See Section 3.8.2 and Appendix C for lists of prohibited concomitant medications. 
f  Body weight of ≥45 kg. Weight should be measured with inner clothing and without shoes. 
g BMI of ≥18 kg/m2 
h Ophthalmic examination includes visual acuity examination, dilatation, and slit lamp examination. On slit lamp examination, orbit, eyelids, lashes, lacrimal 
gland, conjunctiva, cornea, sclera, anterior chamber, and iris are examined. On the dilated fundus examination, lens, vitreous, optic disc, and retina are 
examined. An early termination visit ophthalmic exam is only required if the early termination occurs between weeks 12 and 24 of the dosing period 
i Blood pressure, heart rate, respiratory rate, and body temperature; blood pressure and heart rate should  be measured after 5 minutes in sitting position.  
j Serial ECG (×3) 2 to 3 minutes apart. Patients should rest in a supine position for ≥5 minutes before the ECG recording is made. ECGs must be read by the 
Investigator or a qualified designee, and the results recorded in the CRF. On days that PK sampling is performed, obtain sample for viral load determination 
and conduct ECGs before first dose of lonafarnib/ritonavir. 
k  Each patient must have documentation of a liver biopsy demonstrating evidence of chronic hepatitis. If no liver biopsy was performed or no documentation of 
a biopsy is available, a liver biopsy must be performed within the screening period. To avoid unnecessary biopsies for ineligible patients, it is recommended 
that the liver biopsy be performed after the patient successfully completes all other screening assessments. 
l Patients must fast for at least 3 hours before the Fibroscan is performed. 
m  Hematology assessments include the following: complete blood count (hemoglobin, hematocrit, red blood cell [RBC] count, mean corpuscular volume 
[MCV], mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC), white blood cell [WBC] count with differential, 
absolute lymphocytes, absolute monocytes, absolute neutrophils, absolute eosinophils, absolute basophils, and platelets, and cell morphology). 
n Serum chemistry profile (alanine aminotransferase [ALT], albumin, alkaline phosphatase, amylase, aspartate aminotransferase [AST], bicarbonate, bilirubin 
(direct, indirect, total), blood urea nitrogen [BUN], calcium, chloride, cholesterol, creatine kinase [CK], creatinine, gamma-glutamyl transferase [GGT], 
globulin, glucose (nonfasting), lactate dehydrogenase [LDH], magnesium, phosphorus, potassium, sodium, triglycerides, total protein, and uric acid). 
o  For women of childbearing potential only. 
p  Urine pregnancy test performed before first dose is administered. For women of childbearing potential only. A positive urine pregnancy test requires 
immediate confirmation by serum pregnancy test. 
q  Morning levels of the following: females—luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, progesterone, anit-Müullerian hormone 
(AMH), dehydroepiandrosterone  (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, free testosterone, sex hormone binding 
globulin (SHBG), 17-hydroxyprogesterone (17-OHP); males—inhibin B, LH, FSH, and free and total testosterone. 
r Patients with a positive HCV Ab at screening must have completed a curative antiviral regimen and documented to be HCV RNA negative (undetectable) at 
least 3 months before screening and at screening. 
s HDV serology: positive HDV Ab test of at least 6 months duration. 
t Serum and plasma samples for viral mutation analysis, resistance phenotyping, and analysis of drug mechanism and treatment response. On the day that PK 
sampling is performed, obtain sample for viral load determination and conduct ECGs before first dose of lonafarnib/ritonavir is administered. 
u Perform postbaseline genotypic analysis of large HDV antigen only in case of viral load rebound. 
v Urinalysis assessments include the following: specific gravity, protein, ketones, bilirubin, urobilinogen, blood, nitrite, and microscopic examination of 
sediment. 
w Urine drug screen for cannabinoids, opiates, amphetamines, barbiturates, benzodiazepenes, and cocaine. 


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x PBMC will be drawn at baseline, Weeks 2, 4, 12, 24, 28, 36, and 48. 
y Collect trough PK blood samples at Weeks 2, 4, 6, 8, 12, and 16. Trough PK sample is collected within 30 minutes prior to study drug administration.  At 
either Week 8, 12, or 16 if the patient is on a stable dose for the prior 2 weeks, full PK sampling should be performed.  The time points for full PK sampling 
are as follows: predose (within 30 min before the first dose of the day) and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h postdose. Fasting is not required on the day of PK 
sampling.  On the day that full PK sampling is collected, patients will remain in clinic at least 13 hours. On the day that PK sampling is performed, obtain 
sample for viral load determination and PBMC analysis and conduct ECGs before first dose of lonafarnib/ritonavir. On all days that trough PK sampling is 
done patients should not take the morning dose;  the morning dose should be administered after the trough PK sample is taken. On the day full PK is 
performed, patients should take the morning dose after the pre-dose PK sample is obtained, and the second dose after the final 12 hour PK sample is obtained. 
Note:  For any lonafarnib dose adjustments that occur due to patient tolerability issues (refer to Section 3.6.2), full PK sampling will be performed after the 
patient has been at a stable dose for the 2 weeks before the study visit. If the patient has not been at a stable dose for the 2 weeks before the study visit, full PK 
sampling will be performed at a future visit, after the patient has been on a stable dose for at least 2 weeks. 
z  Before dispensing study drugs, instruct patients to bring back empty bottles or any unused study drug(s) in the original bottle at every postbaseline study visit 
through the end of treatment. 
aa Collect and review the patient diary if the visit occurs during the Treatment Period. 


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APPENDIX B 
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. Patients with a total CTP score of 7 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 
1.72–20 
>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 
Patients with assessments of stage 1–4 are not eligible to participate in this study. 
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 


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APPENDIX C 
PROHIBITED CONCOMITANT DRUGS OR DRUGS 
THAT MAY HAVE SIGNIFICANT INTERACTIONS 
WITH STUDY DRUGS 
 
Table 14 Drugs That Are Contraindicated with Use of Ritonavir 
Class 
Drug 
Clinical Outcome/Rationale 
Alpha1- adrenoreceptor 
antagonist 
Alfuzosin HCL 
Potential for hypotension. 
Increased plasma concentrations 
of alfuzosin which may lead to 
severe hypotension 
Analgesics* 
Pethidine*, piroxicam*, 
propoxyphene* 
Increased plasma concentrations 
of norpethidine, piroxicam and 
propoxyphene. Thereby, 
increasing the risk of serious 
respiratory depression or 
haematologic abnormalities, or 
other serious adverse effects from 
these agents. 
Antiarrhythmics 
Amiodarone, bepridil*, 
encainide*, flecainide, 
propafenone, quinidine 
Potential for cardiac arrhythmias. 
Increased plasma concentrations 
of amiodarone, bepridil, 
encainide, flecainide, 
propafenone, quinidine. Thereby, 
increasing the risk of arrhythmias 
or other serious adverse effects 
from these agents. 
Antibiotic* 
Fusidic acid* 
Increased plasma concentrations 
of fusidic acid and ritonavir. 
Antifungal 
Voriconazole 
Co-administration of 
voriconazole with ritonavir 400 
mg every 12 hours significantly 
decreases voriconazole plasma 
concentrations and may lead to 
loss of antifungal response. 
Voriconazole is contraindicated 
with ritonavir doses of 400 mg 
every 12 hours or greater  
Antihistamines* 
Astemizole*, terfenadine* 
Increased plasma concentrations 
of astemizole and terfenadine. 
Thereby, increasing the risk of 
serious arrhythmias from these 
agents. 
Antimycobacterial* 
Rifabutin* 
Concomitant use of ritonavir 
dosed as an antiretroviral agent 
(600 mg twice daily) and 
rifabutin due to an increase of 
rifabutin serum concentrations 
and risk of adverse reactions 


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Class 
Drug 
Clinical Outcome/Rationale 
including uveitis (see section 
4.4). Recommendations regarding 
use of ritonavir dosed as a 
pharmacokinetic enhancer with 
rifabutin are noted in section 4.5 
Antipsychotics*/Neuroleptics 
Clozapine*, pimozide 
Potential for cardiac arrhythmias. 
Increased plasma concentrations 
of clozapine and pimozide. 
Thereby, increasing the risk of 
serious haematologic 
abnormalities, or other serious 
adverse effects from these agents. 
 
Quetiapine* 
Increased plasma concentrations 
of quetiapine which may lead to 
coma. The concomitant 
administration with quetiapine is 
contraindicated 
Ergot Derivatives 
Dihydroergotamine, ergonovine, 
ergotamine, methylergonovine 
Potential for acute ergot toxicity 
characterized by vasospasm and 
ischemia of the extremities and 
other tissues including the central 
nervous system. 
Gastrointestinal Motility Agent 
Cisapride 
Increased plasma concentrations 
of cisapride. Potential for cardiac 
arrhythmias. 
Herbal Products 
St. John's Wort (hypericum 
perforatum) 
Co-administration of NORVIR 
with St. John’s Wort may result 
in decreased ritonavir plasma 
concentrations and may lead to 
loss of virologic response and 
possible resistance to NORVIR or 
to the class of protease inhibitors. 
HMG-CoA Reductase Inhibitors: 
Lovastatin, simvastatin 
Increased plasma concentrations 
of lovastatin and simvastatin; 
thereby, increasing the risk of 
myopathy including 
rhabdomyolysis 
PDE5 enzyme inhibitor 
Avanafil* 
Increased plasma concentrations 
of avanafil  
 
Sildenafil (Revatio®) only when 
used for the treatment of 
pulmonary arterial hypertension 
(PAH) 
A safe and effective dose has not 
been established when used with 
ritonavir. There is an increased 
potential for sildenafil- associated 
adverse events, including visual 
abnormalities, hypotension, 
prolonged erection, and syncope. 
 
Vardenafil* 
Increased plasma concentrations 
of vardenafil  


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Class 
Drug 
Clinical Outcome/Rationale 
Sedative/hypnotics 
Clorazepate*, diazepam*, 
estazolam*, flurazepam*, oral 
midazolam, triazolam 
Prolonged or increased sedation 
or respiratory depression. 
Thereby, increasing the risk of 
extreme sedation and respiratory 
depression from these agents 
Source:  Prescribing Information for Norvir® [ritonavir] Tablets, 2015. *Additional terms from the Summary of 
Product Characteristics for Norvir® [ritonavir] tablets, 2014 
 
 


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Table 15 Established and Other Potentially Significant Drug Interactions with Use 
of Ritonavir  
Concomitant Drug 
Class: Drug Name 
Effect on Concentration of 
Ritonavir or 
Concomitant Drug 
Clinical Comments 
HIV-Antiviral Agents 
 
 
HIV-1 Protease 
Inhibitor: atazanavir  
When co-administered with 
reduced doses of atazanavir and 
ritonavir ↑ atazanavir (↑ AUC, ↑ 
Cmax, ↑ Cmin)  
Atazanavir plasma concentrations achieved with 
atazanavir 300 mg once daily and ritonavir 100 
mg once daily are higher than those achieved with 
atazanavir 400 mg once daily. See the complete 
prescribing information for Reyataz® (atazanavir) 
for details on co-administration of atazanavir 300 
mg once daily with ritonavir 100 mg once daily.  
HIV-1 Protease 
Inhibitor: darunavir  
When co-administered with 
reduced doses of ritonavir ↑ 
darunavir (↑ AUC, ↑ Cmax, ↑ 
Cmin)  
See the complete prescribing information for 
Prezista® (darunavir) for details on co-
administration of darunavir 600 mg twice daily 
with ritonavir 100 mg twice daily or darunavir 
800 mg once daily with ritonavir 100 mg once 
daily.  
HIV-1 Protease  
Inhibitor: fosamprenavir  
 
When co-administered with 
reduced doses of ritonavir ↑ 
amprenavir (↑ AUC, ↑ Cmax, ↑ 
Cmin)  
 
See the complete prescribing information for  
Lexiva® (fosamprenavir) for details on co-
administration of fosamprenavir 700 mg twice 
daily with ritonavir 100 mg twice daily, 
fosamprenavir 1400 mg once daily with ritonavir 
200 mg once daily or fosamprenavir 1400 mg 
once daily with ritonavir 100 mg once daily.  
HIV-1 Protease 
Inhibitor: indinavir  
When co-administered with 
reduced doses of indinavir and 
ritonavir ↑ indinavir (↔ AUC, ↓ 
Cmax, ↑ Cmin)  
Alterations in concentrations are noted when 
reduced doses of indinavir are co-administered 
with NORVIR. Appropriate doses for this 
combination, with respect to efficacy and safety, 
have not been established.  
HIV-1 Protease 
Inhibitor:  nelfinavir* 
When co-administered with 
ritonavir, ↑ nelfinavir (↑ AUC) 
Ritonavir increases the serum levels of nelfinavir 
as a result of CYP3A4 inhibition. Appropriate 
doses for this combination, with respect to 
efficacy and safety, have not been established.  
HIV-1 Protease 
Inhibitor: saquinavir  
When co-administered with 
reduced doses of ritonavir ↑ 
saquinavir (↑ AUC, ↑ Cmax, ↑ 
Cmin)  
See the complete prescribing information for 
Invirase® (saquinavir) for details on co-
administration of saquinavir 1000 mg twice daily 
with ritonavir 100 mg twice daily. 
Saquinavir/ritonavir should not be given together 
with rifampin, due to the risk of severe 
hepatotoxicity (presenting as increased hepatic 
transaminases) if the three drugs are given 
together.  
HIV-1 Protease 
Inhibitor: tipranavir  
When co-administered with 
reduced doses of ritonavir ↑ 
tipranavir (↑ AUC, ↑ Cmax, ↑ 
Cmin)  
See the complete prescribing information for 
Aptivus® (tipranavir) for details on co-
administration of tipranavir 500 mg twice daily 
with ritonavir 200 mg twice daily. There have 
been reports of clinical hepatitis and hepatic 
decompensation including some fatalities. All 
patients should be followed closely with clinical 


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Concomitant Drug 
Class: Drug Name 
Effect on Concentration of 
Ritonavir or 
Concomitant Drug 
Clinical Comments 
and laboratory monitoring, especially those with 
chronic hepatitis B or C co-infection, as these 
patients have an increased risk of hepatotoxicity. 
Liver function tests should be performed prior to 
initiating therapy with tipranavir/ritonavir, and 
frequently throughout the duration of treatment.  
Nucleoside Reverse 
Transcriptase Inhibitor: 
didanosine* 
↓ didanosine (↓AUC) 
Based on comparison to historical data, the 
pharmacokinetics of delavirdine did not appear to 
be affected by ritonavir. When used in 
combination with delavirdine, dose reduction of 
ritonavir may be considered. 
Non-Nucleoside Reverse 
Transcriptase Inhibitor: 
delavirdine  
↑ ritonavir (↑AUC, ↑Cmax, ↑ 
Cmin)  
Appropriate doses of this combination with 
respect to safety and efficacy have not been 
established.  
Non-Nucleoside Reverse 
Transcriptase Inhibitor: 
efavirenz* 
↑ ritonavir (↑AUC), ↑ efavirenz 
(↑AUC) 
A higher frequency of adverse reactions (eg, 
dizziness, nausea, paraesthesia) and laboratory 
abnormalities (elevated liver enzymes) have been 
observed when efavirenz is co-administered with 
ritonavir dosed as an antiretroviral agent. 
HIV-1 CCR5 – 
antagonist: maraviroc  
↑ maraviroc  
Concurrent administration of maraviroc with 
ritonavir will increase plasma levels of maraviroc. 
For specific dosage adjustment recommendations, 
please refer to the complete prescribing 
information for Selzentry® (maraviroc).  
Integrase Inhibitor:  
Raltegravir  
 
↓ raltegravir  
The effects of ritonavir on raltegravir with  
ritonavir dosage regimens greater than 100 mg 
twice daily have not been evaluated, however 
raltegravir concentrations may be decreased with 
ritonavir coadministration.  
Other Agents  
 
 
Analgesics, Narcotic: 
tramadol, propoxyphene  
 
A dose decrease may be needed for these drugs 
when co-administered with ritonavir. 
Anesthetic: meperidine  
↓ meperidine/ ↑ normeperidine 
(metabolite)  
Dosage increase and long-term use of meperidine 
with ritonavir are not recommended due to the 
increased concentrations of the metabolite 
normeperidine which has both analgesic activity 
and CNS stimulant activity (e.g., seizures).  
Antialcoholics: 
disulfiram/metronidazole  
 
 
Ritonavir formulations contain alcohol, which can 
produce disulfiram-like reactions when co-
administered with disulfiram or other drugs that 
produce this reaction (e.g., metronidazole).  
Antiarrhythmics: 
disopyramide, lidocaine, 
mexiletine  
↑ antiarrhythmics  
Caution is warranted and therapeutic 
concentration monitoring is recommended for 
antiarrhythmics when co-administered with 
ritonavir, if available.  
Anticancer Agents: 
dasatinib, nilotinib, 
vincristine, vinblastine  
↑ anticancer agents  
Concentrations of these drugs may be increased 
when co-administered with ritonavir resulting in 
the potential for increased adverse events usually 


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Concomitant Drug 
Class: Drug Name 
Effect on Concentration of 
Ritonavir or 
Concomitant Drug 
Clinical Comments 
associated with these anticancer agents. For 
vincristine and vinblastine, consideration should 
be given to temporarily withholding the ritonavir 
containing antiretroviral regimen in patients who 
develop significant hematologic or 
gastrointestinal side effects when ritonavir is 
administered concurrently with vincristine or 
vinblastine. Clinicians should be aware that if the 
ritonavir containing regimen is withheld for a 
prolonged period, consideration should be given 
to altering the regimen to not include a CYP3A or 
P-gp inhibitor in order to control HIV-1 viral load. 
A decrease in the dosage or an adjustment of the 
dosing interval of nilotinib and dasatinib may be 
necessary for patients requiring co-administration 
with strong CYP3A inhibitors such as NORVIR. 
Please refer to the nilotinib and dasatinib 
prescribing information for dosing instructions.  
Anticoagulant: warfarin  
↓ R-warfarin ↓↑ S-warfarin  
Initial frequent monitoring of the INR during 
ritonavir and warfarin co-administration is 
indicated.  
Anticoagulant:  
rivaroxaban  
 
↑ rivaroxaban  
Avoid concomitant use of rivaroxaban and  
ritonavir. Co-administration of ritonavir and 
rivaroxaban is expected to result in increased 
exposure of rivaroxaban which may lead to risk of 
increased bleeding.  
Anticonvulsants: 
carbamazepine, 
clonazepam, 
ethosuximide  
↑ anticonvulsants  
Use with caution. A dose decrease may be needed 
for these drugs when co-administered with 
ritonavir and therapeutic concentration monitoring 
is recommended for these anticonvulsants, if 
available.  
Anticonvulsants: 
divalproex, lamotrigine, 
phenytoin  
↓ anticonvulsants  
Use with caution. A dose increase may be needed 
for these drugs when co-administered with 
ritonavir and therapeutic concentration monitoring 
is recommended for these anticonvulsants, if 
available.  
Antidepressants: 
nefazodone; selective 
serotonin reuptake 
inhibitors (SSRIs): eg, 
fluoxetine, paroxetine, 
sertraline*;  tricyclics: 
eg, amitriptyline, 
imipramine*, 
nortriptyline  
↑ antidepressants  
A dose decrease may be needed for these drugs 
when co-administered with ritonavir.  
Antidepressant: 
bupropion  
↓ bupropion ↓ active metabolite, 
hydroxybupropion  
Concurrent administration of bupropion with 
ritonavir may decrease plasma levels of both 
bupropion and its active metabolite 
(hydroxybupropion). Patients receiving ritonavir 


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Concomitant Drug 
Class: Drug Name 
Effect on Concentration of 
Ritonavir or 
Concomitant Drug 
Clinical Comments 
and bupropion concurrently should be monitored 
for an adequate clinical response to bupropion.  
Antidepressant: 
desipramine  
↑ desipramine  
Dosage reduction and concentration monitoring of 
desipramine is recommended.  
Antidepressant: 
trazodone  
↑ trazodone  
Concomitant use of trazodone and NORVIR 
increases plasma concentrations of trazodone. 
Adverse events of nausea, dizziness, hypotension 
and syncope have been observed following co-
administration of trazodone and NORVIR. If 
trazodone is used with a CYP3A4 inhibitor such 
as ritonavir, the combination should be used with 
caution and a lower dose of trazodone should be 
considered.  
Antiemetic: dronabinol  
↑ dronabinol  
A dose decrease of dronabinol may be needed 
when co-administered with ritonavir.  
Antifungal: 
ketoconazole,  
itraconazole, 
voriconazole  
 
↑ ketoconazole  
↑ itraconazole  
↓ voriconazole  
High doses of ketoconazole or itraconazole 
(greater than 200 mg per day) are not  
recommended. Co-administration of voriconazole 
and ritonavir doses of 400 mg every 12 hours or 
greater is contraindicated. Co-administration of 
voriconazole and ritonavir 100 mg should be 
avoided, unless an assessment of the benefit/risk 
to the patient justifies the use of voriconazole.  
Anti-gout: colchicine  
↑ colchicine  
Patients with renal or hepatic impairment should 
not be given colchicine with ritonavir.  
 
Treatment of gout flares-co-administration of 
colchicine in patients on ritonavir:  
0.6 mg (one tablet) for one dose, followed by 0.3 
mg (half tablet) one hour later. Dose to be 
repeated no earlier than three days.  
 
Prophylaxis of gout flares-co-administration of 
colchicine in patients on ritonavir:  
If the original colchicine regimen was 0.6 mg 
twice a day, the regimen should be adjusted to 0.3 
mg once a day.  
If the original colchicine regimen was 0.6 mg 
once a day, the regimen should be adjusted to 0.3 
mg once every other day.  
Treatment of familial Mediterranean fever (FMF)-
co-administration of colchicine in patients on 
ritonavir:  
Maximum daily dose of 0.6 mg (may be given as 
0.3 mg twice a day).  
Antihistamines: 
fexofenadine, loratadine 
↑ fexofenadine 
↑ loratadine 
Ritonavir may modify P-glycoprotein mediated 
fexofenadine efflux when dosed as an 
antriretroviral agent or as a pharmacokinetic 


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Concomitant Drug 
Class: Drug Name 
Effect on Concentration of 
Ritonavir or 
Concomitant Drug 
Clinical Comments 
enhancer resulting in increased concentrations of 
fexofenadine. Increased fexofenadine levels may 
lessen over time as induction develops.  
Ritonavir dosed as a pharmacokinetic enhancer or 
as an antiretroviral agent inhibits CYP3A and as a 
result is expected to increase the plasma 
concentrations of loratadine. Careful monitoring 
of therapeutic and adverse effects is r 
ecommended when loratidine is concomitantly 
administered with ritonavir. 
Anti-infective: 
clarithromycin  
↑ clarithromycin  
For patients with renal impairment the following 
dosage adjustments should be considered:  
• For patients with CLCR 30 to 60 mL per min the 
dose of clarithromycin should be reduced by 50%.  
• For patients with CLCR less than 30 mL per min 
the dose of clarithromycin should be decreased by 
75%.  
 
No dose adjustment for patients with normal renal 
function is necessary.  
Antimycobacterial:  
rifabutin, erythromycin* 
 
↑ rifabutin and rifabutin 
metabolite  
↑ erythromycin 
Dosage reduction of rifabutin by at least three- 
quarters of the usual dose of 300 mg per day is 
recommended (eg, 150 mg every other day or 
three times a week). Further dosage reduction 
may be necessary.  
Ritonavir dosed as a pharmacokinetic enhancer or 
as an antiretroviral agent inhibits CYP3A4 and as 
a result is expected to increase the plasma 
concentrations of erythromycin. Careful 
monitoring of therapeutic and adverse effects is 
recommended when erythromycin is used 
concomitantly administered with ritonavir. 
Antimycobacterial: 
rifampin  
↓ ritonavir  
May lead to loss of virologic response. Alternate 
antimycobacterial agents such as rifabutin should 
be considered (see Antimycobacterial: rifabutin, 
for dose reduction recommendations).  
Antiparasitic: 
atovaquone  
↓ atovaquone  
Clinical significance is unknown; however, 
increase in atovaquone dose may be needed.  
Antiparasitic: quinine  
↑ quinine  
A dose decrease of quinine may be needed when 
co-administered with ritonavir.  
Antipsychotics: 
quetiapine, haloperidol* 
↑ quetiapine  
↑ haloperidol 
Initiation of NORVIR in patients taking 
quetiapine: Consider alternative antiretroviral 
therapy to avoid increases in quetiapine 
exposures. If coadministration is necessary, 
reduce the quetiapine dose to 1/6 of the current 
dose and monitor for quetiapine-associated 
adverse reactions. Refer to the quetiapine 


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Concomitant Drug 
Class: Drug Name 
Effect on Concentration of 
Ritonavir or 
Concomitant Drug 
Clinical Comments 
prescribing information for recommendations on 
adverse reaction monitoring.  
 
Initiation of quetiapine in patients taking 
NORVIR: Refer to the quetiapine prescribing 
information for initial dosing and titration of 
quetiapine.  
 
Ritonavir dosed as an antiretroviral agent is likely 
to inhibit CYP2D6 and as a result is expected to 
increase concentrations of haloperidol. Careful 
monitoring of therapeutic and adverse effects is 
recommended when concomitantly administered 
with antiretroviral doses of ritonavir 
β-Blockers: metoprolol, 
timolol  
↑ Beta-Blockers  
Caution is warranted and clinical monitoring of 
patients is recommended. A dose decrease may be 
needed for these drugs when co-administered with 
ritonavir.  
Bronchodilator: 
theophylline  
↓ theophylline  
Increased dosage of theophylline may be required; 
therapeutic monitoring should be considered.  
Calcium channel 
blockers: diltiazem, 
nifedipine, verapamil, 
amlodipine*  
↑ calcium channel blockers  
Caution is warranted and clinical monitoring of 
patients is recommended. A dose decrease may be 
needed for these drugs when co-administered with 
ritonavir.  
Digoxin  
↑ digoxin  
Concomitant administration of ritonavir with 
digoxin may increase digoxin levels. Caution 
should be exercised when co-administering 
ritonavir with digoxin, with appropriate 
monitoring of serum digoxin levels.  
Endothelin receptor 
antagonists: bosentan  
↑ bosentan  
Co-administration of bosentan in patients on  
ritonavir: In patients who have been receiving 
ritonavir for at least 10 days, start bosentan at 62.5 
mg once daily or every other day based upon 
individual tolerability.  
 
Co-administration of ritonavir in patients on 
bosentan: Discontinue use of bosentan at least 36 
hours prior to initiation of ritonavir. After at least 
10 days following the initiation of ritonavir, 
resume bosentan at 62.5 mg once daily or every 
other day based upon individual tolerability.  
HCV-Protease Inhibitor: 
simeprevir  
↑simeprevir  
It is not recommended to co-administer ritonavir 
with simeprevir.  
HMG-CoA Reductase 
Inhibitor: atorvastatin 
rosuvastatin, 
fluvastatin*, pravastatin*  
↑ atorvastatin a ↑ rosuvastatin a 
↑ fluvastatin a ↑pravastatin a 
Titrate atorvastatin and rosuvastatin dose carefully 
and use the lowest necessary dose. If NORVIR is 
used with another protease inhibitor, see the 
complete prescribing information for the 


Protocol EIG-LNF-002 
Eiger BioPharmaceuticals  |  Confidential and Proprietary  |  Page 103 
Concomitant Drug 
Class: Drug Name 
Effect on Concentration of 
Ritonavir or 
Concomitant Drug 
Clinical Comments 
concomitant protease inhibitor for details on co-
administration with atorvastatin and rosuvastatin.  
 
The metabolism of pravastatin and fluvastatin is 
not dependent on CYP3A, and interactions are not 
expected with ritonavir. If treatment with an 
HMG-CoA reductase inhibitor is indicated, 
pravastatin or fluvastatin is recommended.  
Immunosuppressants: 
cyclosporine, tacrolimus, 
sirolimus (rapamycin)  
↑ immunosuppressants  
Therapeutic concentration monitoring is 
recommended for immunosuppressant agents 
when co-administered with ritonavir.  
Inhaled or Intranasal 
Steroid: e.g. fluticasone 
budesonide  
↑ glucocorticoids  
Concomitant use of ritonavir and fluticasone or 
other glucocorticoids that are metabolized by 
CYP3A is not recommended unless the potential 
benefit of treatment outweighs the risk of 
systemic corticosteroid effects. Concomitant use 
may result in increased steroid concentrations and 
reduced serum cortisol concentrations. Systemic 
corticosteroid effects including Cushing's 
syndrome and adrenal suppression have been 
reported during postmarketing use in patients 
when ritonavir has been coadministered with 
fluticasone propionate or budesonide.  
Long-acting beta-
adrenoceptor agonist: 
salmeterol  
↑ salmeterol  
Concurrent administration of salmeterol and 
ritonavir is not recommended. The combination 
may result in increased risk of cardiovascular  
adverse events associated with salmeterol, 
including QT prolongation, palpitations and sinus 
tachycardia.  
Narcotic Analgesic: 
methadone, fentanyl, 
morphine*  
↓ methadone ↑ fentanyl 
↓ morphine 
Dosage increase of methadone may be considered. 
Concentrations of fentanyl are expected to 
increase. Careful monitoring of therapeutic and 
adverse effects (including potentially fatal 
respiratory depression) is recommended when 
fentanyl is concomitantly administered with 
NORVIR.  
 
Morphine levels may be decreased due to 
induction of glucuronidation by co-administered 
ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer. 
Neuroleptics: 
perphenazine, 
risperidone, thioridazine  
↑ neuroleptics  
A dose decrease may be needed for these drugs 
when co-administered with ritonavir.  
Oral Contraceptives or 
Patch Contraceptives: 
ethinyl estradiol  
↓ ethinyl estradiol  
Alternate methods of contraception should be 
considered.  


Protocol EIG-LNF-002 
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Concomitant Drug 
Class: Drug Name 
Effect on Concentration of 
Ritonavir or 
Concomitant Drug 
Clinical Comments 
PDE5 Inhibitors:  
avanafil, 
sildenafil,  
tadalafil,  
vardenafil  
 
↑ avanafil  
↑ sildenafil  
↑ tadalafil  
↑ vardenafil  
Do not use ritonavir with avanafil because a safe 
and effective avanafil dosage regimen has not 
been established.  
 
Particular caution should be used when 
prescribing sildenafil, tadalafil or vardenafil in 
patients receiving ritonavir. Coadministration of 
ritonavir with these drugs is expected to 
substantially increase their concentrations and 
may result in an increase in PDE5 inhibitor 
associated adverse events, including hypotension, 
syncope, visual changes, and prolonged erection.  
 
Use of PDE5 inhibitors for pulmonary arterial 
hypertension (PAH):  
Sildenafil (Revatio®) is contraindicated when 
used for the treatment of pulmonary arterial 
hypertension (PAH) because a safe and effective 
dose has not been established when used with 
ritonavir. 
The following dose adjustments are recommended 
for use of tadalafil (Adcirca™) with ritonavir:  
 
Co-administration of ADCIRCA in patients on 
ritonavir: In patients receiving ritonavir for at 
least one week, start ADCIRCA at 20 mg once 
daily. Increase to 40 mg once daily based upon 
individual tolerability.  
 
Co-administration of ritonavir in patients on 
ADCIRCA: Avoid use of ADCIRCA during the 
initiation of ritonavir. Stop ADCIRCA at least 24 
hours prior to starting ritonavir. After at least one 
week following the initiation of ritonavir, resume 
ADCIRCA at 20 mg once daily. Increase to 40 
mg once daily based upon individual tolerability. 
 
Use of PDE5 inhibitors for the treatment of 
erectile dysfunction: It is recommended not to 
exceed the following doses:  
• Sildenafil: 25 mg every 48 hours  
• Tadalafil: 10 mg every 72 hours  
• Vardenafil: 2.5 mg every 72 hours  
Use with increased monitoring for adverse events.  
Psychoanaleptics: 
Amphetamine* 
— 
Ritonavir dosed as an antiretroviral agent is likely 
to inhibit CYP2D6 and as a result is expected to 
increase concentrations of amphetamine and its 
derivatives. Careful monitoring of therapeutic and 
adverse effects is recommended when these 


Protocol EIG-LNF-002 
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Concomitant Drug 
Class: Drug Name 
Effect on Concentration of 
Ritonavir or 
Concomitant Drug 
Clinical Comments 
medicines are concomitantly administered with 
antiretroviral doses of ritonavir. 
Sedatives/Hypnotics:  
alprazolam* 
 
Alprazolam metabolism was inhibited following 
the introduction of ritonavir. After ritonavir use 
for 10 days, no inhibitory effect of ritonavir was 
observed. Caution is warranted during the first 
several days when alprazolam is co-administered 
with ritonavir dosed as an antiretroviral agent or 
as a pharmacokinetic enhancer, before induction 
of alprazolam metabolism develops. 
Steriods: fluticasone 
propionate aqueous nasal 
spray* 
 
Systemic corticosteroid effects including 
Cushing's syndrome and adrenal suppression 
(plasma cortisol levels were noted to be decreased 
86% in the study) have been reported in patients 
receiving ritonavir and inhaled or intranasal 
fluticasone propionate; similar effects could also 
occur with other corticosteroids metabolized by 
CYP3A, eg, budesonide.  
Consequently, concomitant administration of 
ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer and these 
glucocorticoids is not recommended unless the 
potential benefit of treatment outweighs the risk 
of systemic corticosteroid. A dose reduction of the 
glucocorticoid should be considered with close 
monitoring of local and systemic effects or a 
switch to a glucocorticoid, which is not a substrate 
for CYP3A4 (eg, beclomethasone). Moreover, in 
case of withdrawal of glucocorticoids progressive 
dose reduction may be required over a longer 
period. 
a As noted in Section 3.8.2, statins are prohibited due to inhibition of mevalonate synthesis, which reduces protein 
prenylation. 
Source:  Prescribing Information for Norvir® [ritonavir] Tablets, 2015. *Additional terms from the Summary of 
Product Characteristics for Norvir® [ritonavir] tablets, 2014 
 


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Eiger BioPharmaceuticals  |  Confidential and Proprietary  |  Page 106 
APPENDIX D 
SAMPLE PATIENT DIARY—
LONAFARNIB/RITONAVIR DOSAGE:  
50 MG BID/100 MG BID 
Please complete this diary every time you take a dose of lonafarnib and ritonavir. 
 Study medication should be taken each morning and each night between HH:MM–HH:MM. 
 
Day 
Date of Dose 
(YYYY/MM/DD) 
Time of dosing 
 (24-hour clock) 
(HH:MM) 
Study Medication 
(LNF = lonafarnib 
RTV = ritonavir) 
Check if 
Taken 
1 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
2 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
3 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
4 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
5 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
6 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
7 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 


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Day 
Date of Dose 
(YYYY/MM/DD) 
Time of dosing 
 (24-hour clock) 
(HH:MM) 
Study Medication 
(LNF = lonafarnib 
RTV = ritonavir) 
Check if 
Taken 
8 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
9 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
10 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
11 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
12 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
13 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
14 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
Evening 
|__|__|:|__|__| 
LNF (1 x 50-mg capsule) 
RTV (1 x 100-mg tablet) 
□ □ 
 
 

SAP_001.pdf: 
 
CONFIDENTIAL 
Page 1 
21SEP2016 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
Study Title: 
A Phase 2, Open-Label Study of the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamic Activity of 
Titrating-Dose Lonafarnib in Combination with Ritonavir in 
Patients Chronically Infected with Hepatitis Delta Virus 
(LOWR-4) 
 
 
Name of Test Drug: 
Lonafarnib (also Sarasar, EBP994, SCH 66336) 
Ritonavir (Norvir) 
 
 
Study Number: 
EIG-LNF-002 
 
 
Protocol Version: 
Amendment 3 
 
 
Protocol Date: 
22 December 2015 
 
 
Analysis Type: 
Week 24 (End of Treatment); Week 48 (End of Study) 
 
 
Analysis Plan Version: 
Final 1.0 
 
 
Analysis Plan Date: 
21 Sep 2016 
 
 
Analysis Plan Author: 
Triangle Biostatistics, LLC 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
 


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EIG-LNF-002 
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SIGNATURE PAGE .............................................................................................................................................. 4 
LIST OF ABBREVIATIONS ................................................................................................................................ 5 
1. 
INTRODUCTION ......................................................................................................................................... 7 
1.1. 
Study Objectives ............................................................................................................................... 7 
1.2. 
Study Design ..................................................................................................................................... 8 
1.3. 
Sample Size and Power ................................................................................................................... 15 
2. 
TYPE OF PLANNED ANALYSIS ............................................................................................................. 17 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ..................................................................... 18 
3.1. 
Analysis Sets ................................................................................................................................... 18 
3.1.1. 
Safety ............................................................................................................................ 18 
3.1.2. 
Efficacy ......................................................................................................................... 18 
3.1.3. 
Pharmacokinetic ............................................................................................................ 18 
3.2. 
Missing Data ................................................................................................................................... 18 
4. 
PATIENT DISPOSITION ........................................................................................................................... 19 
4.1. 
Disposition of Patients .................................................................................................................... 19 
4.2. 
Extent of Exposure .......................................................................................................................... 19 
4.2.1. 
Duration of Exposure to Study Drug ............................................................................. 19 
4.3. 
Protocol Deviations ......................................................................................................................... 20 
5. 
BASELINE DATA ...................................................................................................................................... 21 
5.1. 
Demographics and Baseline Characteristics ................................................................................... 21 
5.2. 
Medical History .............................................................................................................................. 21 
6. 
EFFICACY ANALYSES ............................................................................................................................ 22 
6.1. 
Primary Efficacy Endpoint .............................................................................................................. 22 
6.2. 
Analysis of the Primary Efficacy Endpoint ..................................................................................... 22 
6.3. 
Secondary Efficacy Endpoints ........................................................................................................ 23 
6.4. 
Analysis of the Secondary Efficacy Endpoints ............................................................................... 23 
7. 
SAFETY ANALYSES................................................................................................................................. 24 
7.1. 
Adverse Events and Deaths ............................................................................................................. 24 
7.1.1. 
Adverse Event Dictionary ............................................................................................. 24 
7.1.2. 
Adverse Event Severity ................................................................................................. 24 
7.1.3. 
Relationship of Adverse Events to Study Drug ............................................................. 25 
7.1.4. 
Serious Adverse Events ................................................................................................. 25 
7.1.5. 
Treatment-Emergent Adverse Events ........................................................................... 26 
7.1.5.1. 
Definition of Treatment-Emergent ........................................................... 26 
7.1.5.2. 
Incomplete Dates ..................................................................................... 26 
7.1.6. 
Summaries of Adverse Events and Deaths .................................................................... 26 
7.2. 
Laboratory Evaluations ................................................................................................................... 27 
7.2.1. 
Summaries of Numeric Laboratory Results .................................................................. 27 
7.3. 
Body Weight and Vital Signs .......................................................................................................... 28 
7.4. 
Concomitant Medications ............................................................................................................... 28 
7.5. 
Electrocardiogram (ECG) Results ................................................................................................... 28 
7.6. 
Other Safety Measures .................................................................................................................... 29 
7.7. 
Viral Resistance Analysis ............................................................................................................... 29 
7.8. 
Changes From Protocol-Specified Safety Analyses ........................................................................ 29 


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8. 
PHARMACOKINETIC ANALYSES ......................................................................................................... 30 
9. 
REFERENCES ............................................................................................................................................ 32 
10. SOFTWARE ................................................................................................................................................ 33 
11. SAP REVISION .......................................................................................................................................... 34 
12. APPENDICES ............................................................................................................................................. 35 
 
Appendix 1. 
Table of Contents for Statistical Tables, Figures, and Listings ..................................... 36 
Appendix 2. 
Programming Specifications ......................................................................................... 39 
 


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LIST OF ABBREVIATIONS 
 
 
Ab 
Antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
bid 
Twice each day 
BMI 
Body mass index 
BPM 
Beats per minute 
CDER 
Center for Drug Evaluation and Research 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
EAS 
Efficacy analysis set 
ECG 
Electrocardiogram 
FR 
Federal Register 
FSH 
Follicle-stimulating hormone 
FT 
Farnesyltransferase 
GI 
Gastrointestinal 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDV 
Hepatitis Delta Virus 
HIV 
Human Immunodeficiency Virus 
HLT 
High level term 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
INR 
International normalized ratio 
IUD 
Intrauterine device 
LLT 
Lower level term 
MedDRA 
Medical dictionary for regulatory activities 
NCI 
National Cancer Institute 
PAH 
Pulmonary arterial hypertension  
PK 
Pharmacokinetics 
PT 
Preferred term 
qPCR 
Quantitative polymerase chain reaction 
QTc 
Corrected QT interval 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


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SAS 
Safety analysis set 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
TFLs 
Tables, figures, and listings 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
 




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1. 
INTRODUCTION 
Lonafarnib is an orally administered, potent and selective inhibitor of the enzyme 
farnesyltransferase (FT). Farnesylation is important in allowing association of the large 
hepatitis delta virus (HDV) protein and hepatitis B virus (HBV) surface antigens to form an 
infectious HDV particle. This association is critical in the development of HDV infection 
because HDV can propagate only in the presence of HBV. While HDV can replicate 
autonomously inside the hepatocyte, the virus requires co-infection with HBV to complete 
virion assembly and to facilitate transmission. Assembly of the HDV virion depends on 
prenylation with FT (Bordier, 2003). Compounds with FT inhibitory activity have been 
shown to prevent production of HDV virions after transfection of Huh7 cells with two 
different HDV genotypes (Bordier, 2002). 
Worldwide more than 15 million people are co-infected with HDV and HBV. Co-infection 
results in more severe complications compared with infection with HBV alone, and hepatitis 
D is the most aggressive and virulent of the viral hepatitides. HDV is clinically important 
because, although it suppresses HBV replication, it causes severe liver disease with rapid 
progression to cirrhosis and hepatic decompensation when compared with the clinical course 
associated with HBV mono-infection. The prevalence of HDV is increasing in northern and 
central Europe through migration from areas endemic in HDV. Currently, there is no 
approved therapy for HDV infection. 
Lonafarnib has been studied extensively in patients with cancer (more than 1500 patients in 
Phase 1, 2, and 3 studies) because FT also acts on Ras proteins, which play a central role on 
tumor cell growth. Eiger BioPharmaceuticals, Inc., is currently developing lonafarnib for the 
treatment of patients with chronic HDV infection. Based on the known properties of 
lonafarnib, variable absorption in patients, a metabolic pathway that occurs primarily via 
cytochrome P450 3A4 (CYP3A4), and the occurrence of dose-dependent gastrointestinal 
(GI) adverse events (AEs), Eiger plans to has combined lonafarnib with low-dose ritonavir, a 
potent CYP3A4 inhibitor, to increase systemic concentrations of lonafarnib and to reduce the 
total administered dose of lonafarnib necessary to achieve therapeutic effect. 
 
1.1. Study Objectives 
Primary Study Objectives 
• Evaluate the safety and tolerability of the following 
dose-titration regimen of lonafarnib in combination with 
ritonavir over the 24-week Treatment Period: 
lonafarnib/ritonavir starting at 50 mg bid/100 mg twice 
daily (bid) and escalated to lonafarnib/ritonavir 75 mg 
bid/100 mg bid and then to 100 mg bid/100 mg bid as 
tolerated 
• Evaluate the pharmacodynamic activity (change in 


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hepatitis D viral [HDV] load) of the dose-titration 
regimen of lonafarnib in combination with ritonavir over 
the 24-week Treatment Period                      
Secondary Study Objectives • Evaluate the effect of the dose-titration regimen of 
lonafarnib/ritonavir on the following: 
• Pharmacokinetics (PK) 
• Change in alanine aminotransferase (ALT) levels 
• Change in hepatitis B virus (HBV) DNA levels 
 
1.2. Study Design 
Design Configuration and Patient 
Population 
This is a Phase 2 study of 24 weeks of treatment with 
a dose-titration regimen of lonafarnib/ritonavir in 
patients chronically infected with HDV: lonafarnib 
starting at 50 mg bid and escalating to 75 mg bid and 
then 100 mg bid as tolerated in combination with 
ritonavir (100 mg bid). The initial dose of lonafarnib 
and ritonavir 50 mg bid/100 mg bid will be 
maintained for at least 4 weeks; subsequent dose 
escalation may occur at an interval of no less than 2 
weeks after patients have received a particular dose. 
Up to 15 patients with chronic HDV infection with 
detectable HDV RNA by quantitative polymerase 
chain reaction (qPCR) will be enrolled. 
Treatment Groups 
Open-Label Lonafarnib in Combination with 
Ritonavir 
Key Eligibility Criteria 
Inclusion Criteria 
A patient may be included in this study if he or she 
meets all of the following criteria: 
1. Willing and able to comply with study procedures 
and provide written informed consent. 
2. Male or female, 18 to 65 years of age, inclusive. 
3. Has a body mass index (BMI) of ≥18 kg/m2, 
inclusive, and has a body weight of ≥45 kg. 
4. Chronic HDV infection documented by a positive 
HDV antibody (Ab) test of at least 6 months 
duration and detectable HDV RNA by qPCR at 
study entry. 
5. Liver biopsy demonstrating evidence of chronic 


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hepatitis. 
 
If no liver biopsy is available, the patient must be 
willing to consent to and have no contraindication 
to liver biopsy. Liver biopsy will be performed 
during screening. 
6. Electrocardiogram (ECG) demonstrating no acute 
ischemia or clinically significant abnormality and 
a QT interval corrected for heart rate (QTc) of 
>450 ms using Fridericia correction (ICH 
Guidance for Industry E14: Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs). 
7. Females who meet the following criteria may be 
eligible to enter the study: 
a. Of nonchildbearing potential—defined as 
women who are surgically sterile (have had 
bilateral tubal ligation, bilateral 
oophorectomy, or hysterectomy), have 
medically documented ovarian failure, or are 
postmenopausal (amenorrheic for more than 2 
years, age appropriate, and confirmed by 
follicle-stimulating hormone [FSH] level 
indicating a postmenopausal state). 
b. Of childbearing potential—defined as women 
who have an intact uterus and ovaries and are 
within 1 year since the last menstrual period 
who  
– are not pregnant and have negative serum 
pregnancy test at screening and a negative 
urine pregnancy test on the Baseline/Day 
1 Visit before randomization. 
– Are not lactating or breastfeeding. 
– Agree to use two of the following 
contraceptive methods until 1 month after 
last dose of study drug, of which at least 
one must be a barrier method: 
 Hormonal contraceptives 
Intrauterine device (IUD) in place for 
at least 3 months before the start of 
screening and until 1 month after last 
dose of study drug. 
 Double-barrier methods (use of 
condom [male partner] with either 
diaphragm with spermicide or cervical 


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cap with spermicide) from the start of 
screening until 6 months after last dose 
of study drug. 
 Surgical sterilization of the partner 
(vasectomy for 1 month before the 
start of screening and maintenance 
throughout study). 
8. Males with female partners who are of 
childbearing potential (see above) who meet the 
following criteria may be eligible to enter the 
study: 
a. Are surgically sterile 
or 
b. Agree to practice two effective forms of birth 
control from those listed below from the start 
of screening until 1 month after their last dose 
of study drug, at least one of which must be a 
barrier method: 
– Consistently and correctly use a condom 
and 
– Their partner must agree to use a 
hormonal contraceptive or a nonhormonal 
barrier method (IUD or diaphragm with 
spermicide or cervical cap with 
spermicide). 
 
Exclusion Criteria 
A patient will be excluded from this study if he or she 
meets any of the following criteria: 
General Criteria 
1. Participation in a clinical trial with or use of any 
investigational agent within 30 days of start of 
screening. 
2. Pregnant or lactating/breastfeeding. 
3. Previous use of lonafarnib. 
Patients who previously participated in a clinical 
trial of lonafarnib but are confirmed to have 
received placebo are allowed. 
 
Disease-related Criteria 
4. Co-infected with human immunodeficiency virus 
(HIV) or hepatitis C virus (HCV). 


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5. Positive results for HIV or HCV Ab at screening. 
Patients with a positive HCV Ab at screening are 
allowed if they have completed a curative 
antiviral regimen and are documented to be HCV 
RNA negative (undetectable) at least 3 months 
before screening and at screening. 
6. Active jaundice defined by total bilirubin level 
>2.0 mg/dL and known not to have Gilbert’s 
disease. 
7. Decompensated liver disease or cirrhosis as 
defined by the presence of any of the following 
on screening laboratory tests: 
a. Bilirubin level >2.0 mg/dL 
b. Albumin level <3.0 g/dL 
c. Platelet count <90,000 cells/mm3 
d. International normalized ratio (INR) ≥1.5 
8. History of bleeding esophageal varices, ascites, or 
hepatic encephalopathy. 
9. Patients with any of the following abnormal 
laboratory test results at screening: 
a. White blood cell (WBC) count <3,000 
cells/mm3 
b. Absolute neutrophil count (ANC) <1500 
cells/mm3 
c. Hemoglobin <11 g/dL for women and <12 
g/dL for men 
d. Abnormal thyroid-stimulating hormone 
(TSH), T4, or T3 levels; unless the patient is 
stable on thyroid hormone replacement 
therapy 
10. Serum creatinine concentration ≥1.5 times upper 
limit of normal (ULN). 
11. Evidence of another form of viral hepatitis or 
another form of liver disease (eg, autoimmune 
liver disease, primary biliary cirrhosis, primary 
sclerosing cholangitis, Wilson’s disease, alcoholic 
liver disease, nonalcoholic steatohepatitis, 
hemochromatosis, alpha-1-anti-trypsin 
deficiency) 
12. Evidence of hepatocellular carcinoma 
13. Patients with any one of the following: 
a. An eating disorder or alcohol abuse within the 
past 2 years 
b. Excessive alcohol intake defined as follows: 


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>20 g/day for females (1.5 standard alcohol 
drinks) or >30 g/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) 
14. In the opinion of the Investigator, an alcohol use 
pattern that will interfere with study conduct 
15. Drug abuse within the previous 6 months before 
the screening visit with the exception of 
medically prescribed cannabinoids and their 
derivatives 
16. History or clinical evidence of any of the 
following: 
a. Immunologically mediated disease (eg, 
rheumatoid arthritis, inflammatory bowel 
disease, severe psoriasis, systemic lupus 
erythematosus) that requires more than 
intermittent nonsteroidal anti-inflammatory 
medications for management or that requires 
use of systemic corticosteroids in prior 6 
months (eg, inhaled asthma medications are 
allowed) 
b. History of or evidence of retinal disorder or 
clinically relevant ophthalmic disorder. 
c. Any malignancy within 5 years of the start of 
screening. Exceptions are superficial 
dermatologic malignancies (eg, squamous cell 
or basal cell skin cancer treated with curative 
intent). 
d. Significant or unstable cardiac disease (eg, 
angina, congestive heart failure, uncontrolled 
hypertension, history of arrhythmia) 
e. Chronic pulmonary disease (eg, chronic 
obstructive pulmonary disease) associated 
with functional impairment 
f. Pancreatitis 
g. Severe or uncontrolled psychiatric disease, 
including severe depression, history of 
h. suicidal ideation, suicidal attempts, or 
psychosis requiring medication and/or 
hospitalization 
17. Solid organ transplantation, including liver 


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Criteria Related to Use of Selected Medications 
18. Use of alpha interferon, either interferon alfa-2a 
or interferon alfa-2b, or pegylated interferon alfa-
2a within 2 months before the start of screening 
19. Concomitant use of any of the following: 
a. Medications or foods that are known moderate 
or strong inducers or inhibitors of CYP3A4 or 
CYP2C19 
b. Drugs known to prolong the PR or QT 
interval. 
c. Receipt of systemic immunosuppressive 
therapy within the 3 months before start of 
screening. 
d. Statins, due to inhibition of mevalonate 
synthesis, which reduces protein prenylation 
e. Medications contraindicated in the prescribing 
information for ritonavir: 
– Alpha1-adrenoreceptor antagonist: 
alfuzosin HCL 
– Analgesics*: pethidine*, piroxicam*, 
propoxyphene* 
– Antiarrhythmics: amiodarone, flecainide, 
propafenone, quinidine, bepridil*, 
encainide* 
– Antibiotic*: fusidic acid* 
– Antifungal: voriconazole 
– Antihistamines*: astemizole*, 
terfenadine* 
– Antimycobacterial*: rifabutin* 
– Ergot derivatives: dihydroergotamine, 
ergonovine*, ergotamine, 
methylergonovine 
– Gastrointestinal motility agent: cisapride 
– Herbal products: St. John’s wort 
(hypericum perforatum) 
– HMG-CoA reductase inhibitors: 
lovastatin, simvastatin 
– Antipsychotics*/Neuroleptic: clozapine*, 
pimozide, quetiapine* 
– Phosphodiesterase type 5 (PDE5) enzyme 
inhibitor: sildenafil [Revatio®] only when 
used for the treatment of pulmonary 
arterial hypertension (PAH), avanafil*, 
vardenafil* 


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– Sedative/hypnotics: clorazepate*, 
diazepam*, estazolam*, flurazepam*, oral 
midazolam, triazolam 
(Sources: Prescribing Information for 
Norvir® [ritonavir] Tablets, 2015. 
*Additional terms from the Summary of 
Product Characteristics for Norvir® 
[ritonavir] tablets, 2014) 
f.   History or evidence for any intolerance or 
hypersensitivity to lonafarnib, ritonavir, or 
other substances that are part of the study 
medication. 
 
Other Medical Conditions 
20. Other significant medical condition that may 
require intervention during the duration of the 
study. 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 
patient of participation in the trial. 
Study Periods/Phases 
The study will consist of three periods: 
Screening—At the Screening Visit, patients 
providing written informed consent will have 
required evaluations to determine their eligibility to 
participate in the study.  
Treatment—Each eligible patient will undergo a 
minimum of 10 Treatment Study Visits. 
Follow-up—Follow-up visits will occur monthly for 
6 months.  
 
Schedule of Assessments 
The study will consist of three periods: 
Screening—At the Screening Visit, patients providing written informed consent will 
have required evaluations to determine their eligibility to participate in the study. 


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Screening evaluations may occur over more than one visit, depending on the facilities 
and personnel available at the clinical center. All screening procedures must occur 
within 4 weeks before the start of dosing (Day −28 through Day −1). 
Treatment—Each eligible patient will undergo a minimum of 10 Treatment Study 
Visits: Week 0 (Day 1), Week 1 (Day 8 ± 2 d), Week 2 (Day 15 ± 2 d), Week 4 
(Day 29 ± 2 d), Week 6 (Day 43 ± 2 d), Week 8 (Day 57 ± 5 d), Week 12 (Day 85 ± 5 
d), Week 16 (Day 113 ± 5 d), Week 20 (Day 141 ± 5 d), and Week 24 (Day 169 ± 5 
d). 
Follow-up—Follow-up visits will occur monthly for 6 months. The first Follow-up 
Visit will be on Week 28 (4 weeks after last dose or if the patient discontinues 
treatment early) and will also include evaluation of lonafarnib level. All monthly 
Follow-up Visits will include evaluations of safety (AEs, concomitant medications, 
and laboratory values) and viral loads (HDV and HBV). Alpha-interferon treatments 
will be allowed during the last 5 months of the follow-up period (that is, starting 4 
weeks after last dose of study treatment). 
In addition to the planned visits, unscheduled visits may be required if, in the opinion of the 
Investigator, the clinical status of the patient warrants interim evaluation. 
Study Visits should be scheduled according to the study protocol; however, the window for 
Study Visits for Weeks 1 through 6 will be ±2 days of the nominal Study Visit day, and for 
study visits thereafter the window will be ±5 days. 
 
See Appendix 3 for a complete tabular depiction of study procedures. 
 
Randomization 
Patients will not be randomized in this open-label, single-arm study. 
Site and/or 
Stratum 
Enrollment Limits 
N/A 
Study Duration 
The duration of the study for each patient is approximately 13 months 
(up to 4 weeks for screening, 24 weeks of treatment, 4 weeks for the 
primary follow-up visit, and monthly safety follow-up visits for 5 
months thereafter). The 6-month follow-up after the last dose of study 
drug is designed to allow evaluation of the clinical and virologic 
course after completion of the 24-week Treatment Period. 
 
 
1.3. Sample Size and Power 
Planned Sample Size 
Up to 15 patients 


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Power Statement 
The sample size was chosen to allow assessment of 
the safety and tolerability of the combination of 
lonafarnib/ritonavir, recognizing that drug exposures 
may be highly variable and will likely result in an 
observable range of patient tolerabilities to the same 
administered dose 
 


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2. 
TYPE OF PLANNED ANALYSIS 
This Statistical Analysis Plan (SAP) has been prepared based on the amendment 3 version of 
the protocol (dated December 22, 2015).  This SAP documents the two planned statistical 
analysis of the study for the Week 24 (End of Treatment) and Week 48 (End of Study) 
analysis. 
The interim analysis for Week 24 (End of Treatment) will include all data collected from 
Screening up until the end of the Treatment Period at Week 24 for each subject. The final 
analysis will include all data collected from Screening through the Follow-Up Period/End of 
Study at Week 48 for each subject. As the primary and secondary efficacy endpoints will be 
summarized descriptively and no inferential analysis is planned, there will be no adjustments 
for alpha spending. 


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3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
3.1. Analysis Sets 
Analysis sets define which patients are included in an analysis. 
The assignment of patients to analysis sets will be done before database lock. A summary of 
the number and percent of patients in each analysis set will be provided. 
3.1.1. 
Safety  
The Safety analysis set (SAS) will consist of all patients who receive at least one dose of 
study drug. 
3.1.2. 
Efficacy  
The Efficacy analysis set (EAS) will consist of patients who receive study drug throughout 
the entire 24 week treatment period and for whom viral load data are available from baseline 
and end-of-treatment (Week 24) study visits. 
3.1.3. 
Pharmacokinetic  
The Pharmarcokinetic (PK) analysis set include patients who received at least 2 weeks of 
study drug at a stable dose level, and in whom a sufficient number of blood samples were 
collected, plasma samples were analyzed, concentration data were analyzed, and PK 
parameter values were derived. 
3.2. Missing Data 
A missing datum for a given study visit window may be due to: 
1. a visit occurring in the window but data were not collected or were unusable, 
or 
2. a visit not occurring in the window, or 
3. a patient permanently discontinuing from study before reaching the window. 
Values for missing data will not be imputed. 


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4. 
PATIENT DISPOSITION 
4.1. Disposition of Patients 
A summary of patient disposition will be provided for all subjects.  This summary will 
present the number of patients screened, randomized, included in the safety analysis set, and 
the number and percent of patients:  
• within each dose level of lonafarnib/ritonavir (50 mg /100 mg, 75 mg /100 mg, 
100 mg /100 mg),  
• completing the study treatment period,  
• not completing the study treatment period (with summary of reasons for not completing 
the study treatment period),  
• completing the study (includes the study treatment period and post-treatment follow-up 
period), and  
• not completing the study, (with summary of reasons for not completing the study). 
The denominator for the percentages of patients in each category will be the number of 
patients in the safety analysis set.  
No inferential statistics will be generated. A data listing of reasons for premature study 
treatment/study discontinuation will be provided.  
 
4.2. Extent of Exposure 
4.2.1. 
Duration of Exposure to Study Drug 
Duration of exposure to study drug will be defined as (last dose date – first dose date + 1), 
regardless of temporary interruptions in study drug administration, and will be expressed in 
weeks (recorded to one decimal place, e.g., 4.5 weeks). Duration of exposure to study drug 
will be summarized by dose level using descriptive statistics (sample size, mean, standard 
deviation, median, Q1, Q3, minimum and maximum). 
Summaries will be provided for the safety analysis set.  
No inferential statistics will be provided. 


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4.3. Protocol Deviations 
A summary table of major protocol deviations and a listing of all patients with protocol 
deviations will be presented. 


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5. 
BASELINE DATA 
5.1. Demographics and Baseline Characteristics 
Patient demographic data (e.g., age, sex, race, and ethnicity) and baseline characteristics 
(e.g., body weight, height, BMI, hepatitis history, Fibroscan, liver biopsy) will be 
summarized using descriptive statistics (sample size, mean, standard deviation, median, Q1, 
Q3, minimum and maximum) for continuous data and by the number and percent of patients 
for categorical data. The summaries of demographic data and baseline characteristics will be 
provided for the safety analysis set. 
5.2. Medical History 
Baseline medical histories and pre-existing conditions will be summarized based on mapping 
to system organ classes and preferred terms in the Medical Dictionary for Regulatory 
Activities (MedDRA). 
 


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6. 
EFFICACY ANALYSES  
6.1. Primary Efficacy Endpoint 
The primary PD/efficacy analysis will compare the change from Baseline (Day 1) to Week 
24 (End of Treatment) in HDV RNA (log10 IU/mL).   
HDV RNA will be measured by qPCR. The assay will be performed at Lademannbogen 
Laboratory, a subsidiary of Sonic Healthcare, using the RoboGene HDV RNA Quantification 
Kit. This assay has a limit of quantitation of 14 IU/mL and can detect genotypes 1, 2, 5, 6, 7 
and 8. 
6.2. Analysis of the Primary Efficacy Endpoint 
Pharmacodynamic data will be presented in by dose level summary tabulations and listings 
that will display HDV RNA (log10 IU/mL) at each period/time point collected by patient. 
Mean and median levels and change from baseline of the HDV RNA (log10 IU/mL) will be 
calculated at each time point. For analysis of change from baseline, baseline will be defined 
as the geometric mean of the HDV RNA titer obtained at the Screening and Day 1 
(pretreatment) visits. The number of patients with 1 log10 reduction from baseline will be 
summarized at each time point. The number of patients with reduction in HDV RNA below 
the limit of quantitation and the limit of detection will be summarized. 
HDV RNA (log10 IU/mL) mean levels and mean change from baseline levels at each 
timepoint will be presented graphically. Individual subject plots at each timepoint will also 
be presented graphically. 
Results below the level of detection will be imputed as half the lower limit of detection (14 
IU/mL). Missing data will not be imputed. All summaries and figures will show the number 
of non-missing data at each visit. 
 
 
 


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6.3. Secondary Efficacy Endpoints 
The secondary endpoints of the study are:  
• PK parameters 
• Change in ALT levels  
• Change in HBV DNA levels  
 
6.4. Analysis of the Secondary Efficacy Endpoints 
Plasma concentrations of lonafarnib and ritonavir will be summarized descriptively by dose 
level at each scheduled timepoint. PK parameters for multiple-dose lonafarnib and ritonavir 
defined in Section 8 - Table 4 will be summarized descriptively by dose level. Arithmetic 
means, coefficients of variation (%CV), standard deviations (SD), median, minimum, and 
maximum values; and number of observations PK parameter values will be generated for 
multiple-dose lonafarnib and ritonavir. More detail on the analysis of the PK parameters is 
outlined in Section 8.  
ALT levels and change from baseline will be summarized by descriptive statistics (mean, 
standard deviation, median, and range) for each measurement time point. Baseline is defined 
as the last non-missing  value prior to first dose of study drug.  
HBV DNA (log10 IU/mL) levels and change from baseline will be summarized by 
descriptive statistics (mean, standard deviation, median, and range) for each measurement 
time point. Baseline is defined as the last non-missing value prior to first dose of study drug. 
HBV DNA (log10 IU/mL) mean levels and mean change from baseline levels at each 
timepoint will be presented graphically. Individual subject plots at each timepoint will also 
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7. 
SAFETY ANALYSES 
7.1. Adverse Events and Deaths 
An AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE (also referred to as an adverse experience) 
can be any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a drug, and does not imply any judgment 
about causality. An AE can arise with any use of the drug (eg, off-label use, use in 
combination with another drug) and with any route of administration, formulation, or dose, 
including an overdose. 
7.1.1. 
Adverse Event Dictionary 
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). 
7.1.2. 
Adverse Event Severity 
Adverse events are graded by the investigator according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. For events 
not listed in the CTCAE, the definitions from the CTCAE provided in Table 1 should be used 
to evaluate the grade of severity for the AE. 
Table 1.  
Adverse Event Grades Based on the Common Terminology Criteria for 
Adverse Events 
Grade 
Description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (eg, preparing meals, shopping for 
groceries or clothes, using the telephone, and managing money) 
3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living (eg, bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden) 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
Source: National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 
4.03 


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The severity grade of events for which the investigator did not record severity will be 
categorized as “missing” for tabular summaries and data listings, and will be considered the 
least severe for the purposes of sorting for data presentation. 
7.1.3. 
Relationship of Adverse Events to Study Drug 
The Investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious). An Investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an AE. 
To describe the relationship of the AE to study drug on the AE CRF, the Investigator will use 
the terms and definitions provided in Table 2. For a particular AE, the Investigator will 
assess both the relationship to lonafarnib and the relationship to ritonavir. 
Table 2.  
Categories for Assessing Relationship of Adverse Events to 
Investigational Products 
Assessment of 
Causality 
Definition 
Not related 
No relationship between the event and the administration of study drug 
or another cause of the event is most plausible, the experience does not 
follow a clear temporal association with study drug administration, or 
the event is related to other etiologies such as concomitant medications 
or patient’s clinical state 
Possibly related 
An event that follows a plausible temporal sequence from 
administration of the study drug and follows a known or expected 
response pattern to the suspected study drug but that might have been 
produced by a number of other factors 
Definitely related 
An event that follows a plausible temporal sequence from 
administration of the study drug and without significant alternative 
etiology. In addition, the relationship may be supported by 
improvement on study drug discontinuation and/or a positive 
rechallenge 
 
7.1.4. 
Serious Adverse Events 
An AE or suspected adverse reaction is considered ‘‘serious’’ if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 


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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the patient 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 department or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
7.1.5. 
Treatment-Emergent Adverse Events 
7.1.5.1. 
Definition of Treatment-Emergent 
Events occurring after administration of the first dose of study drug will be 
recorded on the AE CRF. Treatment-emergent AEs (TEAEs) are defined as those that start or 
worsen after the start of study treatment and up to 28 days after the last dose of study 
treatment; any AEs that occur after that time will be considered posttreatment AEs. 
 
7.1.5.2. 
Incomplete Dates 
If the date of onset is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine treatment emergent as follows. The event is treatment emergent 
if the month and year of onset (or year of onset) of the event is 
a) the same as or after the month and year (or year) of the first dose of study 
drug, and 
b) the same as or before the month and year (or year) of the 28th day after the 
date of the last dose of study drug  
7.1.6. 
Summaries of Adverse Events and Deaths 
A brief summary of adverse events will show, by dose level, the number and percentage of 
patients who (1) had any TEAE, (2) had any treatment-emergent serious adverse event 
(TESAE), (3) had any treatment-emergent treatment-related AE, (4) had any treatment-
emergent treatment-related SAE, (5) had any AEs leading to early discontinuation of study 
treatment, (6) had any AEs leading to dose reduction, and (7) died during study. 
Summaries (number and percent of patients) of adverse events (by SOC and PT) will be 
provided by dose level using the safety analysis set as follows: 
• All TEAE,  
• All TESAE 
• All treatment-emergent treatment-related AE,  


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• All treatment-emergent treatment-related SAE,  
• All AEs leading to early discontinuation of study treatment,  
• All AEs leading to dose reduction, and  
• Deaths 
TEAEs and TESAEs will also be summarized by dose level, system organ class, preferred 
term, and severity as well as by dose level, system organ class, preferred term, and the 
event’s relationship to study treatment.  
At each level of summation, patients will be counted only once, under the greatest severity 
and strongest study-drug relationship (as reported by the Investigator). If an AE is reported 
more than once during the study period, the greatest severity and worst-case attribution will 
be presented in tables. For data presentation, SOC will be ordered alphabetically, with PT 
sorted by decreasing total frequency. 
In addition to the by-treatment summaries, data listings will be provided for the following: 
• All adverse events (with a variable indicating whether the event is treatment-emergent) 
• Serious adverse events 
• Deaths 
• Adverse events leading to discontinuation of study drug  
7.2. Laboratory Evaluations 
A list of the routine clinical laboratory test done for this study can be found in Table 5 of the 
study protocol (pp. 55-56). 
Summaries of laboratory data will be provided for the safety analysis set. No inferential 
statistics will be generated. 
7.2.1. 
Summaries of Numeric Laboratory Results 
Clinical laboratory data will be summarized at each measurement time point and for each 
patient’s final post-baseline measurement in the following ways: (1) with descriptive 
statistics(mean, standard deviation, median, and range) for each measurement time point and 
(2) with descriptive statistics for the change from baseline in the measurements at each post-
baseline time point. All clinical laboratory values collected during the study will be listed, 
with values outside the normal ranges flagged for clinical evaluation. Grade 3 and 4 


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laboratory results will be listed and summarized. In addition, ALT, AST, total bilirubin and 
AP will be summarized by CTCAE grade. 
 
7.3. Body Weight and Vital Signs 
Actual values for vital signs and changes from baseline will be summarized and listed for 
each patient. 
Summaries of vital signs will be provided for the safety analysis set.  No inferential statistics 
will be generated. 
7.4. Concomitant Medications 
Concomitant medications will be summarized based on mapping to drug classes and generic 
terms in the World Health Organization Drug Dictionary Enhanced (WHO-DD Enhanced). 
Summaries of concomitant medications will be provided for the safety analysis set.  No 
inferential statistics will be generated. 
7.5. Electrocardiogram (ECG) Results 
Actual values for ECG intervals and changes from baseline will be summarized by study visit 
using descriptive statistics. Clinical interpretation of ECG results will be listed. 
Summaries of ECG results will be provided for the safety analysis set.  No inferential 
statistics will be generated. 


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7.6. Other Safety Measures 
A data listing will be provided for patients experiencing pregnancy during the study. 
7.7. Viral Resistance Analysis 
For resistance surveillance, genotypic analysis of HDV genome from patients with virologic 
failure will be conducted. Virologic failure is defined as an increase in serum HDV RNA of 
at least 1.0 log from the nadir value on 2 consecutive visits in patients who stay on lonafarnib 
treatment. The number and percentage of patients who experience virologic failure will be 
summarized by dose level. 
In addition, the number and percentage of patients who shift from HDV RNA baseline value 
(positive, negative) to post-baseline value (positive, negative) at each post-baseline visit will 
be summarized by dose level. 
In vitro phenotypic analysis may be explored as necessary. 
7.8. Changes From Protocol-Specified Safety Analyses 
There are no changes from the protocol-specified safety analyses. 


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8. 
PHARMACOKINETIC ANALYSES 
All the available data from subjects who have a sufficient number of samples will be used in 
the pharmacokinetic analyses.  Any sample concentration reported as less than the assay limit 
of quantitation will be set to zero for use in the analyses. Analyses will be conducted on 
reported values.  No concentration estimates will be made for missing values. 
Time-sensitive pharmacokinetic parameters (area, time to peak and elimination rate) will be 
calculated using the scheduled times of sample collection unless actual collection times 
deviate significantly. Deviations will be considered significant if the time between scheduled 
and actual times is more than the reporting standards listed in Table 3. 
 
Table 3.  
Time Windows for Collection of Pharmacokinetic Samples 
Nominal Time 
Reporting Standards 
Predose 
Within 30 minutes before first dose 
0.0–2.0 hours 
≤ ±1 minute 
>2.0–8.0 hours 
≤ ±2 minutes 
>8.0-12 hours 
≤ ±5 minutes 
 
A non-compartmental method will be used to derive the PK parameters listed in Table 4 from 
plasma concentrations for lonafarnib and ritonavir. Additional PK parameters using non-
compartmental methods may also be used if data permit. 
 
Table 4.  
Pharmacokinetic Parameters Derived from Plasma Concentrations for 
Lonafarnib and Ritonavir 
PK Parameter 
Definition 
Cmax 
Peak plasma concentration as observed. 
Tmax 
Time of the peak plasma concentration. 
AUC0–τ 
Area under the plasma concentration versus time curve during the 
dosing interval calculated by the linear trapezoidal rule. 
Cavg 
Average plasma drug concentration during multiple-dose 
administration. 
Cmin 
Minimum plasma concentration. 
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 
(eg, three or more non-zero plasma concentrations). 


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Varea/F 
Apparent total volume of distribution calculated as follows: total 
dose/(total AUC0–∞ × Kel). 
CL/F 
Apparent total body clearance, calculated as follows: 
dose/ AUC0–∞ 
Weight-adjusted CL/F (CL/F/kg) will also be calculated. 
T1/2 
Apparent first-order terminal elimination half-life will be calculated as 
0.693/Kel. 
 
Plasma concentrations of lonafarnib and ritonavir will be summarized descriptively by dose 
level at each scheduled timepoint. PK parameters will be summarized descriptively by dose 
level. The following will be calculated for multiple-dose lonafarnib and ritonavir: arithmetic 
means; coefficients of variation (%CV); standard deviations (SD); median, minimum, and 
maximum values; and number of observations PK parameter values will be generated for 
multiple-dose lonafarnib and ritonavir. 
 
Other PK analyses for lonafarnib that will be performed include linearity and dose 
proportionality across the different lonafarnib dose levels. These analyses will be conducted 
for patients who receive titrated doses. Dose proportionality for lonafarnib will be evaluated 
using the relationship between each lonafarnib PK parameter (AUC0–τ and Cmax) and dose 
using the following power model: 
PK parameter = Exp(α)(Dose)β Exp(ε) 
Where, β is a measure of the dose proportionality. Each lonafarnib PK parameter and dose 
will be ln-transformed before analysis therefore the power model can be expressed as: 
ln(PK parameter) = α + β ln(Dose) + ε 
where β, the slope, measures the proportionality between dose and each lonafarnib PK 
parameter. If β=0, then this implies that the response is independent from the dose and when 
β=1, dose proportionality can be determined. 
 
The relationship between lonafarnib dose and achieved AUC, Cmax, and measured viral load 
(PD) may also be explored by plotting the PK parameters versus the dose of lonafarnib and 
viral log decay. The relationship between lonafarnib dose, lonafarnib exposure, and specific 
AEs may also be explored. 
 
No other formal statistical analyses are planned for PK parameters. 
 


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9. 
REFERENCES 
Bordier BB, Marion PL, Ohashi K, Kay MA, Greenberg HB, Casey JL, et al. 2002. 
A prenylation inhibitor prevents production of infectious hepatitis delta virus particles. 
J Virol 76(20):10465-72. 
 
Bordier BB, Ohkanda J, Liu P, Lee SY, Salazar FH, Marion PL, et al. 2003. In vivo antiviral 
efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest 
112(3):407-14. 
 
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Guideline for Industry: E3 Structure and Content of 
Clinical Study Reports Federal Register. July 17, 1996 (61 FR 37320). 
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Guidance for Industry: E9 Statistical Principles for 
Clinical Trials. Federal Register. September 16, 1998 (63 FR 49583). 
U.S Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Guidance for Industry: E14 Clinical Evaluation of 
QT/QTc Interval Prolongation and Pro-arrhythmic Potential for Non-Antiarrhythmic Drugs. 
Federal Register, October 19, 2005 
Karjalainen J, Viitasalo M, Manttari M, Manninen V. 1994. Relation between QT intervals 
and heart rates from 40 to 120 beats/min in rest electrocardiograms of men and a simple 
method to adjust QT interval values. J Am Coll Cardiol 23:1547-1553. 


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10. 
SOFTWARE 
SAS Software Version 9.2. SAS Institute Inc., Cary, NC, USA. 


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11. 
SAP REVISION 
Revision Date 
(dd month, yyyy) 
Section 
Summary of Revision 
Reason for Revision 
 
 
 
 
 
 
 
 
 


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12. 
APPENDICES 
Appendix 1. 
Table of Contents for Statistical Tables, Figures, and Listings 
 
Appendix 2. 
Programming Specifications 
 


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Appendix 1. 
Table of Contents for Statistical Tables, Figures, and Listings 
Tables 
# 
Table 
Analysis Set 
14.1.1 
Patient Disposition 
SAS 
14.1.2 
Extent of Exposure to Study Drug 
SAS 
14.1.3 
Adherence with Study Vaccine Regimen 
SAS 
14.1.4 
Protocol Deviations  
SAS 
14.1.5 
Demographics and Baseline Characteristics 
SAS 
14.1.6 
Medical History 
SAS 
14.1.7 
Concomitant Medications 
SAS 
14.2.1.1 
Viral Load by Dose Level and Time post First Dose of Study Treatment 
EAS 
14.2.1.2 
Number and Percentage of Patients with 1 and 1 Log Reductions from 
Baseline by Dose Level and Time post First Dose of Study Treatment 
EAS 
14.2.1.3 
Number and Percentage of Patients with Reduction in Viral Load Below 
the Limit of Quantitation and the Limit of Detection by Dose Level 
EAS 
14.2.2.1 
Lonafarnib Plasma Concentrations by Dose Level and Timepoint 
PK 
14.2.2.2 
Ritonavir Plasma Concentrations by Dose Level and Timepoint 
PK 
14.2.2.3 
Lonafarnib Pharmacokinetic Parameters by Dose Level 
PK 
14.2.2.4 
Ritonavir Pharmacokinetic Parameters by Dose Level 
PK 
14.2.2.5 
Assessment of Dose Proportionality for Lonafarnib 
PK 
14.2.2.6 
Assessment of Dose Proportionality for Ritonavir 
PK 
14.3.1 
Overall Summary of Adverse Events 
SAS 
14.3.2.1 
Treatment-Emergent Adverse Events by Dose Level, SOC, and PT 
SAS 
14.3.2.2 
Treatment-Emergent Serious Adverse Events by Dose Level, SOC, and 
PT 
SAS 
14.3.2.3 
Treatment-Emergent Treatment-Related Adverse Events by Dose Level, 
SOC, and PT 
SAS 
14.3.2.4 
Treatment-Emergent Treatment-Related Serious Adverse Events by Dose 
Level, SOC, and PT 
SAS 
14.3.2.5 
Adverse Events Leading to Early Discontinuation of Study Treatment by 
Dose Level, SOC, and PT 
SAS 
14.3.2.6 
Adverse Events Leading to Dose Reduction by Dose Level, SOC, and PT 
SAS 
14.3.2.7 
Deaths 
SAS 
14.3.2.8 
Treatment-Emergent Adverse Events by Dose Level, SOC, Preferred 
Term, and Maximum Severity 
SAS 
14.3.2.9 
Treatment-Emergent Adverse Events by Dose Level, SOC, Preferred 
Term, and Maximum Relationship 
SAS 
14.3.2.10 Treatment-Emergent Serious Adverse Events by Dose Level, SOC, 
Preferred Term, and Maximum Severity 
SAS 
14.3.2.11 Treatment-Emergent Serious Adverse Events by Dose Level, SOC, 
Preferred Term, and Maximum Relationship 
SAS 
14.4.1 
Laboratory Summary - Hematology 
SAS 
14.4.2 
Laboratory Summary - Clinical Chemistry 
SAS 
14.4.3 
Laboratory Summary - Coagulation 
SAS 
14.4.4 
Laboratory Summary - Urinalysis 
SAS 
14.4.5 
Laboratory Summary - Viral Serology 
SAS 
14.4.6 
Laboratory Summary - Reproductive Serology (Females) 
SAS 
14.4.7 
Laboratory Summary - Reproductive Serology (Males) 
SAS 
14.4.8 
Laboratory Summary - Quantitative Polymerase Chain Reaction 
SAS 


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14.4.9 
Laboratory Summary - Other Tests 
SAS 
14.4.10 
Categorical Summary of Abnormal Laboratory Results - Hematology 
SAS 
14.4.11 
Categorical Summary of Abnormal Laboratory Results - Clinical 
Chemistry 
SAS 
14.4.12 
Categorical Summary of Abnormal Laboratory Results - Coagulation 
SAS 
14.4.13 
Categorical Summary of Abnormal Laboratory Results - Urinalysis 
SAS 
14.5.1 
ALT Summary by CTCAE Severity Grade 
SAS 
14.5.2 
AST Summary by CTCAE Severity Grade  
SAS 
14.5.3 
Total Bilirubin Summary by CTCAE Severity Grade 
SAS 
14.5.4 
Alkaline Phosphatase Summary by CTCAE Severity Grade 
SAS 
14.6.1 
Vital Signs Summary 
SAS 
14.7.1 
Electrocardiogram Summary 
SAS 
14.8.1 
Viral Resistance Summary 
SAS 
 
Listings 
# 
Listing 
Analysis Set 
16.2.1.1 
Study Disposition 
All Patients 
16.2.1.2 
Reason for Screening Failure 
All Patients 
16.2.2 
Protocol Deviations 
All Patients with Protocol 
Deviations 
16.2.3 
Analysis Sets 
All Patients 
16.2.4.1 
Demographics 
All Patients 
16.2.4.2 
Medical History 
All Patients 
16.2.4.3 
Concomitant Medications 
All Patients 
16.2.5.1 
Study Drug Administration 
All Patients 
16.2.5.2 
Plasma Concentrations 
All Patients 
16.2.5.3 
Pharmacokinetic Parameters 
All Patients 
16.2.7.1 
Adverse Events 
All Patients 
16.2.7.2 Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug 
All Patients 
16.2.7.3 Serious Adverse Events 
All Patients 
16.2.7.4 Deaths (if required) 
All Patients 
16.2.8.1 
Laboratory Results - Hematology 
All Patients 
16.2.8.2 
Laboratory Results - Clinical Chemistry 
All Patients 
16.2.8.3 
Laboratory Results - Coagulation 
All Patients 
16.2.8.4 
Laboratory Results - Urinalysis 
All Patients 
16.2.8.5 
Laboratory Results - Viral Serology 
All Patients 
16.2.8.6 
Laboratory Results - Reproductive Serology (Females) 
All Female Patients 
16.2.8.7 
Laboratory Results - Reproductive Serology (Males) 
All Male Patients 
16.2.8.8 
Laboratory Results - Quantitative Polymerase Chain 
Reaction 
All Patients 
16.2.8.9 
Laboratory Results - Other Tests 
All Patients 
16.2.9 
Vital Sign Results 
All Patients 
16.2.10 
Electrocardiogram Results 
All Patients 
16.2.11 
Viral Resistance Results 
All Patients 
 
 


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Figure 
# 
Figure 
Analysis Set 
1.1 
Mean Change from Baseline in Log10 HDV RNA by Dose Level and Time post 
First Dose of Study Treatment 
EAS 
1.2 
Mean Log10 HDV RNA by Dose Level and Time post First Dose of Study 
Treatment 
EAS 
1.3 
Mean Log10 HBV RNA by Dose Level and Time post First Dose of Study 
Treatment 
EAS 
2.1 
Change from Baseline in Log10 HDV RNA by Dose Level and Time post First 
Dose of Study Treatment 
EAS 
2.2 
Log10 HDV RNA by Dose Level and Time post First Dose of Study Treatment 
EAS 
2.3 
Log10 HBV RNA by Dose Level and Time post First Dose of Study Treatment 
EAS 
3.1 
Lonafarnib Plasma Concentrations vs Time by Dose Level  
PK 
3.2 
Ritonavir Plasma Concentrations vs Time by Dose Level  
PK 
 
 


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Appendix 2. 
Programming Specifications 
 


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Appendix 3. 
Schedule of Study Assessments 
 


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BMI = body mass index, ECG = electrocardiogram, EOT = end of treatment, ET = early termination, HBV = hepatitis B virus, HDV = hepatitis D virus, 
PBMC = peripheral blood mononuclear cell, qPCR = quantitative polymerase chain reaction, 


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a Complete all assessments before the first dose of the day is administered. 
b Early termination visit: Patients who withdraw from treatment early during the Treatment Period should return 4 weeks after their last dose to undergo 
these assessments; patients who withdraw early during the Follow-Up Period should undergo the assessments planned at the next scheduled study visit. 
c Inclusion criteria: Review and confirm inclusion eligibility. 
d Conduct comprehensive physical examination, including measurement of height and weight, calculate BMI, and assess CTP score and encephalopathy 
(see Appendix B of the Protocol) 
e See Section 3.8.2 and Appendix C of the Protocol for lists of prohibited concomitant medications. 
f Body weight of ≥45 kg. Weight should be measured with inner clothing and without shoes. 
g BMI of ≥18 kg/m2 or ≤30 kg/m2, inclusive. 
h Ophthalmic examination includes visual acuity examination, dilatation, and slit lamp examination. On slit lamp examination, orbit, eyelids, lashes, 
lacrimal gland, conjunctiva, cornea, sclera, anterior chamber, and iris are examined. On the dilated fundus examination, lens, vitreous, optic disc, and 
retina are examined. 
i Blood pressure, heart rate, respiratory rate, and body temperature; blood pressure and heart rate should be measured after 5 minutes in sitting position. 
j Serial ECG (×3) 2 to 3 minutes apart. Patients should rest in a supine position for ≥5 minutes before the ECG recording is made. ECGs must be read by 
the Investigator or a qualified designee, and the results recorded in the CRF. On days that PK sampling is performed, obtain sample for viral load 
determination and conduct ECGs before first dose of lonafarnib/ritonavir. 
k Each patient must have documentation of a liver biopsy demonstrating evidence of chronic hepatitis. If no liver biopsy was performed or no 
documentation of a biopsy is available, a liver biopsy must be performed within the screening period. To avoid unnecessary biopsies for ineligible 
patients, it is recommended that the liver biopsy be performed after the patient successfully completes all other screening assessments. 
l Patients must fast for at least 3 hours before the Fibroscan is performed. 
m Hematology assessments include the following: complete blood count (hemoglobin, hematocrit, red blood cell [RBC] count, mean corpuscular volume 
[MCV], mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC), white blood cell [WBC] count with 
differential, absolute lymphocytes, absolute monocytes, absolute neutrophils, absolute eosinophils, absolute basophils, and platelets, and cell 
morphology). 
n Serum chemistry profile (alanine aminotransferase [ALT], albumin, alkaline phosphatase, amylase, aspartate aminotransferase [AST], bicarbonate, 
bilirubin (direct, indirect, total), blood urea nitrogen [BUN], calcium, chloride, cholesterol, creatine kinase [CK], creatinine, gamma-glutamyl 
transferase [GGT], globulin, glucose (nonfasting), lactate dehydrogenase [LDH], magnesium, phosphorus, potassium, sodium, triglycerides, total 
protein, and uric acid). 
o For women of childbearing potential only. 
p Urine pregnancy test performed before first dose is administered. For women of childbearing potential only. A positive urine pregnancy test requires 
immediate confirmation by serum pregnancy test. 
q Morning levels of the following: females—luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, progesterone, anit-Müullerian 
hormone (AMH), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, free testosterone, sex 
hormone binding globulin (SHBG), 17-hydroxyprogesterone (17-OHP); males—inhibin B, LH, FSH, and free and total testosterone. 
r Patients with a positive HCV Ab at screening must have completed a curative antiviral regimen and documented to be HCV RNA negative 
(undetectable) at least 3 months before screening and at screening. 
s HDV serology: positive HDV Ab test of at least 6 months duration. 


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t Serum and plasma samples for viral mutation analysis, resistance phenotyping, and analysis of drug mechanism and treatment response. On the day 
that PK sampling is performed, obtain sample for viral load determination and conduct ECGs before first dose of lonafarnib/ritonavir is administered. 
u Perform postbaseline genotypic analysis of large HDV antigen only in case of viral load rebound. 
v Urinalysis assessments include the following: specific gravity, protein, ketones, bilirubin, urobilinogen, blood, nitrite, and microscopic examination of 
sediment. 
w Urine drug screen for opiates, amphetamines, barbiturates, benzodiazepenes, and cocaine. 
x Collect PK blood samples only once at either Week 8, 12, or 16 if the patient is on a stable dose. On the day that PK sampling is performed, obtain 
sample for viral load determination and PBMC analysis and conduct ECGs before first dose of lonafarnib/ritonavir. Patients providing PK samples will 
remain in clinic at least 13 hours on the day samples are drawn. The time points for PK sampling are as follows: predose (within 30 min before the first 
dose of the day) and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h postdose. Fasting is not required on the day of PK sampling. 
Note: For any lonafarnib dose adjustments that occur due to patient tolerability issues (refer to Section 3.6.2 of the Protocol), PK sampling will be 
performed after the patient has been at a stable dose for the 2 weeks before the study visit. If the patient has not been at a stable dose for the 2 weeks 
before the study visit, PK sampling will be performed at a future visit, after the patient has been on a stable dose for at least 2 weeks. 
y Before dispensing study drugs, instruct patients to bring back empty bottles or any unused study drug(s) in the original bottle at every postbaseline 
study visit through the end of treatment. 
z Collect and review the patient diary if the visit occurs during the Treatment Period.