Conditions: Hepatitis D, Chronic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 33
Healthy volunteers: no

Brief summary:
To evaluate safety and tolerability of lambda over a 48-week treatment period in HDV patients.

Detailed description:
Lambda is the pegylated form of interferon lambda-1a (IFN-λ), a conjugate of recombinant human interleukin 29 (rIL-29) and a linear polyethylene glycol (PEG) chain. IFN-λ and interferon alpha (IFN-α) share the common interferon (IFN)-stimulated gene induction pathway that leads to broad-spectrum antiviral activities. Since IFN-α has demonstrated anti-hepatitis delta virus (HDV) activity in patients with chronic hepatitis delta (CHD), it is postulated that pegylated IFN-λ could also induce HDV ribonucleic acid (RNA) decline in patients with CHD. Based on IFN-λ's more limited receptor distribution and previous data from studies involving treatment with IFN-λ in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV), it is postulated that Lambda treatment could be associated with fewer adverse effects than IFN-α treatment. This Phase II study is designed as randomized, open-label study of Lambda 120 or 180 μg subcutaneous (SC) injection weekly for 48 weeks in patients with chronic HDV infection, and the primary objectives of the study are as follows:

* To evaluate the safety and tolerability of treatment with 2 dose levels of Lambda over a 48-week treatment period.
* To evaluate the effect of treatment with 2 different doses of Lambda on HDV RNA levels.

Arms:
arm 1: Lambda 180 μg once weekly, administered by subcutaneous (SC) injection, for a total of 48 weeks. arm 2: Lambda 120 μg once weekly, administered by subcutaneous (SC) injection, for a total of 48 weeks.

Interventions: intervention 1: Peginterferon Lambda-1A
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 1 
CLINICAL STUDY PROTOCOL 
EIG-LMD-001 
Study Title 
A Phase 2 Study to Evaluate the Safety, Tolerability, and 
Pharmacodynamics of Pegylated Interferon Lambda 
Monotherapy in Patients with Chronic Hepatitis Delta Virus 
Infection (LIMT-1) 
 
Study Phase 
Phase 2 
 
Investigational Product 
Pegylated interferon lambda-1a (Lambda, PEG-IFN-λ) 120 or 
180 µg 
 
Indication 
Chronic hepatitis D viral infection 
IND Number 
133743 
Sponsor 
Eiger BioPharmaceuticals, Inc. 
2155 Park Blvd. 
Palo Alto, CA 94306 
Sponsor Clinical 
Program Manager 
John Ferraro, MBA 
Eiger BioPharmaceuticals 
Medical Monitor 
David Apelian, MD, PhD, MBA 
Executive Medical Officer 
Eiger BioPharmaceuticals, Inc. 
Version 
Amendment 5 
Original Protocol Date 
14 March 2016 
Amendment 1 Date 
16 September 2016 
Amendment 2 Date 
22 February 2017 
Amendment 3 Date 
24 April 2017 
Amendment 4 Date 
11 December 2017 
Amendment 5 Date 
18 April 2019 
 
Conduct: In accordance with International Conference on Harmonisation (ICH) 
guidelines on Good Clinical Practice (GCP) and regulatory requirements as applicable. 
 
CONFIDENTIALITY STATEMENT 
This document is the sole property of Eiger BioPharmaceuticals, Inc. This document and 
any and all information contained herein has to be considered and treated as strictly 
confidential. This document shall be used only for the purpose of the disclosure herein 
provided. No disclosure or publication shall be made without the prior written consent of 
Eiger BioPharmaceuticals, Inc. 


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David Apelian
Digitally signed by David 
Apelian 
Date: 2019.04.22 08:14:59 -07'00'


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 3 
 
INVESTIGATOR SIGNATURE PAGE 
Protocol Title 
A Phase 2 Study to Evaluate the Safety, Tolerability, and 
Pharmacodynamics of Pegylated Interferon Lambda 
Monotherapy in Patients with Chronic Hepatitis Delta Virus 
Infection (LIMT-1) 
 
Protocol Number 
EIG-LMD-001 
Version 
Amendment 5 
Date Final 
18 April 2019 
 
INVESTIGATOR AGREEMENT 
By my signature below, I attest to the following:  
1. I have received and reviewed the Investigator’s Brochure for Peginterferon Lambda 
1-a provided to me by Eiger BioPharmaceuticals or designee.  
2. I have read the attached protocol.  
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 Agency [EMA] and the United States 
Food and Drug Administration [FDA]); the principles of 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 
institutional review board (IRB) or independent ethics committee (IEC). I understand 
that any changes in the protocol must be approved in writing by the sponsor, the 
IRB/IEC, and, in certain cases the FDA or other applicable regulatory agencies, before 
they can be implemented. 
5. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
Signed:  
 
 
  
Signature 
 
 Date 
 
Name 
 Institution 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 4 
PROTOCOL SYNOPSIS 
Sponsor 
Eiger BioPharmaceuticals, Inc. (United States) 
Product 
Pegylated interferon lambda-1a (Lambda, PEG-IFN-λ) 
Title 
A Phase 2 Study to Evaluate the Safety, Tolerability, and 
Pharmacodynamics of Pegylated Interferon Lambda Monotherapy in 
Patients with Chronic Hepatitis Delta Virus Infection (LIMT-1) 
 
Protocol number 
EIG-LMD-001 
Study phase 
Phase 2 
Study center(s) 
Approximately 6 centers globally  
Indication 
Chronic hepatitis D viral infection 
Primary objectives 
The primary objectives of the study are as follows: 
• To evaluate the safety and tolerability of treatment with 2 dose 
levels of Lambda over a 48-week treatment period 
• To evaluate the effect of treatment with 2 different doses of Lambda 
on HDV RNA levels 
Secondary objectives 
The secondary objectives of the study are as follows: 
• To evaluate the proportion of patients with undetectable HDV RNA 
12 weeks after the end of treatment 
• To evaluate the proportion of patients with undetectable HDV RNA 
24 weeks after the end of treatment 
• To evaluate the proportion of patients with undetectable HDV RNA 
approx. 48 weeks after the end of treatment 
• To evaluate the effect of treatment with 2 dose levels of Lambda on 
the following:  
• Alanine aminotransferase (ALT) levels 
o 
ALT levels at approx. 48 weeks after end of treatment 
• Hepatitis B surface antigen (HbsAg) levels 
• Gamma-Glutamyl Transferase (GGT) levels 
Exploratory objective 
The exploratory objectives of the study are to evaluate the effect of 
treatment with 2 dose levels of Lambda on the following: 
• Immunologic parameters 
Study duration 
Approximately 21 months (3 months for enrollment, 12 months of study 
treatment, 6 months of follow-up) 
Study design 
Randomized, open-label study of Lambda 120 or 180 µg subcutaneous 
(SC) injection weekly for 48 weeks in patients with chronic HDV 
infection. Patients will also take an anti-hepatitis B virus (HBV) 
nucleos(t)ide analog (NUC) from baseline (Day 1) through the end of 
the study. Clinic visits at baseline (Day 1), Weeks 1, 2, 4, and every 
4 weeks until Week 48. Pharmacodynamics (PD)/efficacy of Lambda 
will be assessed by measuring HDV and HBV viral loads and viral 
serologies and Fibroscan results. Safety and tolerability of Lambda will 
be assessed by adverse event (AE) monitoring, clinical laboratory tests, 
vital signs and body weight, physical examinations, and concomitant 
medications. All enrolled patients will be followed for an additional 
24 weeks off-treatment. All monthly follow-up visits will include 
evaluations of viral load (HDV and HBV), quantitative HbsAg 
(qHBsAg), and all of the safety measures listed above. Supplemental 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 5 
post-study testing will be conducted approximately 48 weeeks post 
treatment for available patients to assess long term durability of post-
treatment endpoint responses (HDV RNA and ALT).  
Study population and number 
of patients 
Approximately forty patients, 20 in each treatment group (120 or 180 µg 
weekly ) with chronic HDV infection with detectable and quantifiable 
HDV RNA by quantitative polymerase chain reaction (qPCR) will be 
enrolled. 
Patients who discontinue the study before Week 12 for reasons other 
than an AE can be replaced on approval of the sponsor. 
Eligibility criteria 
Inclusion Criteria  
Patients must meet all of the following inclusion criteria before study 
entry to be eligible for enrollment into the study:  
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. Chronic HDV infection of at least 6 months' duration documented 
by a positive HDV antibody (Ab) test; detectable and quantifiable 
HDV RNA by qPCR at study entry 
4. Serum ALT > upper limit of the normal range (ULN) and <10 × 
ULN at screening 
5. Electrocardiogram (ECG) demonstrating no acute ischemia or 
clinically significant abnormality and a QT interval corrected for 
heart rate (QTcF) <450 ms for male patients and <460 ms for 
female patients 
6. Thyroid-stimulating hormone (TSH) and/or free T4 within 0.8 to 
1.2 × ULN, or adequately controlled thyroid function as assessed by 
the investigator 
7. Dilated retinal examination ≤1 year before screening: For patients 
with diabetes, hypertension, or other risk factors for retinal disease, 
performed by a licensed ocular specialist; for all other patients, a 
normal retinal examination as assessed by the investigator or a 
licensed ocular specialist 
8. 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 through 90 days 
after the last dose of study medication. Female patients of 
childbearing potential are all those except patients who are 
surgically sterile, who have medically documented ovarian failure, 
or who are at least 1 year postmenopausal.  
For females: 2 of the following contraceptive methods, with at least 
1 being a barrier method: 
• Hormonal contraceptives for ≥ 27 days before dosing  
• Intrauterine device (IUD) in place ≥ 27 days before dosing  
• Double-barrier methods (use of condom [male partner] with 
either diaphragm with spermicide or cervical cap with 
spermicide) from screening  
• Surgical sterilization of the partner (vasectomy ≥ 1 month 
before screening) 
For males 
• Surgical sterilization (vasectomy ≥ 1 month before screening)  
or 
• Both of the following contraceptive methods from screening: 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 6 
• 
Consistently and correctly use a condom 
• 
Partner must use a hormonal contraceptive or a 
nonhormonal barrier method (IUD or diaphragm with 
spermicide or cervical cap with spermicide)  
9. Willing and able to provide written informed consent 
10. Willing and able to comply with all study procedures 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the 
study: 
General Exclusions 
1. Participation in a clinical trial with or use of any investigational 
agent within 30 days before screening, or treatment with interferons 
(IFNs) or immunomodulators within 12 months before screening 
2. Previous use of Lambda. Patients who previously participated in a 
clinical trial of Lambda but are confirmed to have received placebo 
or other non-Lambda IFNs are allowed.  
3. History or evidence of any intolerance or hypersensitivity to IFNs 
or other substances contained in the study medication. 
4. Female patients who are pregnant or breastfeeding. Male patients 
must confirm that their female sexual partners are not pregnant. 
Female patients must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human 
chorionic gonadotropin [hCG]) within 24 hours prior to the start of 
investigational product. 
 
Exclusions Based on Disease 
5. Current or previous history of decompensated liver disease (Child-
Pugh Class B or C) 
6. Co-infected with human immunodeficiency virus (HIV) or hepatitis 
C virus (HCV). 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. 
7. Past history or current evidence of decompensated liver disease, 
defined as any of the following at screening: 
a. 
Bilirubin level ≥ 2.5 mg/dL unless due to Gilbert’s 
disease 
b. Serum albumin level <3.5 g/dL 
c. 
International normalized ratio (INR) ≥1.5 
d. Alpha fetoprotein ≥100 ng/mL 
8. Evidence of significant portal hypertension such as hepatic venous 
pressure gradient (HVPG) ≥10 mmHg; current presence or history 
of variceal bleeding 
9. Current evidence or history of ascites requiring diuretics or 
paracentesis, or hepatic encephalopathy  
10. Any of the following abnormal laboratory test results at screening:  
a. 
Platelet count <90,000 cells/mm3 
b. White blood cell (WBC) count <3,000 cells/mm3 
c. 
Absolute neutrophil count (ANC) <1,500 cells/mm3 
d. Hemoglobin <11 g/dL for women and <12 g/dL for men 
e. 
Serum creatinine concentration ≥1.5× ULN 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 7 
f. 
Confirmed creatinine clearance (CrCl) < 50 mL/min by 
Cockroft-Gault 
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. History of hepatocellular carcinoma  
13. Patients with any of the following:  
a. 
Current eating disorder or alcohol abuse 
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: 360 mL of beer, 150 mL of 
wine, or 45 mL of spirits 
c. 
In the opinion of the investigator, an alcohol use pattern 
that will interfere with study conduct 
d. Drug abuse within the previous 6 months before 
screening, with the exception of cannabinoids and their 
derivatives 
14. Prior history or current 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 the 6 months before screening (inhaled 
asthma medications are allowed) 
b. Retinal disorder or clinically relevant ophthalmic disorder 
c. 
Any malignancy within 5 years before screening. 
Exceptions are superficial dermatologic malignancies (eg, 
squamous cell or basal cell skin cancer treated with 
curative intent). 
d. Cardiomyopathy or significant ischemic cardiac or 
cerebrovascular disease (including history of angina, 
myocardial infarction, or interventional procedure for 
coronary artery disease) 
e. 
Chronic pulmonary disease (eg, chronic obstructive 
pulmonary disease) associated with functional 
impairment 
f. 
Pancreatitis 
g. Severe or uncontrolled psychiatric disorder, eg, 
depression, manic condition, psychosis, acute and/or 
chronic cognitive dysfunction, suicidal behavior, and 
relapse of substance abuse 
h. Active seizure disorder defined by either an untreated 
seizure disorder or continued seizure activity within the 
preceding year despite treatment with anti-seizure 
medication  
i. 
Bone marrow or solid organ transplantation 
15. Other significant medical condition that may require intervention 
during the study. Patients with any serious condition that, in the 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 8 
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. Patients for whom participation in 
the study would increase their risk. 
 
Exclusions Based on Concurrent Medication Use 
16. Therapy with an immunomodulatory agent; IFN-α (IFN alfa-2a or 
IFN alfa-2b, or pegylated IFN alfa-2a or alfa-2b); cytotoxic agent, 
or systemic corticosteroids within 12 months before screening 
17. Use of telbivudine (Tyzeka or Sebivo) within 3 months before 
screening or during the study 
18. Current use of heparin or Coumadin 
19. Received blood products within 30 days before study randomization 
20. Use of hematologic growth factors within 30 days before study 
randomization 
21. Systemic antibiotics, antifungals, or antivirals for treatment of 
active infection other than HBV within 14 days before study 
randomization 
22. Any prescription or herbal product that is not approved by the 
investigator 
23. Long-term treatment (> 2 weeks) with agents that have a high risk 
for nephrotoxicity or hepatotoxicity unless it is approved by the 
medical monitor 
24. Receipt of systemic immunosuppressive therapy within 3 months 
before screening 
Test product, dose, and 
method of administration 
Pegylated interferon lambda-1a (PEG-IFN-λ) (Lambda) Injection, 
0.18mg/syringe; 120 or 180 µg; weekly SC administration 
Reference therapy, dose, and 
method of administration 
Not applicable 
Duration of treatment 
48 weeks 
Criteria for evaluation 
The primary PD/efficacy endpoints are as follows: 
• Change from baseline in HDV viral load at Week 48 (end of 
treatment [EOT]) 
• Change from baseline in HDV viral load at Week 72 (end of 
follow-up [EOFU]) 
Additional PD/efficacy endpoints include: 
• Proportion of patients with sustained viral response: HDV RNA 
below the lower limit of quantification (LLOQ) 12 weeks after EOT 
(SVR-12)  
• Proportion of patients with sustained viral response: HDV RNA 
below LLOQ 24 weeks after EOT (SVR-24)  
• Proportion of patients with sustained viral response: HDV RNA 
below LLOQ approx. 48 weeks after EOT (SVR-48)  
• Change from baseline in HDV viral load 
• Change from baseline in HBV viral load 
• Change from baseline in HBsAg levels  
• Clearance of HBsAg 
• Change from baseline in Fibroscan results 
• Change in ALT approx. 48 weeks after end of treatment 
Safety endpoints include: 
• Treatment-emergent AEs and serious adverse events (SAEs) 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 9 
• Treatment-emergent treatment-related AEs and SAEs 
• AEs leading to early discontinuation of study treatment 
• AEs leading to dose reduction 
• Treatment-emergent changes in clinical laboratory findings 
• Treatment-emergent changes in vital signs 
• Treatment-emergent changes in ECG findings 
• Treatment-emergent changes in physical examination results 
• Usage of concomitant medications during the study 
Statistical methods 
The sample size of 40 will permit assessment of the safety, tolerability, 
and PD/efficacy of Lambda at 120 vs. 180 µg/week. The primary 
PD/efficacy endpoints will be assessed in the modified intention-to-treat 
(MITT) population, which will consist of all patients who receive at 
least 80% of the total study drug dose throughout the entire 48-week 
treatment period (ie, no dose interruptions or reductions) and for whom 
HDV viral load data are available for the Day 1 (baseline) and end-of-
treatment (Week 48) study visits. 
 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 10 
TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE ...................................................................................3 
PROTOCOL SYNOPSIS...........................................................................................................4 
LIST OF ABBREVIATIONS ..................................................................................................16 
1 INTRODUCTION .............................................................................................................19 
1.1 
Background ..................................................................................................................19 
1.2 
Rationale for the Study ................................................................................................20 
1.3 
Preclinical Experience .................................................................................................21 
1.3.1 Antiviral, Immunologic, and Hematologic Effects ..........................................21 
1.3.2 Toxicology .......................................................................................................22 
1.3.3 Pharmacokinetics .............................................................................................22 
1.4 
Clinical Experience ......................................................................................................23 
1.4.1 Clinical Efficacy/Pharmacodynamics ..............................................................23 
1.4.2 Clinical Safety ..................................................................................................23 
1.4.3 Clinical Pharmacokinetics ...............................................................................25 
1.5 
Potential Risks and Benefits to Human Patients in This Study ...................................26 
2 STUDY OBJECTIVES ......................................................................................................28 
2.1 
Primary Objectives .......................................................................................................28 
2.2 
Secondary Objectives ...................................................................................................28 
2.3 
Exploratory Objectives ................................................................................................28 
3 INVESTIGATIONAL PLAN ............................................................................................29 
3.1 
Overall Study Design ...................................................................................................29 
3.2 
Rationale for Study Design ..........................................................................................30 
3.2.1 Rationale for Dose ...........................................................................................30 
4 STUDY POPULATION SELECTION .............................................................................31 
4.1 
Inclusion Criteria .........................................................................................................31 
4.2 
Exclusion Criteria ........................................................................................................32 
4.3 
Replacement of Patients in Study ................................................................................34 
4.4 
Early Withdrawal from Study by Individual Patients ..................................................34 
4.5 
Early Termination of the Study....................................................................................35 
5 INVESTIGATIONAL PRODUCTS .................................................................................36 
5.1 
Product Description .....................................................................................................36 
5.2 
Treatment Groups ........................................................................................................36 
5.2.1 Method of Assigning Patients to Treatment Groups ........................................36 
5.2.2 Randomization .................................................................................................36 


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5.3 
Blinding........................................................................................................................36 
5.4 
Treatment Administration ............................................................................................36 
5.4.1 Dosage..............................................................................................................37 
5.4.2 Dose Titration ..................................................................................................37 
5.4.3 Dose Interruptions, Reductions, and Discontinuations ....................................37 
5.4.4 Missed Doses ...................................................................................................43 
5.5 
Treatment Compliance .................................................................................................43 
5.6 
Treatment Packaging and Labeling .............................................................................43 
5.7 
Treatment Storage and Retention at Study Site ...........................................................43 
5.8 
Prior and Concomitant Therapies ................................................................................44 
5.8.1 Prior Therapies .................................................................................................44 
5.8.2 Concomitant Therapies ....................................................................................44 
5.8.2.1 Nucleos(t)ide Analog Medication .....................................................44 
5.8.2.2 Prohibited Medications .....................................................................45 
5.8.2.3 Other Restrictions and Precautions ...................................................45 
6 STUDY PROCEDURES AND ASSESSMENTS .............................................................47 
6.1 
Informed Consent.........................................................................................................47 
6.2 
Demographics ..............................................................................................................47 
6.3 
Medical History ...........................................................................................................47 
6.4 
Retinal Examination.....................................................................................................47 
6.5 
Baseline Virology Tests ...............................................................................................47 
6.6 
Inclusion/Exclusion Criteria ........................................................................................47 
6.6.1 Drug and Alcohol Testing ................................................................................47 
6.6.2 Alpha Fetoprotein Screening Test ...................................................................47 
6.6.3 Abdominal Imaging .........................................................................................48 
6.7 
Pregnancy Testing ........................................................................................................48 
6.8 
Study Enrollment .........................................................................................................48 
6.9 
Study Treatment Dispensing ........................................................................................48 
6.9.1 Anti-HBV Nucleos(t)ide Analog Dispensing ..................................................48 
6.10 
Pharmacodynamics/Efficacy Assessments ..................................................................48 
6.10.1 Molecular and Serologic Tests .........................................................................48 
6.10.1.1 Hepatitis D Virus ..............................................................................48 
6.10.1.2 Hepatitis B Virus ...............................................................................49 
6.10.1.3 Hepatitis C ........................................................................................49 
6.10.1.4 HIV ...................................................................................................50 
6.10.2 Fibroscan ..........................................................................................................50 


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6.11 
Safety Assessments ......................................................................................................50 
6.11.1 Adverse Events ................................................................................................50 
6.11.2 Clinical Laboratory Tests .................................................................................50 
6.11.3 Vital Signs ........................................................................................................51 
6.11.4 Physical Examination.......................................................................................52 
6.11.5 Electrocardiograms ..........................................................................................52 
6.11.6 Concomitant Medications ................................................................................52 
6.12 
Exploratory Assessments .............................................................................................52 
6.12.1 Immunologic Assessments...............................................................................52 
6.12.1.1 Genetic Biomarker Testing ...............................................................52 
6.12.1.2 Immunogenicity Testing ...................................................................52 
6.12.1.3 Host Immune Response Biomarker Testing .....................................52 
6.12.1.4 Future Exploratory Assessments .......................................................53 
6.13 
Viral Resistance Analysis ............................................................................................53 
6.14 
Early Termination ........................................................................................................53 
7 STUDY ACTIVITIES .......................................................................................................54 
7.1 
Screening Assessments (Day -27 to 0) ........................................................................54 
7.2 
Baseline Assessments (Day 1) .....................................................................................55 
7.3 
Week 1 Assessments (Day 7 ±5) .................................................................................55 
7.4 
Week 2 Assessments (Day 14 ±5) ...............................................................................56 
7.5 
Week 4 Assessments (Day 28 ±5) ...............................................................................56 
7.6 
Week 8 Assessments (Day 56 ±5) ...............................................................................57 
7.7 
Week 12 Assessments (Day 84 ±5) .............................................................................57 
7.8 
Week 16 Assessments (Day 112 ±5) ...........................................................................58 
7.9 
Week 20 Assessments (Day 140 ±5) ...........................................................................58 
7.10 
Week 24 Assessments (Day 168 ±5) ...........................................................................58 
7.11 
Week 28 Assessments (Day 196 ±5) ...........................................................................59 
7.12 
Week 32 Assessments (Day 224 ±5) ...........................................................................59 
7.13 
Week 36 Assessments (Day 252 ±5) ...........................................................................60 
7.14 
Week 40 Assessments (Day 280 ±5) ...........................................................................60 
7.15 
Week 44 Assessments (Day 308 ±5) ...........................................................................61 
7.16 
Week 48 Assessments (EOT; Day 336 ±5) or Early Termination ...............................61 
7.17 
Follow-up Week 52 (FU1; Day 364 ±5) ......................................................................62 
7.18 
Follow-up Week 56 (FU2; Day 392 ±5) ......................................................................62 
7.19 
Follow-up Week 60 (FU3; Day 420 ±5) ......................................................................62 


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7.20 
Follow-up Week 64 (FU4; Day 448 ±5) ......................................................................63 
7.21 
Follow-up Week 68 (FU5; Day 476 ±5) ......................................................................63 
7.22 
Follow-up Week 72 (FU6; Day 504 ±5) (EOS) ...........................................................64 
7.23 
Unscheduled Visits ......................................................................................................64 
8 STATISTICAL ANALYSIS .............................................................................................65 
8.1 
Randomization and Treatment Assignment .................................................................65 
8.2 
Determination of Sample Size .....................................................................................65 
8.3 
Analysis Populations ....................................................................................................65 
8.4 
Hypothesis Testing.......................................................................................................65 
8.5 
Study Endpoints ...........................................................................................................65 
8.6 
Analysis Plan ...............................................................................................................66 
8.6.1 Demographic and Baseline Data ......................................................................66 
8.6.2 Pharmacodynamics/Efficacy............................................................................67 
8.6.2.1 Viral Loads and Serology .................................................................67 
8.6.2.2 Fibroscan ...........................................................................................67 
8.6.3 Safety Analyses ................................................................................................67 
8.6.3.1 Adverse Events .................................................................................67 
8.6.3.2 Clinical Laboratory Test Results ......................................................68 
8.6.3.3 Vital Signs .........................................................................................68 
8.6.3.4 Physical Examination Findings.........................................................68 
8.6.3.5 ECG Results ......................................................................................68 
8.6.3.6 Concomitant Medications .................................................................68 
8.6.4 Exploratory Analyses .......................................................................................68 
8.6.4.1 Immunologic Analyses .....................................................................69 
8.6.5 Viral Resistance Analysis ................................................................................69 
9 SAFETY EVENTS DOCUMENTATION AND REPORTING .......................................70 
9.1 
Investigator’s Responsibilities .....................................................................................70 
9.2 
Monitoring Safety Data During Study .........................................................................70 
9.3 
Definitions of Types of Adverse Events ......................................................................70 
9.3.1 Adverse Events ................................................................................................70 
9.3.2 Suspected Adverse Reactions ..........................................................................70 
9.3.3 Life-Threatening Adverse Events ....................................................................71 
9.3.4 Serious Adverse Events ...................................................................................71 
9.3.4.1 Potential Treatment Related Liver Event ..........................................71 
9.3.4.2 Clinical Jaundice ...............................................................................71 
9.3.5 Unexpected Adverse Events ............................................................................71 


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9.4 
Adverse Event Classification .......................................................................................72 
9.4.1 Severity Grades of Adverse Events and Serious Adverse Events ...................72 
9.4.2 Relationship of Adverse Event to Investigational Products ............................72 
9.5 
Documentation of Adverse Events ..............................................................................73 
9.5.1 Study Drug Action Taken ................................................................................74 
9.5.2 Outcome of Adverse Event ..............................................................................74 
9.6 
Reporting Serious Adverse Events ..............................................................................75 
9.6.1 Reporting to Sponsor .......................................................................................75 
9.6.2 Reporting to Regulatory Agencies and Independent Ethics Committee .........75 
9.6.3 Emergency Sponsor Contact ............................................................................75 
9.7 
Pregnancy .....................................................................................................................76 
9.8 
Overdose ......................................................................................................................76 
10 DATA QUALITY CONTROL AND ASSURANCE .......................................................77 
10.1 
Overview ......................................................................................................................77 
10.2 
Study Monitoring .........................................................................................................77 
10.3 
Data Management ........................................................................................................78 
10.4 
Quality Assurance Audit ..............................................................................................78 
10.5 
Data Handling and Recordkeeping ..............................................................................78 
10.5.1 Case Report Form Completion ........................................................................78 
10.5.2 Data Handling ..................................................................................................79 
10.5.3 Study Files and Retention of Study Records ...................................................79 
10.6 
Drug Accountability.....................................................................................................79 
11 ETHICAL AND LEGAL CONSIDERATIONS ...............................................................80 
11.1 
Ethical Conduct and Good Clinical Practice ...............................................................80 
11.2 
Institutional Review Board/Independent Ethics Committee ........................................80 
11.3 
Patient and Data Confidentiality ..................................................................................81 
11.4 
Informed Consent.........................................................................................................81 
11.5 
Protocol Amendments ..................................................................................................83 
11.6 
Delegation of Responsibilities of the Principal Investigator .......................................83 
11.7 
Principal Investigator ...................................................................................................83 
11.8 
Compensation, Insurance, and Indemnity ....................................................................83 
11.9 
Publication Policy ........................................................................................................83 
11.10 Direct Access to Source Data ......................................................................................83 
12 REFERENCES ..................................................................................................................84 
13 APPENDICES ...................................................................................................................86 
 


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List of Tables 
Table 1: 
Key Phase 2 Lambda Studies in HCV or HBV .....................................................23 
Table 2: 
Lambda Pharmacokinetic Parameters ....................................................................25 
Table 3: 
Lambda Dose Reduction Dosages .........................................................................38 
Table 4: 
Guidelines for Treatment Interruption or Discontinuation and Dose 
Modification ...........................................................................................................39 
Table 5: 
Depression or Other Neuropsychiatric Disorders: Guidelines for 
Treatment Interruption or Discontinuation or Dose Modifications .......................42 
Table 6: 
Choice of NUC Therapy to Be Taken During Study Conduct ..............................45 
Table 7: 
Serum and Blood Chemistry Laboratory Tests ......................................................51 
Table 8: 
Adverse Event Grades Based on the Common Terminology Criteria for 
Adverse Events ......................................................................................................72 
Table 9: 
Categories for Assessing Relationship of Adverse Events to 
Investigational Products .........................................................................................73 
Table 10: Classifications for Study Drug Action Taken with Regard to an Adverse 
Event ......................................................................................................................74 
Table 11: Classifications for Outcome of an Adverse Event .................................................74 
 
List of Figures 
Figure 1: Mechanism of Action of Interferons ......................................................................20 
Figure 2: Study Schema.........................................................................................................29 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
Ab 
antibody 
AE 
adverse event 
Ag 
antigen 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibody 
ANC 
absolute neutrophil count 
anti-LKM1 
liver kidney microsome type 1 antibody 
anti-SMA 
anti-smooth muscle antibody 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ASV 
asunaprevir 
AUC 
area under the time-concentration curve 
AUCinf 
area under the time-concentration curve from time 0 extrapolated to infinite time 
B2M 
beta-2 microglobulin 
BMI 
body mass index 
BP 
blood pressure 
BSEP 
bile salt efflux protein 
BUN 
blood urea nitrogen 
CHB 
chronic hepatitis B 
CHC 
chronic hepatitis C 
CHD 
chronic hepatitis D (delta) 
CD-1 
cesarean-derived 1 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
Cmax 
maximum observed concentration 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP 
Child-Turcotte-Pugh 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DAA 
direct-acting antiviral 
DB 
direct bilirubin 
DCV 
daclatasvir 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
DR 
dose reduction (DR1=first dose reduction; DR2=second dose reduction) 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EOFU 
end of follow-up (Week 72) 
EOT 
end of treatment (Week 48) 


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Abbreviation 
Definition 
ESRD 
end-stage renal disease 
ET 
early termination 
ETV 
entecavir 
EU 
European Union 
FDA 
Food and Drug Administration 
FU# 
follow-up visit # 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GGT 
gamma-glutamyl transferase  
GM-CSF 
granulocyte macrophage colony-stimulating factor 
GT-x 
genotype-x 
HBeAb 
hepatitis B envelope antibody 
HBeAg 
hepatitis B envelope antigen 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDV 
hepatitis delta virus 
HEENT 
head, eyes, ears, nose, and throat 
HIV 
human immunodeficiency virus 
HSV 
herpes simplex virus 
HVPG 
hepatic venous pressure gradient 
IB 
investigator's brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IFN-α 
interferon alpha 
IFN-λ 
interferon lambda-1a 
IMP 
investigational medicinal product 
IND 
investigational new drug application 
INR 
international normalized ratio 
IRB 
institutional review board 
ISG 
interferon-stimulated genes 
ITT 
intention-to-treat 
IU 
international unit 
IUD 
intrauterine device 
IV 
intravenous 
IWRS 
interactive web response system 
Lambda 
peg-IFN-λ-1a 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
LOD 
limit of detection 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
major histocompatibility class 
MITT 
modified intention to treat 
MRI 
magnetic resonance imaging 


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Abbreviation 
Definition 
MRP# 
multidrug resistance-associated protein# 
NCI 
National Cancer Institute 
NK 
natural killer 
NUC 
nucleos(t)ide analog 
OATP 
organic anion-transporting polypeptide 
PBL 
peripheral blood lymphocyte 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PEG-IFN-λ 
pegylated interferon lambda-1a (Lambda) 
P-gp 
P-glycoprotein 
PI 
principal investigator 
PID 
patient identification number 
PK 
pharmacokinetics 
PT 
prothrombin time 
QA 
quality assurance 
QC 
quality control 
qHBsAg 
quantitative HBsAg 
qPCR 
quantitative polymerase chain reaction 
QTcF 
QT interval corrected using Fridericia formula 
QW 
once each week 
RBV 
ribavirin 
rIL 
recombinant interleukin 
RNA 
ribonucleic acid 
RTU 
ready to use 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SOP 
standard operating procedure 
STAT-1 
signal transducer and activator of transcription 1 
SUSAR 
suspected, unexpected serious adverse reaction 
SVR-xx 
sustained virologic response for xx weeks after EOT 
T1/2 
terminal elimination half-life 
T3 
triidothyronine 
T4 
thyroxine 
TBILI 
total bilirubin 
TDF 
tenofovir disoproxil fumarate 
TEAE 
treatment-emergent adverse event 
TLT 
treatment-limiting toxicity 
Tmax 
time to peak plasma concentration 
TSH 
thyroid-stimulating hormone 
UGT1A1 
uridine diphosphoglucuronosyltransferase 1A1 
ULN 
upper limit of the normal range 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 
WHO-DD Enhanced 
World Health Organization Drug Dictionary Enhanced 
 


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1 
INTRODUCTION 
1.1 
Background 
Hepatitis D virus has been identified as the infectious agent causing viral hepatitis in the 
presence of HBV (Rizzetto et al 1977, Rizzetto et al 1980). While HDV can replicate 
autonomously inside the hepatocyte, the virus requires coinfection with HBV to complete 
virion assembly and to facilitate transmission. HDV uses the hepatitis B surface antigen 
(HBsAg) proteins L, M, and S as its envelope proteins, which are pivotal for HDV exit from 
host cells and transmission to other hepatocytes (Bonino et al 1986). HDV can be considered 
a superinfection among patients chronically infected with HBV or as a simultaneous acute 
coinfection with HBV. The HDV genome is a small circular single-stranded RNA molecule 
that can be classified into 8 different genotypes (Makuwa et al 2008). HDV genotype 1 is the 
most prevalent globally and in Europe and North America.  
HDV is the most aggressive and virulent of the viral hepatitides. Chronic HDV infection 
leads to more severe liver disease than HBV monoinfection and is associated with 
accelerated fibrosis progression and a higher risk of developing hepatocellular carcinoma 
(Rizzetto 2000, Fattovich et al 1987, Uzunalimoglu et al 2001).  
Worldwide, approximately 5% (15–20 million) of HBV-infected individuals are also infected 
with HDV (Wedemeyer & Manns 2010). The prevalence of HDV is increasing in northern 
and central Europe due to migration from areas where HDV is endemic.  
Chronic HDV infections represent a serious unmet medical need, as currently there is no 
approved therapy for HDV infection. Multiple direct antiviral agents directed against HBV 
are available, but these agents have not proven effective against HDV (Wedemeyer et al 
1999, Yurdaydin et al 2002, Lau et al 1999, Niro et al 2006). 
Interferon alpha (IFN-α) or pegylated IFN-α have been tested at different doses and 
durations in patients with chronic HDV. Up to 25% of patients may achieve suppression of 
HDV ribonucleic acid (RNA) after 48 to 96 weeks of treatment, but these treatments are 
associated with a significant relapse rate after discontinuation (Wedemeyer & Manns 2010, 
Wedemeyer et al 2014). Some patients required premature discontinuation or dose reductions 
due to adverse effects (AEs), which may have impacted response rates. In the pegIFN-α-2a 
registration study for the treatment of HBV, 3% to 4% of patients discontinued therapy due 
to a safety reason and 46% to 47% of patients required dose reductions, most commonly for a 
laboratory abnormality (Lau et al 2005). 
Adverse effects associated with use of currently available IFN-α preparations include a “flu-
like” syndrome (manifesting as fever, headache, and myalgia), chronic fatigue, and various 
significant neuropsychiatric events (in particular, depression, insomnia, and irritability). 
Another notable risk associated with IFN-α use is cytopenia, with events of leukopenia, 
neutropenia, and thrombocytopenia most common, and also anemia and pancytopenia. 
Thyroid dysfunction and various forms of retinitis are additional risks associated with IFN-
α therapy.  
Finally, hepatic flare (or alanine aminotransferase [ALT] flare, also referred to in the 
literature as acute exacerbation of hepatitis) is a well described phenomenon during 
IFN-α therapy for chronic HBV (CHB), reported in 25% to 40% of treated patients. In 


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patients with chronic hepatitis D (CHD), ALT flare is also observed during the natural course 
of the disease or in response to IFN-α therapy. The pathogenesis of these events is variable; 
some are host induced, while others are viral induced or of indeterminant etiology. Host-
induced hepatic flares appear to be immune mediated, related to reconstitution of virus-
specific host effector responses in response to declining viremia. In CHB and in previous 
studies in CHD, host-induced hepatic flares are generally well tolerated; they rarely lead to 
hepatic decompensation in patients with compensated liver disease at baseline, and their 
occurrence has been associated with a favorable outcome, including increased rates of 
HBsAg seroconversion. Assessment of these events can be complex, given these events may 
also be spontaneous in nature, related to the underlying viral infection itself as opposed to the 
immune-stimulant effects of IFN-α, or due to an unrelated event. Drug-induced hepatitis 
must also be considered. 
IFN-λ is a different type of IFN (Type III) with different structural features, receptor 
characteristics, and biological activities than IFN-α (Type I) (see Figure 1). IFN-λ was first 
reported in the early 2000s (Kotenko et al 2003, Sheppard et al 2003). Based on IFN-λ's 
more limited receptor distribution and previous data from studies involving treatment with 
IFN-λ in patients with HBV or HCV, it is postulated that IFN-λ could induce HDV RNA 
decline, but with fewer AEs than IFN-α. 
Figure 1: 
Mechanism of Action of Interferons 
 
 
 
 
 
 
 
 
 
 
 
 
Lambda is the pegylated form of IFN-λ, a conjugate of recombinant human interleukin 29 
(rIL-29) and a linear polyethylene glycol (PEG) chain. 
1.2 
Rationale for the Study 
As shown in Figure 1, IFN-λ and IFN-α share the common ISG (interferon-stimulated gene) 
induction pathway that leads to broad-spectrum antiviral activities. Since INF-α has 
demonstrated anti-HDV activity in patients with CHD patients (Wedemeyer & Manns 2010), 


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it is postulated that PEG IFN-λ (Lambda) could also induce HDV RNA decline in patients 
with CHD. 
Based on IFN-λ's more limited receptor distribution and previous data from studies involving 
treatment with IFN-λ in patients with HBV or HCV, it is postulated that Lambda treatment 
could be associated with fewer AEs than IFN-α treatment. 
EIG-LMD-001 is the first study of Lambda in patients with CHD infection. The primary 
aims of the study are to define the safety, tolerability, and pharmacodynamics (PD)/efficacy 
of Lambda monotherapy in patients with CHD.  
The Lambda doses chosen for this study were based on the results from studies in healthy 
volunteers and in patients with CHB or chronic hepatitis C (CHC).  
1.3 
Preclinical Experience 
1.3.1 
Antiviral, Immunologic, and Hematologic Effects 
Results from in vitro and in vivo studies conducted in CD-1 mice and cynomolgus monkeys 
that are relevant to the current study are summarized below. 
In vitro data on inhibition of HDV by IFN are limited. An in vitro study of HDV-infected 
primary human hepatocytes demonstrated that simultaneous addition of IFN-α at 
600 units/mL, a concentration comparable to that achieved in treated patients, the subsequent 
HDV RNA accumulation was inhibited by at least 80%. IFN-α produced significant 
time-dependent increases of host response proteins such as Stat-1, phosphoStat-1, Mx1/2/3 
and PKR (Han et al 2011). 
In a human hepatoma cell line that consistently secretes HBV, IFN-λ inhibited HBV 
replication with kinetics and efficiency similar to that of IFN-α/β (Robek et al 2005). This 
activity was a direct result of the antiviral activity of IFN-λ, not mediated by secondary 
induction of endogenous IFN-α/β. 
Similar results using this HBV-producing hepatoma line and several pegIFN preparations 
were reported by investigators at the Southern Research Institute (ZymoGenetics Report 
RES-10556, 2006). The activity of Lambda in this model was similar to that of the currently 
marketed pegIFN-α preparations (PEGASYS and PEG-INTRON), with no discernible 
in vitro toxicity (selectivity index > 300). 
In in vitro studies using primary human hepatocytes, Lambda induced expression of 
IFN-stimulated genes (ISGs) to an extent and potency similar to that observed with pegIFN-
α-2a. Pharmacology studies conducted in treated cynomolgus monkeys also demonstrated 
induction of ISGs in hepatocytes, however not in circulating peripheral blood lymphocytes 
(PBLs). The number of circulating monocytes, granulocytes, lymphocytes, and lymphocyte 
subsets (B and T lymphocytes and natural killer [NK] cells) did not change following dosing 
with Lambda in cynomolgus monkeys. Expression of major histocompatibility class (MHC) 
Class I molecules on circulating lymphocytes also did not change following administration of 
a single dose of Lambda to monkeys. However, serum beta-2 microglobulin (B2M) was 
induced following Lambda administration; B2M levels increased approximately 40% above 
baseline following a single dose of Lambda. In repeat-dose Lambda studies, doses of at least 


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0.03 mg/kg were required to induce serum B2M; doses above this level induced B2M to a 
similar extent. 
Consistent with the relatively low level of Lambda receptor expression by bone marrow cells, 
Lambda did not affect myeloid or erythroid colony formation in human bone marrow cells, 
while a dose-dependent reduction in colony formation was seen with IFN-α. In addition, no 
decreases in platelets, erythrocytes, or neutrophils were observed in cynomolgus monkeys or 
CD-1 mice following repeat Lambda  dosing. 
Altogether, these findings support the hypothesis that Lambda may be associated with less 
hematological toxicity than IFN-α. 
1.3.2 
Toxicology 
Lambda has been evaluated in cynomolgus monkeys and CD-1 mice, both of which 
demonstrate receptor binding and pharmacological response to drug. 
In toxicology studies conducted in CD-1 mice, Lambda was well tolerated when 
administered alone or in combination with ribavirin (RBV) by subcutaneous (SC) injection. 
Histological examination revealed a generally minimal-to-mild cardiac change consisting of 
focal myocyte degeneration, increased interstitial cellularity, and interstitial fibrosis in some 
mice, and the incidence increased with dose. There were no correlative clinical signs or 
findings associated with these histologic findings. Lambda treatment had no discernible 
effect on serum troponin-I levels in CD-1 mice. Treatment with RBV alone was not 
associated with any cardiac pathology. 
The safety of Lambda (with or without RBV) was assessed in cynomolgus monkeys in 
1-month and 26-week dosing studies. Findings were limited to the transient appearance of 
skin flaking and reddening generalized to various regions of the body, a dose-dependent 
decrease in serum fibrinogen levels, and mononuclear cell infiltrates at the SC injection site. 
The reduction in fibrinogen levels was not considered clinically relevant because 
concentrations generally remained within the normal range for this species and there were no 
concurrent abnormalities in other coagulation parameters. On microscopic analysis, the areas 
of skin change showed an adaptive acanthotic response at the injection sites with or without 
subepithelial perivascular infiltrates of lymphocytes and/or macrophages. In the monkeys 
treated for up to 6 months, there was no histologic evidence of cardiomyocyte injury. 
A dose-ranging embryo-fetal development study was conducted in pregnant CD-1 mice. The 
mice were given daily SC injections of Lambda or placebo on gestation Days 6 through 15, 
then killed on Day 18. Drug-related effects in the fetuses at all doses (≥0.5 mg/kg/day) 
consisted of increases in embryolethality with associated decreases in litter size 
(postimplantation losses averaged 62– 91% compared with 32% in the control group; 43%–
75% of litters consisted entirely of resorptions or dead fetuses compared with 25% in the 
control group). 
1.3.3 
Pharmacokinetics 
The pharmacokinetics (PK) of Lambda was evaluated in the mouse, rat, and monkey. 
Lambda was well absorbed and bioavailable in mice (51%) and monkeys (40%–53%) but 
less so in rats (13%). The volume of distribution at steady state (Vss) for Lambda in mice, 


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rats, and monkeys after intravenous (IV) administration was less than the reported total body 
water volumes for these species, indicating limited extravascular distribution. The total 
plasma clearance in rats with nephrectomy was significantly lower compared with sham-
operated rats, suggesting that changes in renal function may affect the elimination of 
Lambda. In mice, tissue distribution of radioactivity was similar after a single SC dose of 
3 mg/kg [123I]Lambda and after 2 weeks of 3-times-weekly dosing. Lambda did not appear to 
inhibit or induce any of the cytochrome P450 (CYP) isoforms tested in human liver 
microsomes and hepatocytes and did not alter the total CYP content or the individual enzyme 
activities in the livers of treated cynomolgus monkeys.  
1.4 
Clinical Experience 
1.4.1 
Clinical Efficacy/Pharmacodynamics 
Currently there are no clinical data on Lambda for HDV infection. 
1.4.2 
Clinical Safety 
As of 15 September 2014, approximately 3,710 subjects (including 237 healthy subjects; 
3,276 subjects with HCV; and 197 subjects with HBV) have received Lambda or comparator 
in 18 completed, terminated, or ongoing Phase 1, 2, or 3 studies. Study designs for several of 
the studies mentioned below are shown in Table 1. 
Table 1: 
Key Phase 2 Lambda Studies in HCV or HBV 
Study 
Study 
Identifier 
Study 
Population
/ 
Phase 
Treatments Evaluated 
Treatment Duration 
Sample 
Sizes 
EMERGE 
526F06 
HCV 
Phase 2b 
• Lambda 240 µg+RBV 
• Lambda 180 µg+RBV 
• Lambda 120 µg+RBV 
• Alfa-2a 180 µg+RBV 
24 weeks (G2/G3) 
48 weeks (G1/G4) 
• 134 
• 131 
• 127 
• 133 
D-LITE 
AI452008 
HCV 
Phase 2 
• Lambda 180 µg 
+RBV+ASV 
 
• Lambda+RBV+DCV 
• Alfa-2a+RBV 
• 24 or 48 weeks, 
depending on early 
response 
• same as above 
• 48 weeks 
• 44 
 
 
• 49 
• 47 
LIRA-B 
AI452005 
HBV 
Phase 2 
• Lambda 180 µg 
• Alfa-2a 180 µg 
24 weeks 
• 93 
• 83 
 ASV, asunaprevir; DCV, daclatasvir; G#, genotype; RBV, ribavarin 
 
Lambda has been generally well tolerated in clinical studies. A lower frequency of 
musculoskeletal (myalgia, arthralgia, and back pain) and flu-like symptoms (chills, pyrexia, 
and pain) was observed across Phase 2 studies in subjects receiving IFN regimens containing 
Lambda compared with IFN alfa (the drug name of a pharmaceutical product that contains 
IFN-α).  
Hematologic toxicity was notably lacking in the white blood cell (WBC) or platelet lineages 
in subjects receiving Lambda regimens. Hematologic toxicity was less frequent in the 
Lambda group compared with the alfa group in the D-LITE and LIRA-B studies 


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(Lambda/RBV/direct-acting antiviral [DAA] vs. alfa/RBV and Lambda vs. alfa, 
respectively).  
In the EMERGE study, expected decreases in hemoglobin levels were observed with 
concomitant RBV use. However, overall, anemia was less frequent and milder with 
Lambda/RBV than with IFN alfa/RBV.  
In the EMERGE study, laboratory changes associated with autoimmune thyroid disease 
(elevated thyroid-stimulating hormone [TSH] and reduced free T4) were less common with 
Lambda/RBV than with alfa/RBV. Serial troponin measurements and electrocardiogram 
(ECG) findings analyzed at Week 12 of treatment showed no evidence of cardiac toxicity. 
In the EMERGE study, hyperbilirubinemia and transaminase elevations leading to dose 
reduction or discontinuation were observed more frequently with the 240 µg dose than with 
the other tested doses (80, 120, and 180 µg) or the active comparator (180 µg alfa-2a), while 
early virologic response was similarly robust with Lambda 180 µg and 240 µg. Based on 
these findings, further investigation of the Lambda 240 µg dose was discontinued across the 
HCV and HBV programs. After dose reduction or discontinuation of treatment, the 
hyperbilirubinemia events resolved with no laboratory evidence of sustained hepatic 
dysfunction.  
Conjugated hyperbilirubinemia was more common in HCV-infected patients treated with 
Lambda+RBV compared with IFN alfa-2a treatment. Therefore, several in vitro studies were 
conducted to assess any differences in bilirubin-related metabolic or clearance processes 
following treatment with Lambda or alfa-2a in sandwich cultures of primary human 
hepatocytes. Gene expression, inhibition, and confocal microscopy data did not suggest a 
metabolism- or transporter-related rationale to explain the clinically observed difference in 
the type and frequency of hyperbilirubinemia following treatment with the 2 IFNs. This ruled 
out metabolism-related factors of uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) 
and transporter-related factors of organic anion-transporting polypeptide (OATP) 1B1, 
OATP1B3, multidrug resistance-associated proteins MRP3 and MRP2, P-glycoprotein 
(P-gp), and bile salt efflux protein (BSEP).  
When Lambda/RBV was combined with asunaprevir (ASV) in the D-LITE study, a higher 
frequency of concurrent elevations of ALT and total bilirubin (TBILI) was observed, and 
3 cases met the program-defined criteria for potential drug-induced liver injury (DILI). This 
finding led to the discontinuation of the Lambda/RBV/ASV regimen in future development 
plans. The combination of Lambda/RBV and daclatasvir (DCV) was well tolerated.  
In the LIRA-B study, Grade 3 to 4 ALT/aspartate aminotransferase (AST) elevations in 
Lambda-treated patients generally occurred early following initiation of study drug (ie, 
Weeks 1 to 16) and in each case appeared related to an early, on-treatment, host-mediated 
ALT flare.  
Four cases of decompensated cirrhosis have been observed with Lambda. One patient with 
baseline cirrhosis and Gilbert’s disease developed Grade 1 hepatic decompensation and 
ascites while receiving Lambda 120 μg in the EMERGE study; drug treatment was 
interrupted, the events resolved, and the patient subsequently resumed therapy at a lower 
dose. In the Phase 3 study (AI452017) in GT-2 or GT-3 HCV-infected patients, 3 of 
~70 randomized patients with preexisting compensated cirrhosis developed decompensated 


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cirrhosis while on treatment. All 3 patients were Child Pugh Class A at entry and had 
evidence of portal hypertension. Two of these patients subsequently recovered; however, 
1 patient died of infectious complications. Based on these data, Lambda appears to be 
associated with decompensation of cirrhosis especially in the context of portal hypertension. 
Therefore, in prior studies and the current one, enrollment of cirrhotic patients is restricted to 
compensated cirrhotic patients (Child Pugh Class A) without evidence of portal hypertension.  
In summary, across the clinical development program, laboratory abnormalities with Lambda 
treatment were generally low grade and self limited. The main safety finding was a higher 
frequency of transaminase elevations, accompanied in some cases by increases in total and 
conjugated (direct) bilirubin, but no evidence for impaired liver synthetic function such as 
decreased albumin or increased international normalized ratio (INR).  
1.4.3 
Clinical Pharmacokinetics 
Lambda PK has been characterized following single- and multiple-dose SC administration of 
Lambda in healthy subjects and patients with HCV (Table 2). The median time to maximum 
concentration (Tmax) ranged from 8.00 to 25.1 hours (range, 1–120 hours). Following single-
dose administration of Lambda 180 μg, the geometric mean maximum observed 
concentration (Cmax) (coefficient of variation [%CV]) values ranged from 1.06 (102) to 
2.41 (177) ng/mL. Following multiple-dose administration, the geometric mean Cmax (%CV) 
was 1.54 (86.0) ng/mL, demonstrating modest accumulation. The area under the 
concentration-time curve from time zero extrapolated to infinite time (AUCinf) (%CV) 
following single-dose SC administration of Lambda 180 μg to healthy subjects and patients 
with HCV ranged from 116.9 (73.1) to 221 (59) ng⋅h/mL. In general, exposure values (area 
under the concentration-time curve [AUC] and Cmax) were approximately dose proportional 
in the 80 to 240 μg dose range. The mean (standard deviation [SD]) terminal elimination 
half-life (T½) ranged from 50.43 (20.47) to 74.0 (42.7) hours.  
Table 2: 
Lambda Pharmacokinetic Parameters 
PK Parameter 
Values 
Tmax 
Median (range) 
8.00 to 25.1 h 
Range (1–120 h) 
Cmax 
Geometric mean (%CV) 
Single-dose: 1.06 (102) to 2.41 (177) ng/mL 
Multiple-dose: 1.54 (86.0) ng/mL 
AUCinf  
Geometric mean (%CV) 
Single-dose 180 µg to healthy subjects or patients with HCV: 
116.9 (73.1) to 221 (59) ng⋅h/mL  
T½ 
Mean (SD) 
50.43 (20.47) to 74.0 (42.7) h 
 
Population PK modeling has demonstrated that body weight affects clearance, consistent 
with standard allometry; however, while body weight has a significant effect on clearance, 
the effect is small compared with the overall intersubject variability and, thus, does not 
warrant weight-based dosing.  
Preliminary results have shown that renal impairment increases exposure; Cmax and AUC 
were approximately 13% and 20% greater, respectively, in subjects with mild impairment 
and approximately 2-fold greater across the moderate renal dysfunction, severe renal 


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dysfunction, and end-stage renal disease (ESRD) groups compared with subjects with normal 
renal function.  
Preliminary clinical results suggest that following single, 180-µg dose administration, 
Lambda is a mild inhibitor of CYP1A2, CYP2C9, and CYP3A4, and a moderate inhibitor of 
CYP2C19 and CYP2D6.  
1.5 
Potential Risks and Benefits to Human Patients in This Study 
All patients enrolled in this study will receive 48 weeks of treatment with Lambda. Patients 
with HDV, for which no treatment is approved, may experience benefit from receiving an 
investigational IFN that may show efficacy in HDV, with a potentially improved safety 
profile over IFN alfa formulations, based on the available data regarding the biologic effects 
and different distribution patterns of Lambda vs. IFN alfa receptors, in addition to the 
available safety data from studies in patients with chronic HCV and HBV infection. See the 
Peginterferon Lambda-1a investigator brochure (IB) for more information.  
The potential benefits to all study patients may include a beneficial impact on their CHD 
infection, as determined by virologic, serologic, and biochemical responses. An additional 
potential benefit of Lambda therapy is that after a defined treatment period, responses may be 
maintained after discontinuation of therapy, presumably reflective of immunologic control of 
the virus having been attained. Finally, development of viral resistance is not expected based 
on data from previous studies with IFN-α and IFN-λ in patients with CHB or CHC infection.  
For Lambda monotherapy, there are 2 categories of risk: adequacy of the Lambda dose 
selected for this study and potential drug toxicity. To protect against possible inadequacy of 
the Lambda dose, 2 doses (120 and 180 µg/week) were selected for this study. Both Lambda 
and IFN-α have been administered at these doses in studies evaluating efficacy and safety in 
the treatment of CHB and HCV (Cooksley et al 2003, Chan et al 2015). These biologic 
treatments are expected to have the same targeted effect across viral hepatitides—expression 
of the IFN receptors on hepatocytes and other infected cells (Kotenko et al 2003, Sheppard et 
al 2003)—and so using the same doses seems appropriate in this study in HDV.  
Potential drug toxicity risks are based on observations in the nonclinical development 
program (Section 1.3.2) and safety events noted in clinical trials (Section 1.4.2). In the 
preclinical program, a minimal-to-mild cardiomyopathy was observed in mice; however, no 
histologic evidence of cardiomyocyte injury was seen in monkeys treated for up to 6 months. 
In monkeys, the primary safety findings were a dose-dependent decrease in serum fibrinogen 
levels, mononuclear infiltrates at SC injection sites, and the transient appearance of skin 
flaking and reddening. In pregnant mice, Lambda therapy was associated with fetal loss, 
increased incidence of preterm deliveries, developmental mortality, and fetal dysmorphology.  
In completed, Phase 1, single- and multiple-dose studies conducted in healthy volunteers and 
in HBV- and HCV-infected patients, overall Lambda has been well tolerated, with minimal 
constitutional symptoms and hematologic events, and no cardiac toxicity. The primary AEs 
observed included mild, asymptomatic, dose-dependent, primarily isolated, and reversible 
laboratory abnormalities: (1) elevations in serum transaminases, which were accompanied by 
increases in conjugated bilirubin in only a small number of patients; (2) changes in 
coagulation parameters (PT and/or fibrinogen); and (3) increases in serum troponin that were 


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not associated with abnormalities on ECG or cardiac echocardiogram. Most of these 
abnormalities occurred in the highest dose groups. 
Asymptomatic, dose-related, reversible elevations in serum transaminases and/or bilirubin 
levels have been observed in some patients. Incidences of these events with Lambda 120 or 
180 µg/week were similar to those of pegIFN-α, and were higher with Lambda 240 µg/week. 
Dose-related direct bilirubin (DB) elevations were more frequent with Lambda than with 
pegIFN-α; the majority of these events were seen with Lambda 240 µg/week. These findings 
were observed in both noncirrhotic and cirrhotic patients. The current study will not 
investigate the 240 µg dose. 
Resistance development is a risk commonly associated with the use of antiviral agents. 
However, because Lambda is an immunomodulator, the risk of resistance development is 
small. Viral resistance has not developed in previous studies with IFNα in CHB, CHC, or 
CHD, and it is not expected for Lambda therapy. 
To mitigate risk in the current study, patients for whom Lambda therapy is considered 
contraindicated will be excluded from participating. For example, patients with preexisting 
evidence of hepatic impairment (based on serum bilirubin and measures of liver synthetic 
function) will be excluded. In addition, intensive laboratory monitoring will be performed 
throughout the study; detailed requirements for study drug dose interruption, reduction, or 
discontinuation are described in Section 5.4.3.  
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objectives of the study are as follows: 
• To evaluate the safety and tolerability of treatment with 2 dose levels of Lambda 
over a 48-week treatment period 
• To evaluate the effect of treatment with 2 different doses of Lambda on HDV 
RNA levels 
2.2 
Secondary Objectives 
The secondary objectives of the study are as follows: 
• To evaluate the proportion of patients with undetectable HDV RNA 12 weeks 
after the end of treatment 
• To evaluate the proportion of patients with undetectable HDV RNA 24 weeks 
after the end of treatment 
• To evaluate the proportion of patients with undetectable HDV RNA approx. 48 
weeks after the end of treatment 
• To evaluate the effect of treatment with 2 dose levels of Lambda on the following: 
- 
ALT levels including ALT levels at approx. 48 weeks after end of treatment 
– Hepatitis B surface antigen (HbsAg) levels 
– Gamma-Glutamyl Transferase (GGT) levels 
2.3 
Exploratory Objectives 
An exploratory objectives of the study are to evaluate the treatment with 2 dose levels of 
Lambda on the following: 
• Immunologic parameters 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design 
This Phase 2, randomized, open-label, 2 dose level study will assess the safety, tolerability, 
and pharmacodynamics (PD)/efficacy of Lambda in patients with CHD. Up to forty patients 
will be enrolled at approximately 6 study sites globally. Patients will be randomized 1:1 to 
receive 1 of the following treatments with open-label study drug: 
• 120 µg Lambda, weekly SC injection 
• 180 µg Lambda, weekly SC injection  
Eligible patients will have chronic HDV infection (≥ 6 months) confirmed by positive HDV 
antibody (Ab) test and detectable HDV RNA by quantitative polymerase chain reaction 
(qPCR). 
The study will consist of 3 periods (Figure 2): 
• Screening Period: Day –28 to Day 0 (maximum 4 weeks) 
• Treatment Period: Day 1 (first day of treatment) through Week 48 (12 months) 
• Follow-up Period: Week 49 though Week 72 (6 months) 
Figure 2: 
Study Schema 
 
EOT, end of treatment; EOFU, end of follow-up; QW, once a week; SVR 12, sustained virologic response at 
12 weeks after treatment 
 
All patients, whether they complete the treatment period or not, will be followed for 
6 months in the follow-up period. The maximum anticipated time an individual patient will 


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participate in the study will be 19 months (up to 1 month of screening, 12 months of 
treatment, and 6 months of follow-up). 
Supplemental post-study testing will be conducted approximately 48 weeeks post treatment 
for available patients to assess long term durability of post-treatment endpoint responses 
(HDV RNA and ALT). Patients will be required to take an anti-HBV nucleos(t)ide analog 
(NUC) from baseline (Day 1) until the end of the study. Tenofovir disoproxil fumarate (TDF) 
will be prescribed for any patients not already taking one of these medications at baseline; if 
TDF is contraindicated then entecavir (ETV) will be prescribed. This medication will protect 
patients in the case that HDV suppression may lead to HBV flare.  
HDV RNA by qPCR will be measured to assess PD/efficacy. HBV deoxyribonucleic acid 
(DNA) will also be measured throughout the study. Safety measures include AEs, clinical 
laboratory values, vital signs, ECG, physical examination findings, and concomitant 
medication usage. Specific management protocols for several Lambda toxicities documented 
in the literature and/or the product IB are provided in Section 5.4.3, including 
recommendations for drug interruption, dose adjustment, and discontinuation. 
3.2 
Rationale for Study Design 
The assessments planned for this study 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. 
3.2.1 
Rationale for Dose 
The Lambda doses chosen for this study (120 and 180 µg/week) were based on the results 
from studies in healthy volunteers and patients with CHB or CHC. See Section 1.5 for more 
information.  
 


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4 
STUDY POPULATION SELECTION 
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. 
4.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria before study entry to be eligible for 
enrollment into the study: 
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. Chronic HDV infection of at least 6 months' duration documented by a positive HDV Ab 
test;, detectable and quantifiable HDV RNA by qPCR at study entry 
4. Serum ALT > upper limit of the normal range (ULN) and <10 × ULN at screening 
5. ECG demonstrating no acute ischemia or clinically significant abnormality and a QT 
interval corrected for heart rate (QTcF) <450 ms for male patients and <460 ms for 
female patients  
6. TSH and/or free T4 within 0.8 to 1.2 times the normal limit, or adequately controlled 
thyroid function as assessed by the investigator 
7. Dilated retinal examination ≤1 year before screening: For patients with diabetes, 
hypertension, or other risk factors for retinal disease, performed by a licensed ocular 
specialist; for all other patients, a normal retinal examination as assessed by the 
investigator or a licensed ocular specialist  
8. 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 
through 90 days after the last dose of study medication. Female patients of childbearing 
potential are all those except patients who are surgically sterile, who have medically 
documented ovarian failure, or who are at least 1 year postmenopausal.  
For females, 2 of the following contraceptive methods, with at least 1 being a barrier 
method: 
– Hormonal contraceptives for ≥ 27 days before dosing  
– Intrauterine device (IUD) in place ≥ 27 days before dosing  
– Double-barrier methods (use of condom [male partner] with either diaphragm 
with spermicide or cervical cap with spermicide) from screening  
– Surgical sterilization of the partner (vasectomy ≥ 1 month before screening) 
 


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For males 
– Surgical sterilization (vasectomy ≥ 1 month before screening)  
or 
– Both of the following contraceptive methods from screening: 
 Consistently and correctly use a condom 
 Partner must use a hormonal contraceptive or a nonhormonal barrier 
method (IUD or diaphragm with spermicide or cervical cap with 
spermicide)  
9. Willing and able to provide written informed consent 
10. Willing and able to comply with all study procedures 
4.2 
Exclusion Criteria 
A patient will be excluded from this study if he or she meets any of the following criteria: 
General Exclusions 
1. Participation in a clinical trial with, or use of, any investigational agent within 30 days of 
start of screening, or treatment with IFNs or immunomodulators within 12 months of start 
of screening 
2. Previous use of Lambda. Patients who previously participated in a clinical trial of 
Lambda but are confirmed to have received placebo or other non-Lambda IFNs are 
allowed. 
3. History or evidence of any intolerance or hypersensitivity to IFNs or other substances 
contained in the study medication. 
4. Female patients who are pregnant or breastfeeding. Male patients must confirm that their 
female sexual partners are not pregnant. Female patients must have a negative serum or 
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human 
chorionic gonadotropin [hCG]) within 24 hours prior to the start of investigational 
product. 
Exclusions Based on Disease-related Criteria 
5. Current or previous history of decompensated liver disease (Child-Pugh Class B or C) 
6. Co-infected with human immunodeficiency virus (HIV) or hepatitis C virus (HCV). 
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. 
7. Past history or current evidence of decompensated liver disease as defined by the 
presence of any of the following at screening: 
a. Bilirubin level ≥2.5 mg/dL unless due to Gilbert’s disease 
b. Serum albumin level <3.5 g/dL 
c. INR ≥1.5 
d. Alpha fetoprotein ≥100 ng/mL 
8. Evidence of significant portal hypertension such as hepatic venous pressure gradient 
(HVPG) ≥10 mmHg; current presence or history of variceal bleeding 


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9. Current evidence or history of ascites requiring diuretics or paracentesis, or hepatic 
encephalopathy  
10. Patients with any of the following abnormalities at screening:  
a. Platelet count <90,000 cells/mm3 
b. WBC count <3,000 cells/mm3 
c. Absolute neutrophil count (ANC) <1,500 cells/mm3 
d. Hemoglobin <11 g/dL for women and <12 g/dL for men 
e. Serum creatinine concentration ≥1.5 × ULN 
f. Confirmed creatinine clearance (CrCl) <50 mL/min by Cockroft-Gault 
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. History of hepatocellular carcinoma  
13. Patients with any of the following:  
a. Current eating disorder or alcohol abuse 
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: 360 mL of beer, 150 mL of wine, or 45 mL of 
spirits. 
c. In the opinion of the investigator, an alcohol use pattern that will interfere with 
study conduct 
d. Drug abuse within the previous 6 months before the screening visit with the 
exception of cannabinoids and their derivatives 
14. Prior history or current 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 (inhaled asthma 
medications are allowed) 
b. Retinal disorder or clinically relevant ophthalmic disorder 
c. Any malignancy within 5 years before screening. Exceptions are superficial 
dermatologic malignancies (eg, squamous cell or basal cell skin cancer treated 
with curative intent). 
d. Cardiomyopathy or significant ischemic cardiac or cerebrovascular disease 
(including history of angina, myocardial infarction, or interventional procedure 
for coronary artery disease) 
e. Chronic pulmonary disease (eg, chronic obstructive pulmonary disease) 
associated with functional impairment 
f. Pancreatitis 
g. Severe or uncontrolled psychiatric disorder such as depression, manic condition, 
psychosis, acute and/or chronic cognitive dysfunction, suicidal behavior, and 
relapse of substance abuse 


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h. Active seizure disorder defined by either an untreated seizure disorder or 
continued seizure activity within the preceding year despite treatment with anti-
seizure medication  
i. Bone marrow or solid organ transplantation 
15. Other significant medical condition that may require intervention during 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. Patients for whom participation in the study 
would increase their risk. 
Exclusions Related to Use of Selected Medications 
16. Therapy with an immunomodulatory agent; alpha IFN (IFN alfa-2a or IFN alfa-2b, or 
pegylated IFN alfa-2a or alfa-2b); cytotoxic agent, or systemic corticosteroids within 
12 months before screening 
17. Use of telbivudine (Tyzeka or Sebivo) within 3 months before screening or during the 
study 
18. Current use of heparin or Coumadin 
19. Received blood products within 30 days prior to study randomization 
20. Use of hematologic growth factors within 30 days prior to study randomization 
21. Systemic antibiotics, antifungals, or antivirals for treatment of active infection other than 
HBV within 14 days of study randomization 
22. Any prescription or herbal product that is not approved by the investigator 
23. Long-term treatment (> 2 weeks) with agents that have a high risk for nephrotoxicity or 
hepatotoxicity, should be discussed with the medical monitor 
24. Receipt of systemic immunosuppressive therapy within the 3 months before start of 
screening 
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. 
4.4 
Early Withdrawal from Study by Individual Patients 
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  
 
In addition, specific rules are defined regarding actions to be taken (study drug interruption, 
study drug discontinuation, and study drug dosage adjustment) in the case of specific 
toxicities (see Section 5.4.3 ).  


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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.  
When a patient discontinues study drug early, the patient is considered permanently 
discontinued from the study. The reason for early withdrawal will be noted on the 
appropriate electronic case report form (eCRF). Every effort should be made to encourage 
the patient to return to the clinic as soon as possible for early termination (ET) assessments 
(Section 6.14). Patients who discontinue study medication/withdraw from the study, either 
during the treatment period or during the follow-up period, will be encouraged to return for 
all follow-up visits through 24 weeks after drug discontinuation, if possible.  
4.5 
Early Termination of the Study 
Eiger BioPharmaceuticals reserves the right to terminate the study at any time. Reasons for 
terminating the study can 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 institutional review board (IRB)/independent 
ethics committee (IEC) has the authority to stop the study. 


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5 
INVESTIGATIONAL PRODUCTS  
5.1 
Product Description 
The study drug, Lambda, is a conjugate of a recombinant version of human IL-29 (rIL-29) 
and a linear polyethylene glycol (PEG) chain. Other names for Lambda include pegylated 
interferon lambda (pegIFNλ−1a), PEG-rIL-29, and BMS-914143 (it was licensed from 
Bristol-Myers Squibb Company).  
Lambda has a molecular weight of 41,300 ± 88 Da.  The solution appears as  colorless to pale 
yellow , clear to slightly opalescent and essentially free of visible particles.  
Lambda will be provided in ready-to-use (RTU) syringes to be administered via SC injection. 
Each RTU syringe contains a 0.5 mL solution volume at a concentration of 0.4 mg/mL and 
can deliver up to 180 µg Lambda. The syringes have markings to indicate the appropriate 
volume to inject for the 180 µg or 120 µg dose, or for a 80 µg dose if needed for dose-
reduction. 
For additional information on Lambda, please refer to the IB.  
5.2 
Treatment Groups 
5.2.1 
Method of Assigning Patients to Treatment Groups 
Patients will be randomized equally to receive 1 of the 2 study treatments: 120 µg or 180 µg 
Lambda as SC weekly injection. 
Once protocol eligibility criteria have been confirmed for a particular patient, the site staff 
will enroll the patient and assign the patient to 1 of the 2 treatment arms. It is important that 
the investigative staff reconfirm the patient’s willingness to continue in the study prior to 
enrollment and randomization.  
5.2.2 
Randomization 
Patients will be randomly assigned 1:1 to receive either 120 or 180 µg Lambda as SC weekly 
injection by the interactive web response system (IWRS).  
5.3 
Blinding 
This study is open label, therefore no treatment blinding will be used. 
5.4 
Treatment Administration 
Clinic staff will administer each patient's first dose of study drug in the clinic on Day 1. 
Clinic staff will train patients on SC administration of study drug on Day 1, and provide 
written instructions for drug administration and storage and safe handling of needles 
(including discarding instructions and provision of a sharps container).  
Patients will be given sufficient study drug at each visit for the number of weeks until the 
next visit. 


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5.4.1 
Dosage 
The dosage of study drug will be either 120 or 180 µg Lambda, or if a dose reduction was 
required, 120 or 80 µg Lambda (see Section 5.4.3 and Table 3). Patients will self-administer 
study drug doses via SC injection once weekly through the entire dosing period. Patients will 
receive a maximum of 48 doses of study medication, with the final administration of study 
medication at Week 47 (Day 330). 
5.4.2 
Dose Titration 
No dose titration will be included in this study.  
5.4.3 
Dose Interruptions, Reductions, and Discontinuations 
The following section provides management criteria for laboratory and clinical AEs 
occurring during the treatment period (Table 4). Additional guidance is provided for 
occurrences of depression and other neuropsychiatric AEs (Table 5). These recommendations 
are based on the recognized risks of Lambda therapy in patients with CHB and guidance 
from the published literature and/or the IB. Specific guidelines for managing events of direct 
hyperbilirubinemia are included because direct hyperbilirubinemia is a recognized additional 
potential risk of Lambda therapy.  
All assessments regarding a laboratory or clinical AE are to be made by the investigator, 
using the provided guidance. The tables list the following abnormality categories: 
• AEs (Grade 3 at least possibly related and clinically significant, Grade 3 at least 
possibly related and not clinically significant, depression, and ocular symptoms) 
• Hematologic abnormalities (ANC and platelets) 
• Hepatobiliary abnormalities (ALT, AST, TBILI, DB, and INR)  
• Renal abnormalities (creatinine clearance) 
The dose reduction scheme including first and second dose reduction (DR) levels is shown in 
Table 3. Note that patients who require dose reduction in the 180 µg/week dose group will be 
given 120 µg/week in the first dose reduction (DR1) and 80 µg/week in the second dose 
reduction (DR2); patients in the 120 µg/week dose group will be given 80 µg/week in the 
first dose reduction (DR1) and also in the second dose reduction (DR2; in effect, they cannot 
be given a dose below 80 µg/week). 
All subjects who meet the criteria for treatment interruption, reduction and/or 
discontinuation, based on hepatobiliary abnormalities should have a clinical work-up that 
includes the following: 
• Autoimmune markers (antinuclear antibody [ANA], anti-smooth muscle antibody 
[anti-SMA], anti-LC1, anti-SLA liver kidney microsome type 1 and type III antibody 
[anti-LKM1,3]),  
• C3, C4 and CH50,  
• Acute viral hepatitis,  
o Serologies for acute hepatitis A and E (IgM);  
o PCR for HCV, hepatitis E (stool and blood),  
o Cytomegalovirus (CMV), PCR 


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o Epstein-Barr virus (EBV), PCR  
o Herpes simplex viruses 1 and 2 (HSV), PCR  
• Cholestasis work up with a Doppler US of the liver   
• Review of pre-existing hepatic disease (excluding HBV)  
• Review of concomitant medication(s), or herbal medications and substances known to 
be hepatotoxic, tests for alcohol and acetaminophen and drugs of abuse, if indicated 
• Ultrasound of the liver should be performed, including doppler, for subjects with a 
bilirubin level greater than 1.5 times baseline  
• If clinically feasible, a liver biopsy should be performed.  
o When a percutaneous biopsy is contraindicated, a transjugular biopsy may be 
discussed. 
• Liver and chemistry labs should be performed weekly (minimally include ALT, AST, 
bilirubin, INR, alkaline phosphatases and gamma-GT) until the bilirubin returns to 
baseline value. 
• HBV DNA and HDV RNA should be monitored weekly until Bili < 1.5 × ULN 
• 5 ml of serum plus 5 ml of plasma should be collected for possible later biomarker 
analysis  
It is preferable that all labs are processed at the designated Central Lab but it is understood 
that in some instances labs may be drawn at a local lab.  Local labs should be used only after 
consultation with the medical monitor.   
Subjects with a 4× increase in baseline GGT, ALT/AST or alkaline phosphatases or > Bili 
1.5 mg/dL, direct Bilirubin >0.6 (if Gilbert Syndrome is present), may be prescribed 
ursodeoxycholic acid for “liver protection”. 
All confirmed occurrences of potential possible medication related liver injury should be 
reported as Serious Adverse Events (SAE) and result in immediate patient discontinuation 
from study drug as defined above.  However, in cases where no prior evidence of advanced 
hepatic fibrosis or alteration of the hepatic synthetic function exist (normal serum albumin, 
INR, platelet count > 100,000/mm3) dose continuation or reduction should be discussed with 
the Sponsor or designated medical monitor. Tenofovir DF or entecavir for treatment of 
hepatitis B should be maintained. 
Table 3: 
Lambda Dose Reduction Dosages 
Assigned 
Treatment 
Starting Dose 
First Dose Reduction 
(DR1) 
Second Dose Reduction 
(DR2) 
Dose (µg) 
Dose (µg) 
Dose (µg) 
Lambda 
180 
120 
80 
Lambda 
120 
80 
80 
Note: For patients in the 120 µg group, the second DR level is the same as the first (80 µg/week).  
 
 


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Table 4: 
Guidelines for Treatment Interruption or Discontinuation and Dose 
Modification 
Toxicity 
Management, Monitoring, and Dose Modification 
Discontinuation of Drug 
 
Immediate 
Actions/Resolution 
First Recurrence 
 
Adverse Events 
 
 
 
AE ≥ Grade 3, considered at 
least possibly related to study 
drug and clinically significant, 
and no specific guidance given 
below 
Interrupt dosing and 
monitor weekly 
 
Resolution: If event 
resolves to ≤ Grade 1 or 
baseline value, restart 
dosing at DR1 
If AE recurs at DR1, 
interrupt dosing and 
monitor weekly 
 
Resolution: If event 
resolves again to AE 
≤ Grade 1 or baseline value, 
restart dosing at DR2 
If event does not resolve in 
2 weeks (missed 
2 consecutive doses of 
drug) 
or 
If event recurs at DR2, 
discontinue drug 
 
 
AE ≥ Grade 3, considered at 
least possibly related to study 
drug and not clinically 
significant, and no specific 
guidance given below  
Discuss with medical 
monitor. 
 
 
Not all Grade 3 AEs will 
require dose modification. 
 
Depression 
See Table 5 and CTCAE 
neurologic definitions for 
mild/moderate/severe 
depression 
 
 
New ocular symptoms: New 
decrease or loss of vision or 
other clinically significant ocular 
sign or symptom 
Interrupt dosing. 
 
Obtain complete eye 
examination performed by 
an ophthalmologist.  
 
Discuss further 
management with the 
medical monitor prior to 
restarting therapy. 
 
 
Hematologic abnormalities 
 
 
 
ANC 
 
 
 
 
≥750/mm3 
Maintain dose 
 
 
 
≥500/mm3 and < 750/mm3 
Reduce dose to DR1 and 
monitor weekly 
 
 
 
< 500/mm3 
Interrupt dosing 
  
Resolution: If ANC 
> 1000/mm3, restart dosing 
at DR2 
 
If event does not resolve in 
4 weeks (missed 4 
consecutive doses) 
or  
If event recurs (confirmed) 
at DR2, discontinue drug  
Platelets 
 
 
 
 
< 50,000 
Reduce dose to DR2 
 
 
 
< 25,000 
 
 
If event is confirmed, 
discontinue drug 


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Toxicity 
Management, Monitoring, and Dose Modification 
Discontinuation of Drug 
Hepatobiliary abnormalities 
 
For Stage IV liver disease, 
cirrhosis 
 
 
 
ALT/AST  
≥5 × ULN and < 10 × ULN 
Monitor per protocol 
 
 
ALT/AST 
≥10 × ULN and < 15 × ULN  
 
and 
TBILI and/or INR < Grade 2 
Continue dosing 
  
Monitor ALT, AST, TBILI, 
DB, albumin, PT/INR 
weekly 
 
If ALT/AST <10×ULN, 
stop weekly monitoring 
 
 
ALT (or AST) ≥15 × ULN 
 
and  
TBILI and/or INR < Grade 2 
Interrupt dosing 
  
Monitor ALT, AST, TBILI, 
DB, albumin, PT/INR 
weekly 
 
Resolution: If ALT/AST 
<10×ULN, stop weekly 
monitoring and restart 
dosing at DR1 
If event recurs at DR1, 
interrupt dosing and 
monitor weekly 
 
Resolution: If ALT/AST 
<10×ULN, stop weekly 
monitoring and restart 
dosing at DR2 
If event does not resolve in 
4 weeks (missed 4 
consecutive doses) 
or 
If event recurs (confirmed) 
at DR2, discontinue drug 
ALT (or AST) ≥5×ULN  
 
and 
TBILI and/or INR ≥Grade 2 
 
 
If confirmed, discontinue 
druga 
TBILI > 2.5 × ULN 
 
and 
DB > 3 × ULN 
Interrupt dosing 
 
Monitor ALT, AST, AP, 
TBILI, DB, albumin, 
PT/INR weekly 
 
Resolution: If TBILI ≤1.5 
×ULN, stop weekly 
monitoring and restart 
dosing at DR1 
If event recurs at DR1, 
interrupt dosing and 
monitor again 
 
Resolution: If TBILI ≤1.5 × 
ULN, restart dosing at DR2 
If event does not resolve in 
2 weeks (missed 2 
consecutive doses)  
or  
If event recurs (confirmed) 
at DR2, discontinue drug 


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Toxicity 
Management, Monitoring, and Dose Modification 
Discontinuation of Drug 
A potential treatment related 
liver event as defined below that 
would result in the labeling of 
this as a “serious medication 
related liver event” would have 
to satisfy all 5 of the conditions 
below: 
1. 
ALT > 10× ULN 
2. 
ALT > 5× baseline or 
nadir, whichever is 
lower 
3. 
Total bilirubin > 5 × 
ULN  
4. 
INR > 1.5 × ULN 
confirmed with local 
confirmation 
5. 
No other immediately 
apparent possible 
causes of ALT 
elevation and 
hyperbilirubinemia, 
including, but not 
limited to, acute viral 
hepatitis, obstructive 
jaundice, preexisting 
hepatic disease 
excluding HBV, or the 
administration of other 
drug(s), or herbal 
medications and 
substances known to 
be hepatotoxic. 
 
 
If confirmed, and no other 
immediately apparent 
possible causesa, 
discontinue drug and report 
as potential SAE 
(Section 9.3.4.1)  
Renal function abnormalities 
 
 
 
Creatinine clearance 
< 50 mL/min 
 
 
Discontinue drug 
Note:  
Stage IV disease: keep current stopping rules if kPa≥ 11.5 at Baseline as above 
For patients with: 
Stage 0-III disease: ≤ 11.4 kPa at Baseline, new dose interruptions, then reductions then discontinuations is sequence as 
provided; 
• 
In patients with  
o 
Alb >3.5 g/dL AND 
o 
INR <1.5 AND 
o 
Total Bilirubin <3 mg/dL 
• 
Then 
o 
Dose interruption 1 at ALT >20× ULN (>1000 IU/mL) 
o 
Restart at next lower lambda dose when ALT < 10x ULN (<500 IU/mL) 
o 
Next dose interruption 2 at ALT 20× ULN (>1000 IU/mL) 
o 
Restart at next lower lambda dose when ALT < 10× ULN (<500 IU/mL) or stop if at 80 ugm dose if 
bilirubin 3.0 mg/dL or greater 
All dosing discontinuations are permanent. Laboratory abnormalities that result in discontinuation must be reported to the 
medical monitor.  
AE, adverse event; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; 
CTCAE, Common Terminology Criteria for Adverse Events; DB, direct bilirubin; DILI, drug-induced liver injury; PT, 
prothrombin time; SAE, serious adverse event; TBILI, total bilirubin; ULN, upper limit of the normal range 
a Including, but not limited to, acute viral hepatitis, cholestasis, preexisting hepatic disease excluding HBV, or the 
administration of other drug(s), or herbal medications and substances known to be hepatotoxic 
 


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Table 5 lists the guidelines to be used for patients who experience depression or other 
neuropsychiatric disorders during the study. In addition to these recommendations, additional 
drug therapies such as antidepressants can be provided at the discretion of the investigator.  
Table 5: 
Depression or Other Neuropsychiatric Disorders: Guidelines for 
Treatment Interruption or Discontinuation or Dose Modifications  
Severity 
Initial Management 
(4–8 weeks) 
Subsequent Symptoms on Regular Evaluation 
Dose Modification 
Visit 
Schedule 
Symptoms 
Remain Stable 
Symptoms 
Improve 
Symptoms 
 Worsen 
Mild 
No change 
Evaluate weekly 
(visit and/or phone) 
Continue weekly 
visit schedule 
Resume normal 
visit schedule 
Go to moderate or 
severe row of this 
table. 
Moderate 
Decrease dose to 
1st dose reduction 
level (or if 
necessary, to 2nd 
dose reduction 
level) 
Evaluate weekly 
(visit at least every 
2 weeks) 
Consider 
psychiatric 
consultation. 
Continue reduced 
dosing. 
If symptoms 
stable for 4 weeks, 
resume normal 
visit schedule. 
Continue reduced 
dosing. 
Go to severe row 
of this table. 
Severe 
Discontinue dosing. 
Obtain immediate 
psychiatric 
consultation. 
Initiate/continue psychiatric therapy. 
Note: Severity based on definitions in the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(CTCAE 2010)  
 
Additional requirements regarding dose interruption, reduction, or discontinuation are listed 
below.  
For all events, at the investigator’s discretion, patients should be evaluated for other non-
drug-related causes of the event. 
Dose interruption  
• Doses of study drug that are withheld during dose interruption are not to be 
replaced (ie, maximum duration of the treatment period is 48 weeks for all 
patients). 
• The laboratory abnormality or AE that led to dosing interruption will be 
monitored weekly until resolution or discontinuation of study drug. 
• During dose interruption, the patient will maintain the same visit and assessment 
schedule. 
– If HDV RNA testing was not done while study drug was interrupted, an 
unscheduled HDV RNA should be done prior to restarting study drug. 
Dose reductions 
• Following a dose reduction, the dose should NOT be re-escalated. 
• Up to 2 dose reductions will be allowed; events that do not resolve despite 2 dose 
reductions will result in the patient discontinuing study drug.  


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Discontinuations 
• If a laboratory abnormality requires drug discontinuation, the laboratory value 
must be confirmed within 72 hours, and the medical monitor must be informed. 
• If study drug is discontinued based on the above recommendations, the patient 
will be classified as having a treatment-limiting toxicity (TLT). Events meeting 
this criterion must be reported to the sponsor within 2 business days; these events 
will be reviewed and validated by the sponsor for a final determination.  
5.4.4 
Missed Doses 
Patients will be instructed to self-administer Lambda once a week in the evening. If a dosing 
window (±1 day) is missed, the patient should skip the dose completely.  
If a patient misses 4 consecutive Lambda doses, the patient will be discontinued from the 
study. 
5.5 
Treatment Compliance 
At the initial study visit on Day 1, patients will be given a patient diary in which to record 
study drug dosing administrations (dates and times of both Lambda and NUC doses) and 
patient-reported outcomes. A sample diary is included in Appendix 3. Patients will be 
instructed to bring their patient diary when they return to the clinic for their next study visit 
during the treatment period. Adherence with the prescribed regimen for each study drug 
(Lambda and NUC) will be measured using diary information. 
Patients will be reminded to record all drug administrations in the patient diary at each 
applicable study visit (from Day 1 through the Week 44 visit for study drug, and from Day 1 
through the Week 68 penultimate follow-up visit for NUC).  
5.6 
Treatment Packaging and Labeling 
Lambda will be supplied in RTU syringes. Each box of syringes will be labeled for use in an 
open-label study; label information will include protocol, sponsor, contents, storage 
conditions, investigational caution statement, and other information as needed. Each box will 
contain syringes for a 4-week supply of study drug. The number of syringes provided will 
depend on the interval to the next study visit. 
5.7 
Treatment Storage and Retention at Study Site 
Lambda needs to be stored at 2°C to 8°C (35.6°F to 46.4°F). Patients will be provided with 
cooler bags and cool packs at baseline, which should be brought back for each study visit. 
RTU syringes containing Lambda must not be frozen or shaken; they should be protected 
from light. The product storage manager should ensure that the study drug is stored in 
accordance with the environmental conditions (temperature, light, and humidity) as 
determined by the sponsor. If concerns regarding the quality or appearance of the study 
drug arise, the study drug should not be dispensed and the sponsor should be contacted 
immediately. 


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The investigational product should be stored in a secure area according to local regulations. It 
is the responsibility of the investigator to ensure that investigational product is only 
dispensed to study patients. The investigational product must be dispensed only from official 
study sites by authorized personnel according to local regulations. 
Dispensing instruction will be provided in a study manual. 
5.8 
Prior and Concomitant Therapies 
All prior medications taken within 28 days before screening and all concomitant medications 
taken during the study (from Day 1 after the first dose of study drug is administered until the 
last study follow-up visit at Week 72) will be recorded in the eCRF. All prior treatments 
administered for HDV and HBV infections will be recorded on the eCRF. 
5.8.1 
Prior Therapies 
Patients will not be enrolled in the study if they have taken any of the following medications 
within the time frames specified below: 
• Any investigational product within 1 month before screening 
• Systemic immunosuppressive therapy within 3 months before screening 
• An immunomodulatory agent; alpha IFN (IFN alfa-2a or IFN alfa-2b, or 
pegylated IFN alfa-2a or alfa-2b; cytotoxic agent, or systemic corticosteroids 
within 12 months before screening 
• Telbivudine (Tyzeka or Sebivo) within 3 months before screening 
• Blood products within 1 month before study randomization (Day 1) 
• Hematologic growth factors within 1 month before study randomization (Day 1) 
• Systemic antibiotics, antifungals, or antivirals for treatment of active infection 
other than HBV within 14 days of study randomization (Day 1) 
 
In addition, patients with the following drug therapy history must be approved by the medical 
monitor before enrollment: 
• Long-term treatment (>2 weeks) with agents that have a high risk for 
nephrotoxicity or hepatotoxicity 
5.8.2 
Concomitant Therapies 
All prescription and over-the counter medications including herbal products taken during the 
study conduct must be approved by the study investigator.  
5.8.2.1 
Nucleos(t)ide Analog Medication 
Patients will be required to take a NUC from baseline (Day 1) until the end of the study to 
protect them in the case that HDV suppression may lead to HBV flare. NUC therapy will 
continue through the final follow-up visit, regardless of any Lambda dose interruptions, 
reductions, or discontinuation. 


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A NUC will be chosen for each patient at the baseline visit using the scheme shown in 
Table 6. For patients not currently taking a NUC at screening, TDF 300 mg/day will be 
prescribed. Patients taking telbivudine (Tyzeka or Sebivo) will not be permitted to enroll. If 
the patient is already taking ETV (Baraclude) 0.5 mg/day, that treatment will be continued. If 
the patient is already taking any other NUC (not ETV, TDF, or telbivudine) and has a 
documented history of at least 6 months of undetectable HBV DNA, the patient will continue 
that medication at the same dose. 
Table 6: 
Choice of NUC Therapy to Be Taken During Study Conduct 
NUC at Screening 
Action Taken at Baseline Visit 
None 
Start TDF (start ETV if TDF is contraindicated) 
Telbivudine 
Screen failure 
ETV 
Continue ETV 
Any other NUC 
HBV undetectable ≥6 months? 
 Yes: Continue the NUC 
 No: Switch to TDF (switch to ETV if TDF is contraindicated) 
During the study, the investigator can change the NUC medication or dosage if medically 
warranted in a particular patient. The investigator will use clinical judgment and follow the 
applicable NUC prescribing label. The TDF prescribing information can be obtained at 
http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/viread/viread_pi.pdf. 
The ETV prescribing information can be found at 
http://www.hivandhepatitis.com/hep_b/treatment/Baraclude%20PI.pdf. 
5.8.2.2 
Prohibited Medications 
The following concomitant medications are prohibited while the patient is receiving study 
drug: 
•
Any hematopoietic growth factor including granulocyte colony-stimulating factor
(G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF),
pegylated G-CSF, erythropoietin, darbepoetin, eltrombopag, romiplostim, or
oprelvekin
•
Except the prescribed concomitant NUC, any other medications with known or
potential anti-HBV activity, including any other IFNs or other HBV NUCs
•
Heparin or Coumadin
•
Drugs known to prolong the PR or QT interval
In addition, patients taking the following concomitant drug therapies must be approved by 
the medical monitor: 
•
Long-term treatment (> 2 weeks) with agents that have a high risk for
nephrotoxicity or hepatotoxicity
5.8.2.3 
Other Restrictions and Precautions 
Patients who enter the study taking concomitant medications with safety profiles that include 
risks commonly seen with IFN therapy (eg, hematologic, liver, central nervous system 
[CNS]) should be on stable doses of those medications for at least 4 weeks prior to the first 


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dose of study drug. If the patient is on chronic medication, a consistent dosing schedule is 
recommended for the duration of this study, if medically possible. 
Male patients must refrain from sperm donation for 90 days after receiving the last dose of 
study drug. 


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6 
STUDY PROCEDURES AND ASSESSMENTS 
All study procedures and assessments are shown by visit in Appendix 1. 
6.1 
Informed Consent 
Written informed consent must be obtained at screening before initiating any study-mandated 
procedures. See Section 11.4 for additional information regarding informed consent. 
6.2 
Demographics 
At screening, patient demographic (eg, age, sex, race, and ethnicity) and baseline 
characteristics data will be collected. 
6.3 
Medical History 
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.  
6.4 
Retinal Examination 
Retinal examinations will be performed at screening unless the patient has a document record 
of a retinal examination within 1 year before screening, and at Week 48.  
For the screening evaluation only, if the patient has diabetes, hypertension, or other risk 
factors for retinal disease, the retinal examination has to be performed by a licensed ocular 
specialist; for all other patients, the study investigator or a licensed ocular specialist can 
perform the retinal examination. The Week 48 retinal examination can be performed by the 
study investigator in all cases. 
6.5 
Baseline Virology Tests 
Blood samples will be collected at baseline (Day 1) for serum HDV genotypic analysis to 
determine HDV subtypes (1–8) and to understand the natural polymorphisms of HDV. 
6.6 
Inclusion/Exclusion Criteria 
At the screening visit, patients will be interviewed to determine if they meet all of the 
inclusion criteria (Section 4.1) and none of the exclusion criteria (Section 4.2). Prior to 
randomization at baseline (Day 1), patients will be rechecked to be sure that they meet study 
entry criteria. 
6.6.1 
Drug and Alcohol Testing 
At screening, a blood sample will be collected for blood ethanol testing and a urine sample 
will be collected for drugs of abuse testing.  
6.6.2 
Alpha Fetoprotein Screening Test 
In addition to the standard screening blood samples (Section 6.11.2), a blood sample will be 
collected to measure alpha fetoprotein. 


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6.6.3 
Abdominal Imaging 
Abdominal imaging (ultrasound, magnetic resonance imaging [MRI], or computed 
tomography [CT]) will be performed at screening if the patient does not have abdominal 
imaging documentation obtained ≤6 months before screening. 
6.7 
Pregnancy Testing 
For women of childbearing potential (see Section 4.1, Inclusion Criterion 8), a blood sample 
will be collected for a serum hCG test at screening.  
Urine samples will be collected for a urine hCG test at all subsequent visits from baseline 
through follow-up (except the Week 1 visit) in women of childbearing potential. If a urine 
pregnancy test is found to be positive, it will be confirmed immediately with a serum 
pregnancy test. 
6.8 
Study Enrollment 
Patients who meet all of the inclusion criteria and none of the exclusion criteria during the 
screening period and at baseline (Day 1) will be enrolled in the study. Refer to Section 5.2.1 
for the method of assigning patients to treatment groups. 
A screen failure is defined as a patient who has signed the ICF, does not meet all the entry 
criteria as outlined in this protocol, and has not been randomized or received study drug. A 
screening log will be maintained by the investigator or designee, indicating the reason for the 
screen failure. 
6.9 
Study Treatment Dispensing 
A designated member of the study staff will dispense study drug to the patient at each visit 
from baseline (Day 1) through the Week 44 visit based on the treatment assignment and any 
required dose reductions as described in Section 5.4.3. 
6.9.1 
Anti-HBV Nucleos(t)ide Analog Dispensing 
At baseline, the choice of NUC is made for a given patient using the rules specified in 
Section 5.8.2.1.  
If the patient will start a NUC or will change the NUC medication at baseline, the appropriate 
NUC will be dispensed to patients at each study visit from baseline (Day 1) through the 
penultimate follow-up visit at Week 68. Otherwise, the patient will continue his or her 
existing NUC prescription over the same time period. 
6.10 Pharmacodynamics/Efficacy Assessments 
6.10.1 
Molecular and Serologic Tests 
6.10.1.1 
Hepatitis D Virus 
A blood sample will be collected at screening for the HDV serology test. 


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Blood samples will be collected for HDV RNA analysis at all visits from screening though 
the follow-up period including the supplemental test approximately 48 weeks post treatment 
for available patients. 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 HDV GT-1, -2, -5, -6, -7, and -8, applying probes and primers 
specific for a subsequence of the hepatitis delta antigen. The assay has a lower limit of 
quantitation (LLOQ) of 14 IU/mL based on calibrated standards using a reference HDV 
GT-1 positive serum. 
6.10.1.2 
Hepatitis B Virus 
HBV DNA 
Blood samples will be collected for HBV DNA analysis at screening, baseline (Day 1), and 
all visits starting with Week 4 including all follow-up visits.  
HBV DNA will be analysed using the Aptima HBV Quant DX assay via the fully automated 
Hologic Panther system.  Hologic have determined the limit of detection for the Aptima HBV 
assay to be 5.58 IU/ml in plasma and 4.29 IU/ml in serum. This was determined using the 3rd 
WHO international standard and the quantification limit to be 10 IU/ml across HBV 
genotypes A, B, C, D, E, F, G and H. The upper limit of quantification is 109 IU/ml. The 
assay is reported as Not detected, detected <10 IU/ml, or a quantitative result between 10 and 
109 IU/ml, for samples over the upper limit, repeat testing will be done at a 1:100 dilution to 
find the actual value. 
 
If HBV DNA is detectable in the screening sample, a viral genotype analysis will be 
performed. 
HBsAg, HBsAb, HBeAg, HBeAb 
Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B 
envelope antigen (HBeAg), and hepatitis B envelope antibody (HBeAb) levels may be 
important to indicate seroconversion or disease course. 
HBsAg: Blood samples will be obtained for quantitative measurement of HBsAg (qHBsAg) 
at screening, baseline (Day 1), and all visits starting with Week 4 including all follow-up 
visits. 
HBsAb: A blood sample will be obtained for measurement of HBsAb at screening, baseline 
(Day 1), and at the Week 48 and 72 visits. 
HBeAg and HBeAb: Blood samples will be obtained for measurement of HBeAg and 
HBeAb at screening, baseline (Day 1), at the Week 24 and 48 visits, and at the Week 60 and 
72 visits in the follow-up period.  
6.10.1.3 
Hepatitis C  
A blood sample will be obtaining for HCV serology testing at screening. 


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6.10.1.4 
HIV 
A blood sample will be obtaining for HIV serology testing at screening. 
6.10.2 
Fibroscan 
A Fibroscan will be performed at screening, at the end of treatment (Week 48 visit), and at 
the end of the study (Week 72 visit) to measure liver stiffness. Patients must fast for at least 
3 hours before the Fibroscan is performed. Ten stiffness measurements will be obtained, each 
by pressing the probe in between the ribs; a pressure value (in kPa) is read off the instrument 
and recorded on the eCFR. A standard M probe will be used for patients with BMI 
≤30 kg/m2, and an XL probe will be used for patients with BMI >30 kg/m2. 
6.11 Safety Assessments 
6.11.1 
Adverse Events 
Information on adverse events (AEs) will be collected at any time in the study from the 
baseline visit (Day 1) through the follow-up visit. In addition, patients will be asked to 
complete a patient-reported outcomes diary every morning starting on Day 2 through the 
EOFU specifically to record any flu-like symptoms (headache, chills, fever, joint pains, or 
muscle pains) and injection-site reaction symptoms (pain, itching, tenderness, redness, and 
swelling). See Section 9 for a complete description of AE reporting. 
6.11.2 
Clinical Laboratory Tests 
Blood samples will be collected for clinical laboratory tests (hematology, coagulation, 
thyroid panel, and clinical chemistry) at screening, baseline (Day 1) and every subsequent 
visit during the treatment and follow-up periods. Urine samples will be collected for 
urinalysis at screening, baseline (Day 1), and at the Week 8, 16, 24, 32, 40, and 48 visits in 
the treatment period and the Week 60 and 72 visits in the follow-up period including the 
supplemental test approximately 48 weeks post treatment for available patients. Safety 
laboratory analytes are listed in Table 7. All samples will be sent to the central laboratory for 
analysis. Additional information on sample collection and processing can be found in the 
study laboratory manual.  
If any test returns an abnormal result, the test will be repeated at the subsequent visit.  


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Table 7: 
Serum and Blood Chemistry Laboratory Tests 
Test Category 
Hematology 
Clinical Chemistry 
Hemoglobin 
Alanine aminotransferase (ALT) 
Hematocrit 
Albumin 
Erythrocyte count (red blood cell) 
Alkaline phosphatase (ALP) 
Mean corpuscular volume (MCV) 
Amylase 
Mean corpuscular hemoglobin (MCH) 
Aspartate aminotransferase (AST) 
Mean corpuscular hemoglobin concentration (MCHC) 
Bicarbonate 
Leukocytes (WBCs) 
Bilirubin (direct, indirect, and total) 
Neutrophils, segmented 
Blood urea nitrogen (BUN) 
Lymphocytes 
Calcium 
Monocytes 
Chloride 
Eosinophils 
Cholesterol 
Basophils 
Creatine kinase (CK) 
Platelets 
Creatinine; calculate creatinine clearance 
 
Gamma-glutamyl transferase (GGT) 
Coagulation 
Globulin 
Prothrombin time (PT) 
Glucose, nonfasting 
Fibrinogen (if > Grade 2, do activated partial 
thromboplastin time [APTT]) 
Lactate dehydrogenase (LDH) 
INR 
Magnesium 
Thyroid Panel 
Phosphorus 
TSH 
Potassium 
Free thyroxine (free T4) 
Sodium 
Total or free triiodothyronine (total or free T3) 
Triglycerides 
Urinalysis 
Total protein 
Specific gravity 
Uric acid 
Bilirubin  
Additional Screening Tests 
Glucose 
Alpha fetoprotein 
pH 
 
Blood 
 
Ketones 
 
Protein  
 
Urobilinogen 
 
Nitrite 
 
Microscopic examination of sediment 
 
 
6.11.3 
Vital Signs 
Vital signs (blood pressure [BP], heart rate, respiratory rate, and body temperature) will be 
measured at screening, baseline (Day 1), and all subsequent visits in the treatment and 
follow-up periods. BP and heart rate should be measured after the patient has been sitting for 
5 minutes.  
Body weight will also be measured at all visits (without shoes and heavy outerwear such as 
jackets and coats). 
Height will be measured at screening. Body mass index (BMI) will be calculated at 
screening.  


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6.11.4 
Physical Examination 
A comprehensive physical examination including all body systems pertinent to the patient 
will be performed at screening. Child-Turcotte-Pugh (CTP) scoring and an encephalopathy 
assessment will be included (see Appendix 2).  
Brief, directed physical examinations will be performed at every subsequent visit in the 
treatment and follow-up periods; these will include the head, eyes, ears, nose, and throat 
(HEENT), heart, lungs, abdomen, and lower extremity.  
Any clinically significant abnormalities observed before Day 1 will be reported in the 
patient’s medical history. Any new clinically significant abnormality observed on or after 
Day 1 will be reported as an AE. 
6.11.5 
Electrocardiograms 
Twelve-lead serial ECGs will be performed at screening, baseline (Day 1), Week 4, 12, and 
48 after the patient has rested in a supine position for ≥5 minutes. All ECGs will be 
performed in triplicate (×3) 2 to 3 minutes apart, and 3 interpretable ECGS recordings (ie, 
without artifacts) should be obtained. (Single ECG recordings can be obtained at 
unscheduled time points if needed.) 
ECGs must be read by the investigator or a qualified designee, and the results recorded in the 
eCRF. On-treatment ECG results should be compared with the patient’s baseline ECG values 
as part of routine safety monitoring. All clinically relevant abnormalities will be reported as 
AEs.  ECG printouts will be maintained with the study records. 
6.11.6 
Concomitant Medications 
Information about the usage of concomitant medications will be recorded at each visit from 
screening through the end of the follow-up period.  
6.12 Exploratory Assessments 
6.12.1 
Immunologic Assessments 
6.12.1.1 
Genetic Biomarker Testing 
A blood sample will be collected at baseline (Day 1) for future exploratory polymorphism 
analysis, ie, to explore the relationship of host genotype (for Il28A, IL28B, IL29, IFNAR2, 
IL10RB genes) and response to Lambda (New Zealand and US only). 
6.12.1.2 
Immunogenicity Testing 
A blood sample will be collected for serum immunogenicity testing at baseline (Day 1), at 
the Week 1, 2, 4, 12, 24, 36, and 48 visits, and at the Week 60 and 72 visits in the follow-up 
period. This test will quantitate formation of Lambda antibodies over time. 
6.12.1.3 
Host Immune Response Biomarker Testing 
Blood samples will be collected at baseline (Day 1), at the Week 4, 12, 24, and 48 visits, and 
at the final follow-up visit at Week 72 for biomarker analysis. These tests will explore the 


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effect of Lambda on host immune responses to HDV (cell surface markers, cytokines, and 
chemokines) over time (New Zealand and US only). 
6.12.1.4 
Future Exploratory Assessments 
Blood samples will be collected for peripheral blood mononuclear cells (PBMCs) at baseline 
(Day 1) and at the Week 12, 24, and 48 visits and at the Week 72 follow-up visit for future 
analysis (New Zealand and US only). 
6.13 Viral Resistance Analysis 
If a patient experiences virologic failure, a blood sample will be collected for genotypic 
analysis of HDV.  
Virologic failure is defined as any of the following: 
• Serum HDV RNA increases at least 1.0 log above the nadir value on 2 consecutive 
visits in patients who are on Lambda treatment 
• Serum HDV RNA detectable by qPCR in patients who had undetectable HDV RNA 
during therapy (breakthrough) or during the follow-up period (relapse). 
• Serum HDV RNA less than 1 log reduced from the baseline value to the EOT value 
6.14 Early Termination 
Patients who discontinue from the study in the treatment period will be asked to return for an 
ET visit (Section 7.16) within 5 days of stopping study drug, and will continue in the follow-
up period with 6 monthly visits. Patients who discontinue from the study in the follow-up 
period will be encouraged to complete the 6 follow-up visits if possible. 
If a patient withdraws, all efforts should be made to complete and report the observations, 
particularly the follow-up examinations, as thoroughly as possible. The investigator should 
contact the patient either by telephone or through a personal visit, or a responsible relative 
should be contacted to determine as completely as possible the reason for the withdrawal. If 
the reason for removal of a patient from the study is an AE or an abnormal laboratory result, 
the principal scientific event or test will be recorded on the appropriate eCRF. If the patient is 
withdrawn from the study because of a treatment-limiting AE, thorough efforts should be 
made to clearly document the AE outcome. 


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7 
STUDY ACTIVITIES 
The study comprises 3 periods: the screening period, treatment period, and follow-up period. 
Patients will return to the clinic for enrollment, randomization, and dosing on Day 1 
(baseline), and again at Week 1, Week 4, and then every 4 weeks until the final end-of-
treatment (EOT) visit at Week 48. After patients complete (or discontinue) treatment, they 
will be encouraged to return for monthly follow-up visits for 6 months including the 
supplemental test approximately 48 weeks post treatment for available patients.  
Visit windows are ±5 days.  Specifically for the 48 week post treatment visit the visit 
window is anytime post week 48. 
In addition to these planned visits, unscheduled visits may be required if, in the opinion of 
the investigator, the clinical status of the patient warrants interim evaluation. 
7.1 
Screening Assessments (Day -27 to 0) 
At the start of the screening period, the site staff will register the patient and obtain a patient 
identification number (PID) using the EDC system and IWRS. 
Screening evaluations can occur at ≥1 visit within 4 weeks before Day 1, when the patient 
will be enrolled, randomized, and started on study drug. Patients may be rescreened a single 
time (for a total of 2 screens), 2 weeks after the initial screening, if it can be reasonably 
expected that study criteria will be met. However, beyond this, patients should be re-
evaluated only after consultation with the study team. 
One of the screening assessments, Fibroscan, is conducted when the patient is in a fasted 
state (no solid food for 3 hours). 
Following screening, the IWRS will be used to enroll and randomize a patient who meets all 
of the eligibility criteria. The EDC system will be used to register patients who do not meet 
the eligibility criteria as screen failures. 
The screening assessments are as follows: 
• Obtain informed consent 
• Review inclusion/exclusion criteria 
• Obtain medical history 
• Obtain demographics and baseline characteristics 
• Review prior and concomitant medications 
• Conduct retinal examination for patients without documentation of retinal exam 
≤ 1 year before screening. Must be performed by a licensed ocular specialist if 
patient has diabetes, hypertension, or other risk factors for retinal disease; 
otherwise, can be performed by study investigator or licensed ocular specialist. 
• Conduct Fibroscan after 3-hour fast 
• Conduct a complete physical examination 
• Measure vital signs 
• Obtain height and body weight; calculate BMI 


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• Perform 12-lead ECGs 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), serology tests 
(HDV, HCV, HIV, HBV including qHBsAg, HBsAb, HBeAg, and HBeAb), 
clinical laboratory tests (hematology, clinical chemistry, coagulation, thyroid 
panel), alpha-fetoprotein, drug test, alcohol test, serum pregnancy test (for female 
patients of childbearing potential) 
• Collect urine samples for clinical laboratory tests (urinalysis) 
• Abdominal imaging (ultrasound, MRI, or CT) if patient does not have prior 
documentation ≤6 months before screening. 
7.2 
Baseline Assessments (Day 1) 
• Review inclusion/exclusion criteria 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Perform 12-lead ECGs 
• Collect blood samples for HDV genotype, viral loads (HDV RNA, HBV DNA), 
qHBsAg, HBsAb, HBeAg, HBeAb, clinical laboratory tests (hematology, clinical 
chemistry, coagulation, thyroid panel), immunogenicity testing; for New Zealand 
and US sites the following should also be collected: immune biomarker testing, 
PBMCs, and polymorphism analysis  
• Collect urine samples for clinical laboratory tests (urinalysis), pregnancy test (for 
female patients of childbearing potential) 
• Record any AEs 
• Record concomitant medications 
• Enroll eligible patients and randomize to dose group 
• Administer first dose of study drug 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (for patients not continuing the same NUC 
therapy from before the study) 
• Distribute patient diary 
7.3 
Week 1 Assessments (Day 7 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 


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• Collect blood samples for viral load (HDV RNA), clinical laboratory tests 
(hematology, clinical chemistry, coagulation, thyroid panel), immunogenicity 
testing 
• Record any AEs 
• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.4 
Week 2 Assessments (Day 14 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral load (HDV RNA), clinical laboratory tests 
(hematology, clinical chemistry, coagulation, thyroid panel), immunogenicity 
testing 
• Record any AEs 
• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.5 
Week 4 Assessments (Day 28 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Perform 12-lead ECGs 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel), 
immunogenicity testing; for New Zealand and US sites the following should also 
be collected: immune biomarker testing  
• Collect urine sample for pregnancy test (for female patients of childbearing 
potential) 
• Record any AEs 
• Record concomitant medications 


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• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.6 
Week 8 Assessments (Day 56 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel) 
• Collect urine samples for clinical laboratory tests (urinalysis) and pregnancy test 
(for female patients of childbearing potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.7 
Week 12 Assessments (Day 84 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel), 
immunogenicity testing; for New Zealand and US sites the following should also 
be collected: immune biomarker testing and PBMCs 
• Collect urine sample for pregnancy test (for female patients of childbearing 
potential)  
• Perform 12-lead ECGs 
• Record any AEs 
• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 


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7.8 
Week 16 Assessments (Day 112 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel) 
• Collect urine samples for clinical laboratory tests (urinalysis) and pregnancy test 
(for female patients of childbearing potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.9 
Week 20 Assessments (Day 140 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel) 
• Collect urine sample for pregnancy test (for female patients of childbearing 
potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.10 Week 24 Assessments (Day 168 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 


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• Collect blood samples for viral load (HDV RNA, HBV DNA), qHBsAg, HBeAg, 
HBeAb, clinical laboratory tests (hematology, clinical chemistry, coagulation, 
thyroid panel), immunogenicity testing; for New Zealand and US sites the 
following should also be collected: immune biomarker testing and PBMCs 
• Collect urine samples for clinical laboratory tests (urinalysis) and pregnancy test 
(for female patients of childbearing potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.11 Week 28 Assessments (Day 196 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel) 
• Collect urine sample for pregnancy test (for female patients of childbearing 
potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.12 Week 32 Assessments (Day 224 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel) 
• Collect urine samples for clinical laboratory tests (urinalysis) and pregnancy test 
(for female patients of childbearing potential) 
• Record any AEs 


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• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.13 Week 36 Assessments (Day 252 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel), 
immunogenicity testing 
• Collect urine sample for pregnancy test (for female patients of childbearing 
potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.14 Week 40 Assessments (Day 280 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel) 
• Collect urine samples for clinical laboratory tests (urinalysis) and pregnancy test 
(for female patients of childbearing potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 


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7.15 Week 44 Assessments (Day 308 ±5) 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel) 
• Collect urine sample for pregnancy test (for female patients of childbearing 
potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense sufficient study drug to last until the next visit 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.16 Week 48 Assessments (EOT; Day 336 ±5) or Early Termination 
• Collect and review patient diary, assess compliance, record patient-reported 
outcomes 
• Conduct Fibroscan after 3-hour fast 
• Conduct retinal examination (unless patient discontinues early from the study 
before Week 12); this exam can be performed by the study investigator 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Perform 12-lead ECGs 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, HBsAb, 
HBeAg, HBeAb, clinical laboratory tests (hematology, clinical chemistry, 
coagulation, thyroid panel), immunogenicity testing; for New Zealand and US 
sites the following should also be collected: immune biomarker testing and 
PBMCs 
• Collect urine samples for clinical laboratory tests (urinalysis), pregnancy test (for 
female patients of childbearing potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 


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7.17 Follow-up Week 52 (FU1; Day 364 ±5) 
• Collect and review patient diary, assess NUC compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel) 
• Collect urine sample for pregnancy test (for female patients of childbearing 
potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense anti-HBV NUC medication (if applicable) 
• Distribute patient diary 
7.18 Follow-up Week 56 (FU2; Day 392 ±5) 
• Collect and review patient diary, assess NUC compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel) 
• Collect urine sample for pregnancy test (for female patients of childbearing 
potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense anti-HBV NUC medication 
• Distribute patient diary 
7.19 Follow-up Week 60 (FU3; Day 420 ±5) 
• Collect and review patient diary, assess NUC compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, 
HBeAg, HBeAb, clinical laboratory tests (hematology, clinical chemistry, 
coagulation, thyroid panel), immunogenicity testing 


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• Collect urine samples for clinical laboratory tests (urinalysis), pregnancy test (for 
female patients of childbearing potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense anti-HBV NUC medication 
• Distribute patient diary 
7.20 Follow-up Week 64 (FU4; Day 448 ±5) 
• Collect and review patient diary, assess NUC compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel) 
• Collect urine sample for pregnancy test (for female patients of childbearing 
potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense anti-HBV NUC medication 
• Distribute patient diary 
7.21 Follow-up Week 68 (FU5; Day 476 ±5) 
• Collect and review patient diary, assess NUC compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, clinical 
laboratory tests (hematology, clinical chemistry, coagulation, thyroid panel) 
• Collect urine sample for pregnancy test (for female patients of childbearing 
potential) 
• Record any AEs 
• Record concomitant medications 
• Dispense anti-HBV NUC medication 
• Distribute patient diary 


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7.22 Follow-up Week 72 (FU6; Day 504 ±5) (EOS) 
• Collect and review patient diary, assess NUC compliance, record patient-reported 
outcomes 
• Conduct a brief, directed physical examination 
• Measure vital signs 
• Measure body weight 
• Collect blood samples for viral loads (HDV RNA, HBV DNA), qHBsAg, HBsAb, 
HBeAg, HBeAb, clinical laboratory tests (hematology, clinical chemistry, 
coagulation, thyroid panel), immunogenicity testing; for New Zealand and US 
sites the following should also be collected: immune biomarker testing and 
PBMCs 
• Collect urine samples for clinical laboratory tests (urinalysis), pregnancy test (for 
female patients of childbearing potential) 
• Conduct Fibroscan after 3-hour fast 
• Record any AEs 
• Record concomitant medications 
7.23 Supplemental Testing Visit approximately 48 weeks post treatment 
• Collect blood samples for viral loads (HDV RNA), chemistry panel including 
ALT 
• Record concomitant medications related to HDV 
7.24 Unscheduled Visits 
Study visits not specified in the protocol may be scheduled at the discretion of the 
investigator. 


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8 
STATISTICAL ANALYSIS 
The objectives of this study are to evaluate the safety, tolerability, and PD/efficacy of 
Lambda treatment (120 or 180 µg/week SC) over the 48-week treatment period and 24-week 
follow-up period in patients with CHD infection. 
8.1 
Randomization and Treatment Assignment 
In this randomized, open-label, uncontrolled study, 40 patients will be randomized to receive 
either Lambda 120 or 180 µg/week in a 1:1 ratio. A block randomization will be used. 
8.2 
Determination of Sample Size 
A sample size of 40 was chosen to allow assessment of the safety, tolerability, and 
PD/efficacy of Lambda at 120 vs. 180 µg/week. The sample size was not formally calculated 
using power analysis. 
8.3 
Analysis Populations 
The modified intention-to-treat (MITT) population will consist of all patients who receive at 
least 80% of the total study drug dose throughout the entire 48-week treatment period and for 
whom HDV viral load data are available for the Day 1 (baseline) and end-of-treatment 
(Week 48) study visits. Patients who receive less than 80% of the dose on any given 
treatment day (eg, dose missed, interrupted, or reduced to DR1 or DR2) would be excluded. 
This population will be used for analysis of the primary PD/efficacy endpoints. 
The intention-to-treat (ITT) population will consist of all patients who receive at least 
1 postbaseline HDV RNA measurement. This population will be used for analysis of the 
secondary PD/efficacy endpoints. 
The safety population will consist of all patients who receive at least 1 dose of study drug. 
This population will be used for analysis of all safety endpoints. 
In each study population, patients will be analyzed according to the dose group to which they 
are randomized. 
8.4 
Hypothesis Testing 
No formal hypothesis testing will be performed in this study.  
8.5 
Study Endpoints 
The primary PD/efficacy endpoints are as follows: 
• Change from baseline in HDV viral load at Week 48 (EOT) 
• Change from baseline in HDV viral load at Week 72 (end of follow-up [EOFU]) 
 
Additional PD/efficacy endpoints include: 
• Proportion of patients with sustained viral response: HDV RNA below the lower 
limit of quantification (LLOQ) 12 weeks after EOT (SVR-12)  


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• Proportion of patients with sustained viral response: HDV RNA below the LLOQ 
24 weeks after EOT (SVR-24)  
• Proportion of patients with sustained viral response: HDV RNA below LLOQ 
approx. 48 weeks after EOT (SVR-48)  
• Proportion of patients with ALT > ULN at baseline who normalize ALT at 
approx. 48 weeks post-treatment 
• Change from baseline in HDV viral load 
• Change from baseline in HBV viral load 
• Change from baseline in HBsAg levels  
• Clearance of HBsAg 
• Change from baseline in Fibroscan results 
 
The safety endpoints are as follows: 
• Treatment-emergent AEs and SAEs 
• Treatment-emergent treatment-related AEs and SAEs 
• AEs leading to early discontinuation of study treatment 
• AEs leading to dose reduction 
• Treatment-emergent changes in clinical laboratory findings 
• Treatment-emergent changes in vital signs 
• Treatment-emergent changes in ECG findings 
• Treatment-emergent changes in physical examination results 
• Usage of concomitant medications during the study 
 
The exploratory endpoints will be provided in the statistical analysis report (SAP). 
8.6 
Analysis Plan 
8.6.1 
Demographic and Baseline Data 
Descriptive statistics will be used to summarize demographic and baseline patient 
characteristics. Continuous-scale variables (eg, age) will be summarized with mean, median, 
SD, quartiles, and minimum and maximum values. Categorical variables (eg, sex) will be 
summarized using patient counts and percentages.  
Baseline medical histories and preexisting 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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8.6.2 
Pharmacodynamics/Efficacy 
8.6.2.1 
Viral Loads and Serology 
Viral load and serology concentration data will be presented by dose group and time point in 
summary tabulations and by-patient listings. 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 HDV change from baseline, baseline will be defined as the 
geometric mean of the HDV RNA titer obtained at the screening and pretreatment baseline 
(Day 1) visits. The numbers and percentages of patients with 1 log reduction from baseline in 
viral load (HDV, HBV) will be summarized at each time point. The numbers and percentages 
of patients with reductions in viral load below the LLOQ and below the LOD will be 
summarized by dose group and time point. HBsAg clearance will be summarized as number 
and percentage of patients who are HBsAg reactive/nonreactive at each time point.  
Missing data will not be imputed. All summaries and figures will show the number of non-
missing data at each visit. 
8.6.2.2 
Fibroscan 
Fibroscan results in kPa will be summarized by dose group at each time point using summary 
statistics for absolute and change-from-baseline values and listed by patient. 
8.6.3 
Safety Analyses 
No inferential statistics are planned for safety data.  
8.6.3.1 
Adverse Events 
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.  
Summaries by dose group, system organ class, and preferred term will be provided for 
TEAEs (overall, by event severity and by the event’s relationship to Lambda treatment), 
treatment-emergent SAEs (overall and by the event's relationship to Lambda treatment), AEs 
that lead to early discontinuation, and AEs that lead to Lambda dose reduction.  
At each level of summation, patients will be counted only once for a given event, under the 
greatest severity and strongest study-drug relationship (as reported by the investigator). 
Events with missing severity will be classified as Grade 3; events with missing attribution 
will be classified as related to study drug. 
AEs will be listed by patient, along with information regarding onset, duration, severity, and 
relationship to study drug. SAEs and AEs that lead to early discontinuation will also be listed 
by patient.  
Posttreatment AEs will also be summarized and listed by patient. 


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Patient-reported Outcomes 
Patient-reported outcomes from the patient diaries (flu-like symptoms and injection-site 
reactions) will be summarized by event for each dose group and listed by patient. 
8.6.3.2 
Clinical Laboratory Test Results 
Clinical laboratory data will be summarized using descriptive statistics (mean, SD, median, 
and range) for actual and change-from-baseline values at each time point. Shift tables will be 
presented for baseline and highest postbaseline clinical laboratory values by Common 
Terminology Criteria for Adverse Events (CTCAE) grade for each dose group. 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 summarized 
and listed by patient. In addition, ALT, AST, total bilirubin, and AP values will be 
summarized by CTCAE grade for each dose group.  
8.6.3.3 
Vital Signs 
Vital sign data (actual values and change-from-baseline values) will be summarized by dose 
group at each time point and listed by patient. Body weight will be summarized by dose 
group at each time point and listed by patient. 
8.6.3.4 
Physical Examination Findings 
Full physical examination findings will be summarized by body system and listed by patient 
at screening. The subsequent limited examinations will not be summarized, but any clinically 
significant finding will be reported as an AE.  
8.6.3.5 
ECG Results 
ECG interval results will be calculated by averaging results from the 3 recordings at each 
time point. QT interval data will be corrected using Fridericia correction (ICH 2005). ECG 
interval data (actual values and change-from-baseline values) will be summarized by dose 
group for each time point using descriptive statistics and listed by patient. Clinical 
interpretations of ECG results will also be listed by patient. 
8.6.3.6 
Concomitant Medications 
A medication that was started or increased in dose after the first dose of study drug until 
28 days after the final dose of study drug will be considered a concomitant medication. 
Concomitant medications will be mapped to drug classes and generic terms in the World 
Health Organization Drug Dictionary Enhanced (WHO-DD Enhanced), then summarized by 
dose group for each time point. All medications will be listed by patient. 
Medications that are used within 28 days before screening will be considered prior 
medications; these will be summarized separately using WHO-DD Enhanced and listed by 
patient.  
8.6.4 
Exploratory Analyses 
The exploratory analyses will be described in the SAP. 


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8.6.4.1 
Immunologic Analyses 
Polymorphism Analysis 
IL-28B polymorphisms have been associated with response to therapy in patients infected 
with HCV and possibly in patients with HBV as well. Host DNA samples (peripheral blood 
cells)  will be collected from consenting patients to assess IL-28B polymorphisms and their 
correlation with HDV RNA responses (New Zealand and US only). 
Immunogenicity Analysis 
Serum samples will be stored for later analysis. The immunogenicity testing strategy will use 
a tiered approach that is designed to screen for binding antibodies, confirm antibody 
specificity, determine antibody titer, and assess the neutralizing potential of antibodies to 
Lambda in patient serum samples.  
Immune Biomarker Analysis 
Serum samples from select sites will be stored for later analysis. 
PBMC Analysis 
PBMC samples from select sites will be stored for later analysis. 
8.6.5 
Viral Resistance Analysis 
For resistance surveillance, genotypic analysis and sequencing of HDV from patients with 
virologic failure will be conducted. Virologic failure is defined in Section 6.13. 


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9 
SAFETY EVENTS DOCUMENTATION AND REPORTING 
9.1 
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 eCRF 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 IRB/IEC as required by local regulations and guidelines. The 
investigator is responsible for reporting the relationship to study drug for each 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. 
9.2 
Monitoring Safety Data During Study 
Safety results collected during the study (eg, AEs, laboratory test results, physical 
examination findings, ECGs) will be monitored on an ongoing basis by the medical monitor 
and the investigator. 
9.3 
Definitions of Types of Adverse Events 
9.3.1 
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. 
9.3.2 
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. 


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9.3.3 
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 include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death. 
9.3.4 
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 9.3.3) 
• 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. 
9.3.4.1 
Potential Treatment Related Liver Event  
A potential treatment related liver event as defined below that would result in the labeling of 
this as a “serious medication related liver event” would have to satisfy all 5 of the conditions 
below: 
• ALT > 10 × ULN 
• ALT > 5 × baseline or nadir, whichever is lower 
• Total bilirubin > 5 × ULN  
• INR > 1.5 × ULN confirmed with local confirmation 
• No other immediately apparent possible causes of ALT elevation and 
hyperbilirubinemia, including, but not limited to, acute viral hepatitis, obstructive 
jaundice, preexisting hepatic disease excluding HBV, or the administration of other 
drug(s), or herbal medications and substances known to be hepatotoxic. 
9.3.4.2 
Clinical Jaundice 
Any occurrence of clinical jaundice must be reported as an SAE in this study. 
9.3.5 
Unexpected Adverse Events 
An AE or suspected adverse reaction is considered ‘‘unexpected’’ if it meets any of the 
following criteria: 


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• It is not listed in the IB or is not listed at the specificity or severity that has been 
observed.  
• If an IB 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.  
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the IB referred only to elevated hepatic enzymes or hepatitis. Similarly, 
cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents.  
‘‘Unexpected,’’ as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the IB 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. 
9.4 
Adverse Event Classification 
9.4.1 
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 eCRF, the investigator will use the National Cancer 
Institute (NCI) CTCAE, Version 4.03 (CTCAE 2010). For events not listed in the CTCAE, 
the definitions from the CTCAE provided in Table 8 should be used to evaluate the grade of 
severity for the AE. 
Table 8: 
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: NCI CTCAE, Version 4.03 (CTCAE 2010) 
9.4.2 
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 eCRF, the investigator will 
use the terms and definitions provided in Table 9. For a particular AE, the investigator will 
assess the relationship to study drug (Lambda).  


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Table 9: 
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 
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  
 
9.5 
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 eCRF. Events occurring or worsening after administration of the first dose 
of study drug will be recorded on the AE eCRF. AEs that occur up to and including 28 days 
after administration of the last dose of study drug will be considered to be treatment 
emergent. Any AE that occurs more than 28 days after the last dose of study drug will be 
considered a posttreatment AE. 
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 eCRF 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 eCRF. 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 9.6.1. 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 9.4.2) to study 
drug and all SAEs will be followed until resolved or until a stable status has been achieved. 
9.5.1 
Study Drug Action Taken 
The action taken for each study drug should be classified according to the categories shown 
in Table 10. 
Table 10: 
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). 
9.5.2 
Outcome of Adverse Event 
The outcome should be classified according to the categories shown in Table 11. All AEs 
considered to be related (definitely or probably related, see Section 9.4.2) to study drug and 
all SAEs will be followed until resolved or until a stable status has been achieved. 
Table 11: 
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. eg, a patient lost to follow-up 
 


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9.6 
Reporting Serious Adverse Events 
9.6.1 
Reporting to Sponsor 
The SAE form must be completed within 1 day of the investigator becoming aware of the 
SAE. The completed SAE form should be emailed or faxed to Novella Clinical within 1 day 
(pvgsafety@novellaclinical.com) as follows: 
Country Name 
Telephone Number 
Fax Number 
United States 
1.866.758.2798 
1.866.761.1274 
Israel 
1.809.42.4626 
1.919.313.1412 
New Zealand 
0800.447.176 
0800.446.957 
Pakistan 
1.919.313.7111 
1.919.313.1412 
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 of the 
investigator becoming 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 the IB. The report must include an assessment of 
causality (see Section 9.4.2).  
For all SAEs, the investigator is obligated to obtain and provide information to the sponsor in 
accordance with the time frames 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 
eCRF. 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. 
9.6.2 
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 IRB/IEC of all SUSARs 
involving risk to patients. 
9.6.3 
Emergency Sponsor 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 : 


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David Apelian, MD, PhD, MBA 
Executive medical Officer 
Eiger BioPharmaceuticals, Inc. 
2155 Park Blvd. 
Palo Alto, CA 94306 USA 
Telephone: +1 203.415.5579 
Email address: dapelian@eigerbio.com  
9.7 
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. 
9.8 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. If a higher dose is taken, it is recommended that 
supportive measures be given until the drug clears.  


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10 DATA QUALITY CONTROL AND ASSURANCE 
10.1 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. 
QC 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 QC 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. 
10.2 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 and CRO 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 eCRFs 
• Compare entries in eCRFs 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 any 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 Code of Federal Regulations (CFR) 
Title 21, Parts 50, 56, and 312; EU Directive 2005/28/EC; and the ICH GCP guideline. 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. 
10.3 Data Management 
Study data will be handled according to the relevant SOPs of the data management and 
biostatistics departments of the sponsor or CRO. 
10.4 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. 
10.5 Data Handling and Recordkeeping 
10.5.1 
Case Report Form Completion 
eCRFs will be completed for each patient enrolled in the study.  
Only data for the procedures and assessments specified in this protocol should be submitted 
to Eiger on a eCRF. Additional procedures and assessments may be performed as part of 
standard of care; however, data for these assessments should remain in the patient’s medical 
record and should not be provided to Eiger, unless specifically requested from the sponsor. 
It is the investigator’s responsibility to ensure the accuracy, completeness, and timeliness of 
the data reported on the patient’s eCRF. Source documentation supporting the eCRF 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 eCRF according to SOP specifications. 
For patients who discontinue treatment or withdraw from the study, the eCRFs will be 
completed as much as possible, and the reason for the discontinuation or withdrawal clearly 
and concisely specified on the appropriate eCRF. 


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Data will be entered into the eCRF by site personnel using a secure, validated web-based 
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.  
10.5.2 
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. 
10.5.3 
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 eCRFs, 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 (at select sites only) 
analyses of polymorphisms that may impact drug response. 
10.6 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 confirmed by the monitor, 
the study site will dispose of and/or destroy all unused investigational product supplies, 
including empty containers, according to standard procedures. 


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11 ETHICAL AND LEGAL CONSIDERATIONS 
11.1 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 Food and Drug Administration [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 patient. For studies 
conducted under a United States IND application, the investigator will ensure that the basic 
principles of “Good Clinical Practice,” as outlined in the US 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 adherence to 21 CFR, 
Part 54 “Financial Disclosure by Clinical Investigators”. 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 1 year 
following completion of the study. Study completion is defined as the date that the last 
patient has completed the protocol-defined activities. 
11.2 Institutional Review Board/Independent Ethics Committee 
All IRBs/IECs will meet all FDA requirements governing IRBs (21 CFR Part 56 
“Institutional Review Boards”) and the EU requirements outlined in Directive 2001/20/EC. 
The protocol and ICFs that will be used must be approved by the IRB/IEC before the study is 
initiated; documentation of this approval (ie, a copy of the document showing IRB/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 IRB/IEC requirements include the 
following: 
• Submit to the IRB/IEC 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 


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• During the conduct of the study, submit timely and accurate progress reports to 
the IRB/IEC, if required, and request re-review of the study at least once a year 
• Report, in writing, to the IRB/IEC any SAEs that occur during the study or SAEs 
reported in other studies using Lambda, per local IRB/IEC regulations 
• Inform the IRB/IEC of any changes in the protocol and obtain documented 
IRB/IEC approval of the changes 
• Provide the IRB/IEC 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 
IRB/IEC 
11.3 Patient and Data Confidentiality 
Patient Data--The investigator must ensure that the patient’s confidentiality is maintained. 
All eCRFs, 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 eCRFs, 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, IRB/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, patient 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. 
11.4 Informed Consent 
The investigator or designee is responsible for the content of the ICF, but the content must be 
approved by the IRB/IEC 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 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 82 
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 IRB/IEC and the sponsor.  
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. The samples will retain only the patient’s randomization number so 
that they cannot be linked back to an individual patient. Because these tests are 
investigational and not yet validated, the patients will not receive their results. The samples 
will be kept for a minimum of 10 years or until the testing can be completed, whichever is 
longer. 
New Zealand only: samples will be obtained for future determination of active metabolite 
concentrations and host DNA analyses of polymorphisms that may impact the course of the 
disease and/or drug response. Genetic polymorphisms have been demonstrated to alter the 
development and clinical course of a number of different diseases. The purpose of assessing 
genetic polymorphisms in this study is to understand their potential role in the pathogenesis 
of HDV and in clinical outcomes. Some countries, municipalities, institutions, or local 
IRBs/IECs do not allow the study of genetic polymorphisms or RNA testing. Therefore, 
these assessments will only be conducted at institutions in which such research is in 
accordance with local law and institutional regulations. Patient participation in these 
assessments is voluntary, and declining participation will in no way influence eligibility for 
this study. This information will be outlined either in the ICF or in some cases in a separate 
genetic consent, depending on the local IRB requirements. 
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. 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 83 
11.5 Protocol Amendments 
Protocol amendments should be approved by the sponsor and the IRB/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 IRB/IEC, as 
appropriate. 
11.6 Delegation of Responsibilities of the Principal Investigator 
The principal investigator (PI) 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 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. 
11.7 Principal Investigator 
The PI will be responsible for signing the final clinical study report and assuring that the 
study has been executed according to the protocol. 
11.8 Compensation, Insurance, and Indemnity 
Information regarding compensation, insurance, and indemnity will be provided to the 
investigator in a separate document. 
11.9 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 the 
sponsor. 
11.10 Direct Access to Source Data 
The investigator/institution and study site will permit study-related monitoring, audits, 
IRB/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 eCRFs. 
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 eCRFs for 
patient enrolled in the study. 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
Confidential • Page 84 
12 REFERENCES 
Bonino F, Heermann KH, Rizzetto M, Gerlich WH. Hepatitis delta virus: Protein 
composition of delta antigen and its hepatitis B virus-derived envelope. J Virol 
1986;58(3):945-950. 
Chan HL, Ahn SH, Chang TT, Peng CY, Wong D, Coffin CS, et al. Peginterferon Lambda 
for the treatment of HBeAg-positive chronic hepatitis B: a randomized phase 2b study 
(LIRA-B). J Hepatol 2015. EPUB ahead of print. DOI:10.1016/j.jhep.2015.12.018. 
Cooksley WGE, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al. 
Peginterferon α-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive 
chronic hepatitis B. J Viral Hepat 2003;10:298-305. 
CTCAE. 2010. Common Terminology Criteria for Adverse Events, Version 4.03, 
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 
Fattovich G, Boscaro S, Noventa F, Pornaro E, Stenico D, Alberti A, et al. Influence of 
hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B. J Infect 
Dis 1987;155(5):931-935. 
Han Z, Nogusa S, Nicolas E, Balachandran S, Taylor J. Interferon impedes an early step of 
hepatitis delta virus infection. PLOS One. 2011;6(7):e22415. 
ICH. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential 
for non-antiarrhythmic drugs. E14. 12 May 2005. Accessed at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14
_Guideline.pdf  
Kotenko SV, Gallagher VV, Baurin A, Lewis-Antes A, Shen M, Shah NK, et al. IFN-
lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. 
Nat Immunol 2003;4(1):69-77. 
Lau DT, Doo E, Park Y, Kleiner DE, Schmid P, Kuhns MC, et al. Lamivudine for chronic 
delta hepatitis. Hepatology 1999;30(2):546-549. 
Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. 
Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic 
hepatitis B. N Engl J Med 2005;352(26):2682-2695. 
Makuwa M, Caron M, Souquiere S, Malonga-Mouelet G, Mahe A, Kazanji M. Prevalence 
and genetic diversity of hepatitis B and delta viruses in pregnant women in Gabon: Molecular 
evidence that hepatitis delta virus clade 8 originates from and is endemic in central Africa. J 
Clin Microbiol 2008;46(2):754-756. 
Niro GA, Ciancio A, Gaeta GB, Smedile A, Marrone A, Olivero A, et al. Pegylated 
interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis 
delta. Hepatology 2006;44(3):713-720. 
Rizzetto M. Hepatitis D: Virology, clinical and epidemiological aspects. Acta Gastroenterol 
Belg 2000;63(2):221-224. 


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Confidential • Page 85 
Rizzetto M, Canese MG, Arico S, Crivelli O, Trepo C, Bonino F, et al. Immunofluorescence 
detection of a new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus 
in liver and in serum in HBsAg carriers. Gut 1977;18(12):997-1003. 
Rizzetto M, Hoyer B, Canese MG, Shih JW, Purcell RH, Gerin JL. Delta agent: Association 
of delta antigen with hepatitis B surface antigen and RNA in delta-infected chimpanzees. 
Proc Natl Acad Sci U S A 1980;77(10):6124-6128. 
Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus 
replication. J Virol 2005;79(6):3851-3854. 
Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S Whitmore TE, et al. IL-28, 
IL-29 and their class II cytokine receptor IL-28R. Nat Immunol 2003;4:63-68. 
Uzunalimoglu O, Yurdaydin C, Cetinkaya H, Bozkaya H, Sahin T, Colakoglu S, et al. Risk 
factors for hepatocellular carcinoma in Turkey. Dig Dis Sci 2001;46(5):1022-1028. 
Wedemeyer H et al for the HIDIT-2 Study Group. Prolonged therapy of hepatitis delta for 
96 weeks with PEG-IFNa-2a plus tenofovir or placebo does not prevent HDV RNA relapse: 
The HIDIT-2 study. EASL, London UK, April 9-13 2014. 
Wedemeyer H, Boker KH, Pethig K, Petzold DR, Flemming P, Tillmann HL, et al. 
Famciclovir treatment of hepatitis B in heart transplant recipients: A prospective trial. 
Transplantation 1999;68(10):1503-1511.  
Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: 
Update and challenges ahead. Nat Rev Gastroenterol Hepatol 2010;7(1):31-40. 
Yurdaydin C, Bozkaya H, Gurel S, Tillmann HL, Aslan N, Okcu-Heper A, et al. Famciclovir 
treatment of chronic delta hepatitis. J Hepatol 2002;37(2):266-271. 
 
 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 86 
13 APPENDICES 
 
APPENDIX 1 
SCHEDULE OF ASSESSMENTS AND PROCEDURES .......................87 
APPENDIX 2 
HEPATIC SCREENING ASSESSMENTS ..............................................90 
APPENDIX 3 
SAMPLE PATIENT DOSING DIARY AND PATIENT-REPORTED 
OUTCOMES DIARY ................................................................................91 
 
 
 
 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 87 
 
APPENDIX 1 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
 
 
Treatment Period 
Follow-Up Period 
Visit 
SCR 
BL 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
(EOT/
ETa) 
FU1 
FU2 
FU3 
FU4 
FU5 
FU6/
EOS 
FU12/
EOS 
Week 
 
 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
96 
Day 
–27 to 
0 
1 
7±5 
14±5 
28±5 
56±5 
84±5 112±5 140±5 168±5 196±5 224±5 252±5 280±5 308±5 336±5 364±5 392±5 420±5 448±5 476±5 504±5 N/A 
Event/Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal imagingb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Retinal examc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
 
 
 
 
 
 
 
Blood sample: HDV genotype 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample: HBV genotype 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample: alpha fetoprotein 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples: Serology tests 
HDV, HCV, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
qHBsAg 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HBsAb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
HBeAg and HBeAb 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Blood samples: Exploratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Polymorphism analysis (New 
Zealand and US only) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 88 
 
 
Treatment Period 
Follow-Up Period 
Visit 
SCR 
BL 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
(EOT/
ETa) 
FU1 
FU2 
FU3 
FU4 
FU5 
FU6/
EOS 
FU12/
EOS 
Week 
 
 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
96 
Day 
–27 to 
0 
1 
7±5 
14±5 
28±5 
56±5 
84±5 112±5 140±5 168±5 196±5 224±5 252±5 280±5 308±5 336±5 364±5 392±5 420±5 448±5 476±5 504±5 N/A 
Immunogenicity testing 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Immune biomarker testing (New 
Zealand and US only) 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PBMC collection (New Zealand 
and US only) 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
12-lead ECGf 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Drug/alcohol lab tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testg 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Efficacy measures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample: HDV RNA 
(qPCR) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample: HBV DNA 
(COBAS) 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fibroscanh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Safety measures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weightk 
Xl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sample: clinical 
laboratory testsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine sample: urinalysis 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral resistance analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample: viral resistancen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 89 
 
 
Treatment Period 
Follow-Up Period 
Visit 
SCR 
BL 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
(EOT/
ETa) 
FU1 
FU2 
FU3 
FU4 
FU5 
FU6/
EOS 
FU12/
EOS 
Week 
 
 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
96 
Day 
–27 to 
0 
1 
7±5 
14±5 
28±5 
56±5 
84±5 112±5 140±5 168±5 196±5 224±5 252±5 280±5 308±5 336±5 364±5 392±5 420±5 448±5 476±5 504±5 N/A 
Study conduct: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment, randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense/administer study drug 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Dispense anti-HBV NUCo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Distribute/review patient diaryp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BL, baseline; EOS, end of study; EOT, end of treatment; ET, early termination; SCR, screening 
a All patients who discontinue the study early are asked to return within 5 days for an ET visit. All assessments done at the Week 48 visit will be done at the ET visit. Patients will be asked to return for 
6 follow-up visits after the ET visit. 
b Abdominal imaging (ultrasound, MRI, or CT) performed only if patient does not have abdominal imaging documentation ≤6 months before screening. 
c In patients without documented record of retinal exam within 1 year 
d Unless patient discontinued study before Week 12 
e HBV genotype test done only if HBV DNA is detectable at screening. 
f 12-lead ECGs performed after patient has rested in a supine position for ≥5 minutes. Triplicate ECGs obtained, each 2-3 minutes apart, and each interpretable (ie, without artifacts).  
g In female patients of childbearing potential: Human chorionic gonadotropin (hCG) pregnancy tests at screening (serum); all subsequent tests are in urine. If urine pregnancy test result is positive, 
confirm immediately with serum pregnancy test. 
h Patient must fast for 3 hours before Fibroscan. 
i Complete physical exam at screening including all body systems pertinent to the patient, including CTP scoring and encephalopathy assessment. Brief, directed physical exam at all other visits, 
including HEENT, heart, lungs, abdomen, and lower extremity. 
j Vital signs include heart rate, BP, respiratory rate, and body temperature. Measure BP and heart rate after the patient has been sitting for 5 minutes. 
k Measure body weight without shoes or heavy outerwear. 
l BMI will be calculated at screening. 
m Safety clinical laboratory tests include hematology, coagulation, thyroid panel, and clinical chemistry  
n Blood sample collected only if a patient experiences virologic failure or virologic rebound (see Section 6.13 for more information) 
o The appropriate NUC will be dispensed to all patients who are not already on the appropriate NUC at baseline. 
p Patient will document dosing of both study drug and NUC in the diary; compliance will be assessed for both drugs through EOT and also for NUCs in the follow-up period. 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
Confidential • Page 90 
APPENDIX 2 
HEPATIC SCREENING 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 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
Confidential • Page 91 
APPENDIX 3 
SAMPLE PATIENT DOSING DIARY AND PATIENT-
REPORTED OUTCOMES DIARY 
Please complete this diary every time you take a dose of Lambda or NUC. 
 Lambda study medication (injection) should be taken once a week on the same evening. 
NUC medication should be taken according to its prescribing information. 
Day 
Week 
Date of Dose 
(YYYY/MM/DD) 
Time of dosing 
 (24-hour clock) 
(HH:MM) 
Study 
Medication 
Check if 
Taken 
1 
1 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
Evening 
|__|__|:|__|__| 
LAMBDA 
□
2 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
3 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
4 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
5 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
6 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
7 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
Confidential • Page 92 
Day 
Week 
Date of Dose 
(YYYY/MM/DD) 
Time of dosing 
 (24-hour clock) 
(HH:MM) 
Study 
Medication 
Check if 
Taken 
8 
2 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
Evening 
|__|__|:|__|__| 
LAMBDA 
□
9 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
10 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
11 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
12 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
13 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□
14 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 93 
 
Day 
Week 
Date of Dose 
(YYYY/MM/DD) 
Time of dosing 
 (24-hour clock) 
(HH:MM) 
Study 
Medication 
 
Check if 
Taken 
15 
3 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□ 
Evening 
|__|__|:|__|__| 
LAMBDA 
□ 
16 
 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□ 
17 
 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□ 
18 
 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□ 
19 
 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□ 
20 
 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□ 
21 
 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□ 
 
 
 


Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 94 
 
Day 
Week 
Date of Dose 
(YYYY/MM/DD) 
Time of dosing 
 (24-hour clock) 
(HH:MM) 
Study 
Medication 
 
Check if 
Taken 
22 
4 
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Morning 
|__|__|:|__|__| 
NUC 
□ 
Evening 
|__|__|:|__|__| 
LAMBDA 
□ 
23 
 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
|__|__|:|__|__| 
NUC 
□ 
24 
 
|__|__|__|__|/|__|__|/|__|__| 
Morning 
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NUC 
□ 
25 
 
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Morning 
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NUC 
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26 
 
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Morning 
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NUC 
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27 
 
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Morning 
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Eiger BioPharmaceuticals, Inc. 
Lambda • Clinical Study Protocol EIG-LMD-001 Amendment 5 
 
Confidential • Page 95 
Please complete this diary every morning to record your symptoms, if you happen to have any of the 
symptoms listed below. You should also record any reactions you may have at the site of the last 
injection. 
 
PATIENT REPORTED OUTCOMES 
Have you experienced headache, chills, fever, joint pains, or 
muscle pains today?           
0 No    
1 Yes   
If Yes, select each Flu Like Symptom: 
 
1 Headache 
1 Chills 
1 Fever 
1 Joint Pain  
1 Muscle Pain 
 
Each symptom 
caused: 
0 No effect on daily activities 
1 Some effect on daily activities 
2 Significant effect with daily activities 
 
 
 
 
 
Have you experienced pain, itching, tenderness, redness, or 
swelling at an injection site today? 
If Yes, select each Injection Reaction Symptom: 
0 No    
1 Yes   
 
1 Pain 
1 Itching 
1 Tenderness 
1 Redness 
1 Swelling 
 
 
Each symptom 
caused: 
0 No effect on daily activities 
1 Some effect on daily activities 
2 Significant effect with daily activities 
 
 

SAP_001.pdf: 
CONFIDENTIAL 
 
Eiger BioPharmaceuticals, Inc. 
Protocol EIG-LMD-001 
 
A Phase 2 Study to Evaluate the Safety, Tolerability, and 
Pharmacodynamics of Pegylated Interferon Lambda 
Monotherapy in 
Patients with Chronic Hepatitis Delta Virus Infection (LIMT-1) 
 
FINAL v3 
Statistical Analysis Plan 
June 25, 2019 
Revised: April 1, 2020 
 
Prepared by: 
Aparna Anderson, Ph.D. 
Statistics Collaborative, Inc. 
© 2020 Statistics Collaborative, Inc. 
 
 


4/1/20


 
CONFIDENTIAL 
Document history 
Document 
Date of Issue 
Summary of Key Changes 
Statistical 
Analysis Plan 
(SAP) v1 
June 25, 2019 
Not applicable (original SAP) 
Revised SAP v2 
September 19, 2019 
Reference to Week 96 hepatitis delta virus (HDV) 
ribonucleic acid (RNA) assessment was added. 
Virologic response at Week 48 and sustained virologic 
response (SVR) were added as endpoints, and the 
definition of durable virologic response (DVR) was 
clarified and limited to the 24-week post-treatment visit 
(Week 72). 
Hepatitis B surface antigen (HBsAg) categories were 
updated. 
Proportion of patients with alanine 
aminotransferase (ALT) normalization was added as an 
endpoint at Weeks 48, 72, and 96. 
The analysis population section was edited to (a) clarify 
that analyses of the modified intention-to-treat (MITT) 
population will be considered sensitivity analyses, and 
(b) add the treatment completer population, defined as 
patients who received study therapy at the Week 48 visit. 
Visit windows were added between Weeks 72 and 96; the 
Week 72 imputation rule now follows the same rule as 
other visits bracketed by adjacent visits on both sides. 
Among patients who do not meet MITT criteria, dose 
reduction and treatment through Week 48 were added to 
the patient disposition summary. 
“Relevant protocol deviations” was changed to “important 
protocol deviations,” and the list of important protocol 
deviations was expanded to include all programmable 
eligibility deviations and additional on-study deviations. 


Document history, continued 
Revised SAP v2 
September 19, 2019 
Descriptive statistics for baseline ALT and HBsAg as well 
as proportion of patients with ALT ≤ and > upper limit of 
normal (ULN) were added. Prothrombin time was added 
to baseline laboratory summaries. 
The term “compliance” has been replaced by 
“adherence.” 
Summary of dose modifications was added for patients 
who did not meet the MITT criteria. 
A sentence was added to make clear that efficacy analyses 
of HDV RNA should first transform the HDV RNA values 
to the log10 IU/mL scale. 
Efficacy analyses were defined for the MITT and 
treatment completer populations. 
Sensitivity analyses of DVR and SVR have been added: 
(a) excluding patients with baseline HDV RNA below the 
lower limit of quantification (LLOQ) from the 
denominator of each proportion calculation, and (b) 
excluding responders with virologic failure from the 
numerator of each proportion calculation. 
It was clarified that interim data snapshot for purposes of 
data review and presentation would occur and will not 
require multiplicity adjustment. 
The safety analysis section was edited to clarify that safety 
presentations will include data through the patient’s last 
study visit. Reference to summaries of adverse events by 
study month was removed. 
Revised SAP v3 
April 1, 2020 
The following were corrected: 
• 
References to pharmacokinetics and 
electrocardiogram (ECG) were removed. 
• 
Section 8.2: MITT analyses will be limited to the 
primary efficacy endpoint and a select set of 
exploratory efficacy endpoints. Reference to other 
MITT analyses was deleted. 
 
 


 
CONFIDENTIAL 
Document history, continued 
Revised SAP v3 
April 1, 2020 
• 
The list of endpoints in Sections 3.6.1 and 8.2 were 
reconciled. 
• 
Virologic response rate at Week 48 included 
reference to “12 weeks” in the endpoint definition, 
which was deleted. 
• 
Reference to “ITT population” was removed and 
replaced with “randomized population.” 
Clarifying edits were added to visit labels, 
e.g., “(Week 72)” was included after “24 weeks after 
Week 48.” 
SVR24 and DVR24 were added to the study schema. 
The definition of ALT normalization was added. It was 
also clarified how patients with ALT<ULN at baseline 
would be handled in the analysis of the proportion of 
patients with ALT normalization at a given visit.  
“Treatment completer population” was changed to 
“treatment completion population.” 
In Section 5.3: Because the SAP was written toward the 
completion of the study, the algorithms in the previous 
versions of the SAP did not match the investigator 
electronic case report form (eCRF) visit labels. Therefore, 
the following updates have been made to this section:  
• 
Header was changed from “Visit windows” to 
“Visit labels.” 
• 
Derived visit windows were removed. All visit 
labels will come from eCRF pages.  
• 
Conventions were added for visit labels in 
patients who have early termination of treatment 
before Week 48. 
Because the last dose of study therapy is not captured on 
the eCRF, the patient visit date recorded in the patient 
registration portal and labeled as “Week 48 / EOT Date” 
will be used as the date of last dose. This convention was 
added to the study therapy administration and adherence 
section. 


Document history, continued 
Revised SAP v3 
April 1, 2020 
In addition to patient disposition, a summary of analysis 
populations was added. 
Baseline HDV RNA level as a continuous measure with 
descriptive statistics was added to the list of analyses for 
baseline disease characteristics. 
Reason for dose reduction was removed as it was not 
collected. 
Proportion of patients with virologic failure was added to 
Section 8.2 (Efficacy exploratory endpoints) and refined to 
align with definitions in FDA’s guidance document. 
Rash was removed as an adverse event (AE) of special 
interest. Safety presentations will include AEs up to 28 
days after the last dose of study treatment. 
Anti-hepatitis B virus (anti-HBV) therapies other than 
entecavir and tenofovir were removed in the protocol 
deviation table. Also, the derivation for absolute 
neutrophil count (ANC) was added, as ANC was not 
provided by the central laboratory. 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page i 
CONFIDENTIAL 
Contents 
1. Introduction ....................................................................................................................................... 1 
2. Study objectives ................................................................................................................................ 2 
2.1. 
Primary objective .................................................................................................................... 2 
2.2. 
Secondary objectives .............................................................................................................. 2 
2.3. 
Exploratory objective ............................................................................................................. 3 
3. Study design and conduct ............................................................................................................... 3 
3.1. 
Study design ............................................................................................................................ 3 
3.2. 
Study treatments..................................................................................................................... 4 
3.3. 
Study visits and assessments ................................................................................................ 5 
3.4. 
Eligibility ................................................................................................................................. 6 
3.5. 
Sample size ............................................................................................................................ 10 
3.6. 
Study endpoints .................................................................................................................... 10 
3.6.1. 
Efficacy endpoints ................................................................................................... 10 
3.6.2. 
Safety endpoints ...................................................................................................... 12 
4. Analysis populations ...................................................................................................................... 13 
5. General conventions and statistical considerations ................................................................... 14 
5.1. 
Study days ............................................................................................................................. 15 
5.2. 
Baseline .................................................................................................................................. 15 
5.3. 
Visit labels ............................................................................................................................. 15 
5.4. 
Imputation rules for partial or missing data .................................................................... 16 
5.4.1. 
Partial or missing efficacy measurements ........................................................... 16 
5.4.2. 
Partial or missing dates .......................................................................................... 18 
5.5. 
Software ................................................................................................................................. 18 
6. Study population summaries ........................................................................................................ 18 
6.1. 
Patient disposition ................................................................................................................ 18 
6.2. 
Protocol deviations ............................................................................................................... 19 
6.3. 
Demographics and baseline characteristics ...................................................................... 20 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page ii 
CONFIDENTIAL 
Contents, continued 
6.4. 
Prior medications ................................................................................................................. 21 
6.5. 
Medical history ..................................................................................................................... 21 
7. Exposure .......................................................................................................................................... 21 
7.1. 
Administration of study therapy and adherence............................................................. 21 
7.2. 
Discontinuation of study therapy ...................................................................................... 22 
7.3. 
Dose reduction and dose interruption .............................................................................. 22 
7.4. 
Concomitant medications.................................................................................................... 23 
8. Efficacy analyses ............................................................................................................................. 23 
8.1. 
Primary efficacy endpoint ................................................................................................... 23 
8.2. 
Efficacy exploratory endpoints ........................................................................................... 23 
8.3. 
Sensitivity analyses .............................................................................................................. 26 
8.4. 
Interim analyses and data monitoring .............................................................................. 26 
8.5. 
Multiplicity ............................................................................................................................ 26 
9. Safety summaries ............................................................................................................................ 27 
9.1. 
Adverse events...................................................................................................................... 27 
9.2. 
Deaths .................................................................................................................................... 28 
9.3. 
Vital signs .............................................................................................................................. 28 
9.4. 
Laboratory parameters ........................................................................................................ 28 
9.4.1. 
Hematology ............................................................................................................. 28 
9.4.2. 
Serum chemistry ..................................................................................................... 29 
9.4.3. 
Electrolytes ............................................................................................................... 29 
9.4.4. 
Hepatic function and ALT flares .......................................................................... 29 
9.5. 
Immunogenicity analyses.................................................................................................... 30 
10. References ........................................................................................................................................ 31 
11. Appendix: Important protocol deviations .................................................................................. 32 
 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page iii 
CONFIDENTIAL 
Exhibits 
Exhibit 1. Study schema ....................................................................................................................... 4 
Exhibit 2. Inclusion and exclusion criteria......................................................................................... 7 
Exhibit 3. Important protocol deviations ......................................................................................... 33 
 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page iv 
CONFIDENTIAL 
Abbreviations 
Ab 
antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CI 
confidence interval 
CrCl 
creatinine clearance 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
deoxyribonucleic acid 
DR 
dose reduction (DR1 = first DR; DR2 = second DR) 
DVR 
durable virologic response  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOFU 
end of follow-up 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
FU 
follow-up 
GGT 
gamma-glutamyl transferase 
HBV 
hepatitis B virus 
HBsAb 
hepatitis B surface antibody 
HBeAb 
hepatitis B envelope antibody 
HBeAg 
hepatitis B envelope antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDV 
hepatitis delta virus 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IFN 
interferon 
IFN-α 
interferon alpha 
(continued) 
 
 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page v 
CONFIDENTIAL 
Abbreviations, continued 
INR 
international normalized ratio 
IUD 
intrauterine device 
IWRS 
interactive web response system 
LOD 
limit of detection 
LLOQ 
lower limit of quantification 
mcg 
micrograms 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intention-to-treat 
NCI  
National Cancer Institute  
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PT 
preferred term 
qPCR 
quantitative polymerase chain reaction 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using Fridericia formula 
QW 
once a week 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SVR 
sustained virologic response  
TBILI 
total bilirubin 
TDF 
tenofovir disoproxil fumarate 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of the normal range 
WBC 
white blood cell  
WHO 
World Health Organization 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
 




EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page 1 
CONFIDENTIAL 
1. 
Introduction 
Peginterferon lambda-1a (Lambda) is a well-characterized, late-stage, first-in-class, type III 
interferon (IFN) that has demonstrated activity and favorable tolerability as compared to 
pegylated alfa interferon (Alfa) in human studies against hepatitis B and C viruses 
(HBV, HCV, respectively). Lambda exerts its antiviral effects through direct inhibitory and 
indirect immune-mediated mechanisms of action. In proof of concept preclinical studies, 
Lambda has demonstrated activity against hepatitis D virus (HDV) that is comparable to Alfa. 
Accordingly, Lambda is postulated to induce HDV ribonucleic acid (RNA) decline in humans, 
but with fewer adverse events (AEs) than Alfa.  
EIG-LMD-001 is the first study of Lambda in patients with chronic HDV infection. The 
primary aims of the study are to define the safety, tolerability, and 
pharmacodynamics (PD)/efficacy of Lambda monotherapy in patients with chronic HDV 
infection. The Lambda doses chosen for this study were based on the results from studies in 
healthy volunteers and in patients with chronic HBV or chronic HCV infection. 
This statistical analysis plan (SAP) is based on the protocol for study EIG-LMD-001 
(Amendment 5), dated April 18, 2019. The SAP summarizes key aspects of the study to 
provide context for statistical methods and presents details of the planned statistical methods 
addressing the study aims. This analysis plan will serve as the final documentation for the 
planned statistical analyses for study EIG-LMD-001 and will supersede the protocol if there 
are any discrepancies. 
The statistical principles applied in the design and planned analyses of this study are 
consistent with the International Conference on Harmonization (ICH) guidelines E9 
(Statistical Principles for Clinical Trials) [1]. 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page 2 
CONFIDENTIAL 
2. 
Study objectives 
2.1. 
Primary objective 
The primary objectives of the study are as follows: 
• 
To evaluate the safety and tolerability of treatment with 2 dose levels of Lambda 
over a 48-week treatment period 
• 
To evaluate the effect of treatment with two different doses of Lambda on HDV RNA 
levels 
2.2. 
Secondary objectives 
The secondary objectives of the study are as follows: 
• 
To evaluate the proportion of patients with undetectable HDV RNA 12 weeks after 
the end of treatment 
• 
To evaluate the proportion of patients with undetectable HDV RNA 24 weeks after 
the end of treatment 
• 
To evaluate the proportion of patients with undetectable HDV RNA approx. 
48 weeks after the end of treatment 
• 
To evaluate the effect of treatment with two dose levels of Lambda on the following: 
• 
Alanine aminotransferase (ALT) levels including ALT levels at approx. 48 weeks 
after end of treatment 
• 
Hepatitis B surface antigen levels  
NOTE: This will be assessed by quantitative polymerase chain reaction (qPCR) 
assay (qHBsAg). 
• 
Gamma-glutamyl transferase (GGT) levels 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page 3 
CONFIDENTIAL 
2.3. 
Exploratory objective 
An exploratory objective of the study is to evaluate the effect of treatment with two dose levels 
of Lambda on immunologic parameters. This analysis plan will focus only on immunogenicity 
analyses that will be included in the clinical study report. Other analyses related to 
immunologic parameters, if conducted, will not be included in the Clinical Study Report and 
are therefore not described in this SAP. 
3. 
Study design and conduct 
3.1. 
Study design 
This Phase 2, randomized, open-label, two dose level study will assess the safety, tolerability, 
and PD/efficacy of Lambda in patients with chronic HDV infection. Up to 40 patients will be 
enrolled at approximately 6 study sites globally. Patients will be randomized 1:1 to receive one 
of the following treatments with open-label study drug: 
• 
120 mcg Lambda, weekly subcutaneous (SC) injection 
• 
180 mcg Lambda, weekly SC injection 
Eligible patients will have chronic HDV infection (≥6 months) confirmed by positive HDV 
antibody (Ab) test and detectable HDV RNA by qPCR. 
The study will consist of three periods (Exhibit 1): 
• 
Screening Period: Day -28 to Day 0 (maximum 4 weeks) 
• 
Treatment Period: Day 1 (first day of treatment) through Week 48 (12 months) 
• 
Follow-up (post-treatment) Period: Week 49 though Week 72 (6 months) 
In addition, a Week 96 visit (Week 48 post-treatment) will occur to collect a blood sample for 
HDV RNA for qPCR and clinical laboratory tests; concomitant medications will also be 
captured at this visit. [The study schema shown in Exhibit 1 is taken from the protocol. See 
Section 3.6.1 for definitions of “sustained virologic response (SVR)” as well as the additional 
endpoint, “durable virologic response (DVR).”]All patients, whether they complete the 
treatment period or not, will be followed for 24 weeks in the post-dosing follow-up period 
with an additional visit at Week 96 to assess long-term durability of post-treatment endpoint 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page 4 
CONFIDENTIAL 
responses (HDV RNA and serum ALT). Therefore, the maximum anticipated time an 
individual patient will participate in the study will be 96 weeks after the screening is complete. 
Patients will be required to take an anti-HBV nucleos(t)ide analog from baseline (Day 1) until 
the end of the study. Tenofovir disoproxil fumarate (TDF) will be prescribed for any patients 
not already taking one of these medications at baseline; if TDF is contraindicated then 
entecavir will be prescribed. This medication will protect patients from occurrences of HBV-
related ALT flares related to unchecked HBV replication, with resulting secondary negative 
effects on the patient’s HDV status (virologic control and hepatic status). 
Exhibit 1. Study schema 
 
 
3.2. 
Study treatments 
Patients will be randomly assigned 1:1 to receive either 120 mcg or 180 mcg open-label 
Lambda as SC weekly injection by the interactive web response system (IWRS). Lambda will 
be provided in ready-to-use syringes to be administered via SC injection. 
Sustained virologic response and durable virologic response at 24 weeks after treatment, SVR24 and 
DVR24, will also be evaluated. 
↑ 
SVR24 
and 
DVR24 
↓ 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page 5 
CONFIDENTIAL 
Clinic staff will administer each patient's first dose of study drug in the clinic on Day 1. Clinic 
staff will train patients on SC administration of study drug on Day 1 and provide written 
instructions for drug administration and storage and safe handling of needles (including 
discarding instructions and provision of a sharps container). Patients will be given sufficient 
study drug at each visit for the number of weeks until the next visit. 
Patients who require dose reduction in the 180 mcg/week dose group will be given 
120 mcg/week in the first dose reduction (DR1) and 80 mcg/week in the second dose 
reduction (DR2); patients in the 120 mcg/week dose group will be given 80 mcg/week in DR1 
and also in DR2; in effect, patients cannot be given a dose below 80 mcg/week. 
3.3. 
Study visits and assessments 
The following assessments are planned: 
• 
Inclusion/exclusion criteria (baseline) 
• 
Demography, including age, sex, race, and ethnicity (baseline) 
• 
Medical history (baseline) 
• 
Retinal examination (within 1 year of screening and at Week 48) 
• 
Blood sampling for the following efficacy testing: 
• 
HDV RNA viral load analysis using RoboGene® [2] HDV RNA Quantification Kit 
(baseline and all visits starting with Week 4, including all on-treatment and 
post-treatment follow-up visits) 
• 
HBV deoxyribonucleic acid (DNA) analysis using Aptima HBV Quant DX assay via 
the fully automated Hologic Panther system (baseline and all visits starting with 
Week 4, including all on-treatment and post-treatment follow-up visits) 
• 
HBsAg levels by Architect (Abbott) quantitative HBsAg (qHBsAg) assay (baseline 
and all visits starting with Week 4, including all on-treatment and post-treatment 
follow-up visits) 
• 
HBsAg status (positive or negative) by Architect (Abbott) qHBsAg assay and 
Hepatitis B surface antibody (HBsAb) by Elecsys (Roche) qualitative antibody assay 
(baseline and at the Week 48 visit in the treatment period and at the Week 72 visit in 
the post-treatment follow-up period) 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page 6 
CONFIDENTIAL 
• 
Hepatitis B envelope antigen (HBeAg), and hepatitis B envelope antibody (HBeAb) 
by Elecsys (Roche) qualitative antigen and antibody assays (baseline, at the Week 24 
and 48 visits in the treatment period, and at the Week 60 and 72 visits in the 
post-treatment follow-up period) 
• 
Fibroscan testing (baseline and Week 48 [end of treatment, EOT]) 
• 
AEs (collected at baseline and throughout the study through the follow-up period) 
• 
Patient reported outcomes (Day 2 through post-treatment follow-up period) 
• 
Laboratory assessments 
• 
HCV and human immunodeficiency virus (HIV) testing (baseline) 
• 
Blood samples for hematology, coagulation, thyroid panel, and clinical chemistry 
(baseline and every subsequent visit during treatment and post-treatment follow-up 
periods) 
• 
Urine samples (baseline, Week 8, 16, 24, 32, 40, and 48 visits in the treatment period 
and the Week 60, 72, and 96 visits in the post-treatment follow-up period) 
• 
Vital signs, including body weight, blood pressure, heart rate, respiratory rate, and 
body temperature (baseline and every subsequent visit during treatment and 
follow-up periods); height and body mass index (BMI) (baseline) 
• 
Concomitant medications (baseline and every subsequent visit during treatment and 
post-treatment follow-up periods) 
Refer to Appendix 1 of the protocol for the Schedule of Assessments and Procedures. 
3.4. 
Eligibility 
Patients must meet all of the inclusion criteria and none of the exclusion criteria to be eligible 
for enrollment into the study. 
 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
June 25, 2019 
Page 7 
CONFIDENTIAL 
Exhibit 2. Inclusion and exclusion criteria 
Inclusion criteria 
Exclusion criteria 
• 
Willing and able to comply with study procedures and provide 
written informed consent 
• 
Male or female, 18 to 65 years of age, inclusive 
• 
Chronic HDV infection of at least 6 months' duration documented 
by a positive HDV Ab test; detectable and quantifiable HDV RNA 
by qPCR at study entry 
• 
Serum ALT > upper limit of the normal range (ULN) and 
<10 × ULN at screening 
• 
ECG demonstrating no acute ischemia or clinically significant 
abnormality and a QT interval corrected for heart rate (QTcF) 
<450 ms for male patients and <460 ms for female patients 
• 
Thyroid stimulating hormone (TSH) and/or free T4 within 0.8 to 
1.2 × ULN, or adequately controlled thyroid function as assessed 
by the investigator 
• 
Dilated retinal examination ≤1 year before screening: For patients 
with diabetes, hypertension, or other risk factors for retinal 
disease, performed by a licensed ocular specialist; for all other 
patients, a normal retinal examination as assessed by the 
investigator or a licensed ocular specialist 
 
General exclusions 
• 
Participation in a clinical trial with, or use of, any investigational 
agent within 30 days of start of screening, or treatment with IFNs 
or immunomodulators within 12 months of start of screening 
• 
Previous use of Lambda. Patients who previously participated in 
a clinical trial of Lambda but are confirmed to have received 
placebo or other non-Lambda IFNs are allowed. 
• 
History or evidence of any intolerance or hypersensitivity to IFNs 
or other substances contained in the study medication. 
• 
Female patients who are pregnant or breastfeeding. Male patients 
must confirm that their female sexual partners are not pregnant. 
Female patients must have a negative serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of human 
chorionic gonadotropin [hCG]) within 24 hours prior to the start 
of investigational product. 
Exclusions based on disease-related criteria (abbreviated) 
• 
Current or previous history of decompensated liver disease  
• 
Co-infected with HIV or HCV 
• 
Past history or current evidence of decompensated liver disease  
• 
Evidence of significant portal hypertension; current presence or 
history of variceal bleeding 
• 
Current evidence or history of ascites requiring diuretics or 
paracentesis, or hepatic encephalopathy 
(continued) 


EIGER PROTOCOL EIG-LMD-001: STATISTICAL ANALYSIS PLAN 
April 1, 2020 
Page 8 
CONFIDENTIAL 
Exhibit 2. Inclusion and exclusion criteria 
Inclusion criteria 
Exclusion criteria 
• 
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 through 90 days 
after the last dose of study medication. Female patients of 
childbearing potential are all those except patients who are 
surgically sterile, who have medically documented ovarian 
failure, or who are at least one year postmenopausal. 
o 
For females, 2 of the following contraceptive methods, with 
at least 1 being a barrier method: Hormonal contraceptives for 
≥27 days before dosing; intrauterine device (IUD) in place 
≥27 days before dosing; double-barrier methods (use of 
condom [male partner] with either diaphragm with 
spermicide or cervical cap with spermicide) from screening; 
or surgical sterilization of the partner (vasectomy ≥1 month 
before screening). 
o 
For males, surgical sterilization (vasectomy ≥1 month before 
screening) or both consistent and correct use of condoms and 
partner must use a hormonal contraceptive or a nonhormonal 
barrier method (IUD or diaphragm with spermicide or 
cervical cap with spermicide) 
• 
Willing and able to provide written informed consent 
• 
Willing and able to comply with all study procedures 
• 
Patients with any of the following abnormalities at screening: 
platelet count <90,000 cells/mm3; white blood cell (WBC) count 
<3,000 cells/mm3; absolute neutrophil count (ANC) 
<1,500 cells/mm3; hemoglobin <11 g/dL for women and <12 g/dL 
for men; serum creatinine concentration ≥1.5 × ULN; or creatinine 
clearance (CrCl) <50 mL/min by Cockroft-Gault 
• 
Evidence of another form of viral hepatitis or another form of 
liver disease  
• 
History of hepatocellular carcinoma 
• 
Patients with any of the following: current eating disorder or 
alcohol abuse; excessive alcohol intake; alcohol use that will 
interfere with study conduct; or drug abuse within the previous 
6 months before the screening visit with the exception of 
cannabinoids and their derivatives 
• 
Prior history or current evidence of any of the following: 
immunologically mediated disease; retinal disorder or clinically 
relevant ophthalmic disorder; any malignancy within five years 
before screening; cardiomyopathy or significant ischemic cardiac 
or cerebrovascular disease; chronic pulmonary disease associated 
with functional impairment; pancreatitis; severe or uncontrolled 
psychiatric disorder; active seizure disorder; or bone marrow or 
solid organ transplantation 
• 
Other significant medical condition that may require intervention 
during the study.  
(continued) 


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Exhibit 2. Inclusion and exclusion criteria 
Inclusion criteria 
Exclusion criteria 
 
Exclusions related to use of selected medications 
• 
Therapy with an immunomodulatory agent; IFN-α (IFN alfa-2a 
or IFN alfa-2b, or pegylated IFN alfa-2a or alfa-2b); cytotoxic 
agent, or systemic corticosteroids within 12 months before 
screening 
• 
Use of telbivudine within three months before screening or 
during the study 
• 
Current use of Heparin or Coumadin 
• 
Received blood products within 30 days prior to study 
randomization 
• 
Use of hematologic growth factors within 30 days prior to study 
randomization 
• 
Systemic antibiotics, antifungals, or antivirals for treatment of 
active infection other than HBV within 14 days of study 
randomization 
• 
Any prescription or herbal product that is not approved by the 
investigator 
• 
Long-term treatment (>2 weeks) with agents that have a high risk 
for nephrotoxicity or hepatotoxicity, should be discussed with the 
medical monitor 
• 
Receipt of systemic immunosuppressive therapy within the three 
months before start of screening 
 
 


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3.5. 
Sample size 
A sample size of 40 was chosen to allow assessment of the safety, tolerability, and PD/efficacy 
of Lambda at 120 vs. 180 mcg/week. The sample size was not formally calculated using power 
analysis. 
3.6. 
Study endpoints 
3.6.1. 
Efficacy endpoints 
The primary endpoints and additional exploratory efficacy endpoints are listed in this section. 
All efficacy endpoints are defined in Sections 8.1 and 8.2.  
The primary efficacy endpoints are as follows: 
• 
Change from baseline in HDV viral load at Week 48 (EOT) 
• 
Change from baseline in HDV viral load at Week 72 
The following additional efficacy endpoints will also be analyzed: 
• 
Virologic response rate at Week 48 (EOT): Proportion of patients with HDV RNA 
below LLOQ at Week 48 (EOT) 
• 
DVR rate: Proportion of patients with HDV RNA below LLOQ 24 weeks after 
Week 48 (Week 72) 
• 
Virologic response rate at 12 weeks post-treatment (Week 60): Proportion of patients 
with HDV RNA below LLOQ 12 weeks after Week 48 (Week 60) 
• 
Virologic response rate at 48 weeks post-treatment (Week 96): Proportion of patients 
with HDV RNA below LLOQ 48 weeks after Week 48 (Week 96) 
• 
Sustained virologic response rate at 12 weeks post-treatment (SVR-12): Proportion of 
patients with HDV RNA below the LLOQ at Week 48 (EOT) and 12 weeks after 
Week 48 (Week 60) 
• 
Sustained virologic response rate at 24 weeks post-treatment (SVR-24): Proportion of 
patients with HDV RNA below the LLOQ at Week 48 (EOT) and 24 weeks after 
Week 48 (Week 72) 


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• 
Sustained virologic response rate at 48 weeks post-treatment (SVR-48): Proportion of 
patients with HDV RNA below the LLOQ at Week 48 (EOT) and 48 weeks after 
Week 48 (Week 96) 
• 
Proportion of patients with virologic failure (defined in Section 8.2) 
• 
Change from baseline in HDV viral load by visit 
• 
Change from baseline in HBV viral load by visit 
• 
Change from baseline in HBsAg levels by visit 
• 
Proportion of patients with clearance of HBsAg, where clearance is defined as 
undetectable HBsAg by current quantitative assay 
• 
Proportion of patients with change from baseline in HBsAg categories on log10 scale 
(<0.25, 0.25 to <0.5, 0.5 to <0.75, 0.75 to <1, 1 to <1.25, 1.25 to <1.5, and ≥1.5) by visit 
• 
Proportion of patients falling within HBsAg categories (<100 IU/mL, 100 to 
<200 IU/mL, 200 to <500 IU/mL, 500 to <1000 IU/mL, 1000 to <2000 IU/mL, 2000 to 
<10,000 IU/mL, ≥10,000 IU/mL) at each of the following times: Weeks 12, 24, and 48; 
at 12 and 24 weeks after EOT (Weeks 60 and 72) 
• 
Proportion of patients with clearance of HBsAg at Weeks 12, 24, and 48; at 12 and 
24 weeks after EOT (Weeks 60 and 72) 
• 
Change from baseline in Fibroscan results at Week 48 (EOT) and 24 weeks after EOT 
(Week 72) 
• 
Change from baseline in ALT at Week 48 (EOT), 24 weeks after EOT (Week 72), and 
48 weeks after EOT (Week 96) 
• 
Proportion of patients with ALT normalization (i.e., ALT ≤ULN) at Week 48 (EOT), 
24 weeks after EOT (Week 72), and 48 weeks after EOT (Week 96). Note: A patient 
who has baseline ALT ≤ ULN cannot qualify for assessment of ALT normalization. 
Therefore, two separate analyses will be performed: (a) patients with baseline 
ALT ≤ ULN will be included in the denominator and considered “non-responders” 
in the proportion calculation, and (b) patients with baseline ALT ≤ ULN will be 
excluded altogether from the proportion calculation. 


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(Note: After finalization of the protocol, the sponsor has clarified the definition of “sustained 
virologic response [SVR]” and included “durable virologic response [DVR]” as an additional 
endpoint. The introduction of DVR is intended to differentiate the endpoint from SVR, which 
has historically been used in clinical trials of therapeutic agents for the treatment of chronic 
HCV infection.) 
HDV RNA was measured using the RoboGene® [2] HDV RNA Quantification Kit 2.0 reverse 
transcription-polymerase chain reaction assay. The assay is designed to detect eight HDV 
genotypes, applying probes and primers specific for a subsequence of the hepatitis D antigen. 
The assay has a LLOQ of 14 IU/mL and limit of detection (LOD) of 6 IU/mL based on 
calibrated standards using a reference HDV GT-1 positive serum. 
The Architect (Abbott) quantitative assay will be used to measure HBsAg (both quantitative 
and qualitative assessments and presence of antigen [positive, negative]), given the LLOQ of 
this assay is lower than that of the Architect (Abbott) qualitative assay. The HBsAg levels will 
be measured at screening, Day 1, and Weeks 12, 24, and 48 during the treatment period, and 
12 and 24 weeks post-treatment (Weeks 60 and 72). HBsAg values will be converted to the 
log10 scale for purposes of analysis and summarization.  
HBsAb, HBeAg and HBeAb will be measured using Elecsys (Roche) qualitative assays.  
HBV DNA will be measured by the Aptima quantitative nucleic acid amplification 
assay [Hologic]. The linear range is 10 to 1,000,000,000 IU/mL (or 1 to 9 log10 IU/mL).  
3.6.2. 
Safety endpoints 
Safety endpoints include the following: 
• 
Treatment-emergent AEs and serious adverse events (SAEs) 
• 
Treatment-emergent treatment-related AEs and SAEs 
• 
AEs leading to early discontinuation of study treatment 
• 
AEs leading to dose reduction 
• 
AEs leading to dose interruption 


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• 
ALT flares  
• 
Treatment-emergent changes in clinical laboratory findings 
• 
Anti-drug antibodies, neutralizing and non-neutralizing  
• 
Treatment-emergent changes in vital signs 
• 
Treatment-emergent changes in ECG findings 
• 
Treatment-emergent changes in physical examination results 
• 
Usage of concomitant medications during the study 
4. 
Analysis populations 
All enrolled population is defined as patients who signed the informed consent form and 
were assigned a patient identification number. Patient disposition and protocol deviations will 
be analyzed in this population. 
Randomized population is defined as patients who are enrolled, randomized, and assigned to 
a treatment group using the IWRS system. Patients are classified according to the randomized 
treatment group. Note: An exception to this classification will be patients who were 
randomized to 180 mcg but were moved to the 120 mcg group before receiving their first dose 
of study drug; these patients will be included in the 120 mcg treatment group and are 
identified in the manually identified (non-programmable) protocol deviation spreadsheet. 
Analyses of baseline characteristics and efficacy will be performed on this population. 
Modified intention-to-treat (MITT) population is defined as those patients in the randomized 
population who receive at least 80% of the total planned number of study drug doses for this 
protocol throughout the entire 48 week treatment period and for whom HDV viral load data 
are available for the Day 1 (baseline) and EOT (Week 48) study visits. Patients who receive less 
than 80% of the assigned dose on any given treatment day (e.g., dose missed, interrupted, or 
reduced to DR1 or DR2) will be excluded from this analysis population. Sensitivity analyses of 
efficacy and safety may be performed on patients in the MITT population; this is an update to 
what is stated in the protocol. 


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Treatment completion population is defined as randomized patients who were treated to 
Week 48, i.e., received a dose of study therapy in the Week 48 visit window, irrespective of 
dose modifications between Day 1 and Week 48. Patients in this population are classified 
according to treatment received. 
Safety population is defined as randomized patients who received at least one dose of study 
therapy. Patients who receive at least one dose of assigned study therapy will be analyzed as 
randomized; otherwise, patients are analyzed with the treatment group that corresponds to 
actual treatment received as their first dose. Exposure and safety analyses will be performed 
on this population.  
5. 
General conventions and statistical considerations 
Categorical variables will be summarized as counts and percentages. Continuous variables 
will be summarized using number of patients (n), mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum.  
All summaries will be presented by treatment group. Medical history, concomitant 
medications, and AEs will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA®) and World Health Organization Drug Dictionary 
Enhanced (WHODDE), as applicable. 
Tabular presentations will display two columns to summarize results for each of the two dose 
regimens; by-patient listings will present relevant electronic case report form (eCRF) data. All 
data listings, summaries, and statistical analyses will be generated using SAS® Version 9.1 or 
higher [3] or other validated software.  
The following sections describe additional conventions to be used for the analyses. 


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5.1. 
Study days 
For the purpose of efficacy analyses and study visits, the date of randomization will be 
considered Day 1, and study day will be calculated relative to the date of randomization. 
Specifically: Study day = date of visit/test/procedure – Day 1 date + 1. 
For the purpose of safety analyses, study day will be calculated relative to the date of first dose 
of study therapy. Specifically: Study day = date of adverse event or laboratory 
abnormality – date of first dose + 1. 
The following conversion factors will be used to convert days to months or years: 
1 month = 30.4375 days and 1 year = 365.25 days. 
5.2. 
Baseline 
Baseline measures for non-safety evaluations are defined as the last measure on or before the 
date of randomization. Baseline measures for safety evaluations of laboratory tests, pulse 
oximetry, and vital signs are defined as the last measure on or before the date of first dose of 
study therapy; see Section 9.1 for the definition of a treatment-emergent adverse event. 
5.3. 
Visit labels 
All analyses requiring measurements at a specified visit (e.g., baseline, Week 48, Week 72, etc.) 
will use the eCRF visit label as the basis for the visit classification. In addition, the following 
conventions will be applied to the final visit label for each assessment date. 
• 
If the assessment date was recorded as an unscheduled visit according to the eCRF 
label, then the visit label will be “Unscheduled Visit X” as noted in the eCRF label, 
where “X” is the unscheduled visit number. 
• 
For patients who have early termination (ET) of treatment before Week 48, then the 
visit label associated with EOT should be labeled as “Week X / ET” where Week X is 
the next scheduled 4-week visit. If a patient discontinues treatment prior to Week 48 
and between regularly scheduled visits, then the follow-up visits will be derived and 
labeled in four-week increments from the date of treatment discontinuation as 


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“Week X / FU”. If the patient completes treatment to Week 48, then the eCRF visit 
labels for “Follow-Up 1 (Week 52),” “Follow-Up 2 (Week 56),” etc. will be relabeled 
as “Week X / FU,” where X is the applicable week of the visit in the follow-up period. 
5.4. 
Imputation rules for partial or missing data 
5.4.1. 
Partial or missing efficacy measurements 
This section describes imputation rules for addressing missing values. For graphical displays, 
imputed data will be shown only for partially missing data. By-patient listings will show raw, 
un-imputed results.  
For the purpose of calculating endpoints involving HDV RNA measurements, values deemed 
less than the limit of detection (<LOD) or less than the lower limit of quantitation (<LLOQ) will 
be imputed as follows.  
• 
If the HDV RNA value is “<LOD” or “<6 IU/mL”, then the RNA value will be 
imputed as the midpoint between 0 and 6: 6/2 = 3.0 IU/mL.  
• 
If the HDV RNA value is “<LLOQ” or “<14 IU/mL”, then the RNA value will be 
imputed as the midpoint between 6 and 14: [(14-6)/2] + 6 = 10 IU/mL. 
Several planned endpoints require measurements at specified visits – e.g., change from 
baseline in HDV viral load at Weeks 48 and 72; proportion of patients with durable virologic 
response at 24 weeks after EOT (DVR); virologic response at Week 48 (EOT), at 12 weeks 
post-treatment, and at 48 weeks post-treatment; SVR-12, SVR-24, and SVR-48; and change 
from baseline in ALT 24 and 48 weeks after EOT. The specified visits may have missing data 
for one of the following reasons: 
• 
A visit occurred, but the relevant data were not collected  
• 
A visit occurred, and data were collected, but the visit fell outside of the visit 
window defined in Section 5.3 
• 
A visit did not occur 
• 
The patient withdrew from the study or was lost to follow-up before reaching the 
visit window 


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A missing HDV RNA value at the Week 48 visit and Week 60 visit (12 weeks after EOT) will 
be imputed as follows: 
• 
A missing value bracketed by prior and subsequent values of “<LOD” from the 
adjacent visit windows will be imputed as 3.0 IU/mL.  
• 
A missing value bracketed by prior and subsequent values of “<LLOQ” will be 
imputed as 10 IU/mL. 
• 
A missing value bracketed by a prior value of “<LOD” and a subsequent value of 
“<LLOQ”, or vice versa, will be imputed as 10 IU/mL. 
• 
For virologic response at Week 48, DVR, virologic response at 12 weeks 
post-treatment, virologic response at 48 weeks post-treatment, SVR-12, SVR-24, and 
SVR-48, a missing value at the timepoint of interest bracketed by non-missing values 
from adjacent visits will be imputed as a responder if both adjacent values show 
HDV RNA values below LLOQ. Otherwise, the missing value will result in the 
patient being counted as a non-responder.  
• 
If the Week 96 value is missing and the prior adjacent visit has a non-missing value, 
then the prior value will be carried forward to Week 96.  
• 
For a given HDV RNA endpoint, if the Week 96 value is missing, the adjacent visit 
prior to Week 96 is a response (as defined for the HDV RNA endpoint), and a visit 
occurred within -1 month and +6 months of Week 96 showing response, then the 
endpoint will be imputed as a responder; otherwise, it will not be imputed. A patient 
with a missing value at this visit will be counted as a non-responder in the 
calculation of the endpoint. 
• 
A missing value due to early treatment discontinuation, study withdrawal, or loss to 
follow-up will result in the patient being counted as a non-responder in the 
calculation of virologic response at Week 48, DVR, virologic response 12 weeks 
post-treatment, virologic response 48 weeks post-treatment, SVR-12, SVR-24, and 
SVR-48. 


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5.4.2. 
Partial or missing dates 
For death dates, the following conventions will be used for imputing partial dates: 
• 
If only the day of the month is missing, the first of the month will be used to replace 
the missing day. The imputed date will be compared to the last known alive date + 1 
and the maximum will be considered as the death date. 
• 
If the month or the year is missing, the death date will be imputed as the last known 
alive date + 1. 
• 
If the date is completely missing but a reason for death is present, the death date will 
be imputed as the last known alive date + 1. 
For other partially missing dates, the following conventions will be used: 
• 
If only the day of the month is missing, the 15th of the month will be used to replace 
the missing day. 
• 
If both the day and the month are missing, July 1st will replace the missing 
information. 
• 
Exception: If an AE has a partially missing date with missing day and the month is 
the same month as first dose date, then the date will be imputed to be the first dose 
date so that the AE is considered treatment-emergent. 
If a date is completely missing, it will be considered as missing. 
5.5. 
Software 
All data listings, summaries, figures, and statistical analyses will be generated using SAS 
Version 9.1 or higher [3] or other validated software. 
6. 
Study population summaries 
6.1. 
Patient disposition 
The total number of patients enrolled (randomized or not randomized) will be presented along 
with the reason for not being randomized. The number and percentage of randomized patients 
who were treated and not treated and who withdrew early from the study will be presented 


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by treatment group (as randomized), along with the reason for not receiving treatment and 
reason for study withdrawal. The number and percentage of treated patients who had early 
treatment discontinuation will be presented by treatment, along with the reason for treatment 
discontinuation. The number and percentage of patients in each analysis population will also 
be presented. 
The number and percentage of patients in each of the analysis populations will be summarized 
in a separate table. The populations are as follows: 
• 
All enrolled population 
• 
Randomized population 
• 
MITT population 
• 
Treatment completion population 
• 
Safety population. 
Patients who do not meet the criteria for the MITT population will be further classified as 
follows: the number and percentage who had a dose reduction and continued treatment to 
Week 48, and the number and percentage who had a dose reduction and discontinued 
treatment prior to Week 48. 
6.2. 
Protocol deviations 
The programmable deviations from the eligibility criteria and on-study requirements as shown 
in the appendix (Section 11) will be considered important protocol deviations. (Note: ICH E3 
defines “important protocol deviations” as a subset of protocol deviations that might 
significantly affect the completeness, accuracy, and/or reliability of the study data or that 
might significantly affect a patient’s rights, safety, or well-being.) 
Non-programmable important eligibility and on-treatment protocol deviations will be 
identified through manual reviews and recorded separately for inclusion in the clinical study 
report.  


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6.3. 
Demographics and baseline characteristics 
The following demographic and baseline characteristics will be summarized. Unless otherwise 
noted, the analyses will be performed for randomized population by treatment group as 
randomized. 
Demography: 
• 
Age (descriptive statistics) 
• 
Age (65, ≥65 – <75, ≥ 75) 
• 
Gender, race/ethnicity, region 
Physical measurements: 
• 
Height (descriptive statistics, in meters) 
• 
Weight (descriptive statistics, in kilograms) 
• 
BMI (descriptive statistics, in kg/m2) 
• 
BMI (<25, 25 – < 30, ≥ 30 kg/m2) 
Disease characteristics: 
• 
Baseline HDV RNA level (descriptive statistics) 
• 
Baseline HDV RNA category (≤ 4 log10 IU/mL or > 4 log10 IU/mL)  
• 
Baseline ALT threshold (< 2×ULN, ≥ 2×ULN and ≤ 5×ULN, > 5×ULN and ≤ 10×ULN, 
> 10×ULN) 
• 
Baseline ALT category (≤ ULN, > ULN) 
• 
Baseline ALT level (descriptive statistics) 
• 
Baseline HBsAg and HBeAg status (positive, negative) 
• 
Baseline HBsAg category (>1500 IU/mL, 1500–20,000 IU/mL, >20,000 IU/mL) 
• 
Baseline HBsAg level (descriptive statistics) 
• 
Baseline Fibroscan exam (2–7 kPa, >7 kPa; summary statistics for ratio of 
interquartile range liver stiffness to median liver stiffness [%]) 
• 
Baseline retinal exam results (normal vs. abnormal), by eye (left, right) 


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Other commonly collected baseline laboratory measurements will be summarized for all 
randomized patients by treatment group as treated and grade (0, 1, 2, 3, 4). These tests include, 
but are not limited to:  
• 
Hepatobiliary: albumin, alkaline phosphatase, aspartate aminotransferase (AST), 
direct bilirubin, indirect bilirubin, total bilirubin, and GGT 
• 
Hematology: ANC, hemoglobin, international normalized ratio (INR), prothrombin 
time, lymphocytes (absolute), platelets, WBC count 
6.4. 
Prior medications 
The following will be summarized by treatment group as randomized: 
• 
Prior treatment with HBV or HDV medication (yes/no) 
• 
Prior HBV or HDV treatments (drug name, number of HBV or HDV treatments 
received) 
6.5. 
Medical history 
General medical history will be summarized and listed by patient. 
7. 
 Exposure 
Extent of exposure will be summarized for the safety population by treatment group as 
treated.  
7.1. 
Administration of study therapy and adherence 
Site staff will count syringes to monitor study treatment adherence. The number of doses of 
each Lambda treatment will be summarized by treatment group with descriptive statistics.  
For each patient, the number of expected doses of an assigned treatment component is the 
total number of days from Day 1 to the last scheduled day for treatment administration. For a 
patient who discontinued from a treatment component permanently, the number of expected 
doses for that treatment component is the total number of days from Day 1 to the date of the 
last dose of study medication. Percent adherence will be calculated as follows. 


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Percent adherence = 100 × (Number of Actual Doses / Number of Expected Doses) 
Because the last dose of study therapy is not captured on the eCRF, the patient visit date 
recorded in the patient registration portal and labeled as “Week 48 / EOT Date” will be used as 
the date of last dose. 
7.2. 
Discontinuation of study therapy 
The reason for discontinuation of study therapy will be summarized by study therapy and 
component of the regimen. In addition, duration of treatment (time to last dose) will be 
presented by treatment group as a Kaplan-Meier analysis, where the last dose date for a study 
drug within the treatment regimen will be the event date. The study has a 48 week fixed 
treatment period. Therefore, all patients will have a last dose date, i.e., there should be no 
censoring, and the curves will represent the cumulative treatment discontinuation rate over 
time. The median duration of treatment and associated 95% CI will be presented.  
7.3. 
Dose reduction and dose interruption 
The following analyses will summarize timing of first dose relative to randomization, dose 
interruptions and dose reductions: 
• 
Time from randomization to first dose of study therapy (0–3, > 3 to 7, > 7 to 14, 
> 14 to 21, > 21 to 28, > 28 days) 
• 
Number and percentage of patients with at least one interrupted dose 
• 
Reason for first dose interruption 
• 
Number and percentage of patients with a dose reduction 
• 
Total number of dose reductions (descriptive statistics) 
• 
Total number of dose interruptions (descriptive statistics) 
The analyses described in this section will also be produced for patients who did not meet the 
MITT criteria. 


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7.4. 
Concomitant medications 
Concomitant medications are summarized by treatment group for patients in the safety 
population. These are medications taken any time on or after the first dose of study therapy 
and on or before the last dose of study therapy. Medications will be presented alphabetically 
by anatomic class, therapeutic class and generic name using the World Health 
Organization (WHO) dictionary. 
8. 
Efficacy analyses 
All efficacy analyses of HDV RNA will transform the raw values to the log10 IU/mL scale 
before conducting the analyses. Listings will include both the raw and transformed values. 
8.1. 
Primary efficacy endpoint 
The primary endpoints are change from baseline in HDV viral load at Week 48 and change 
from baseline in HDV viral load at Week 72. The primary endpoints for each treatment group 
will be summarized by visit with descriptive statistics (n, mean, median, standard deviation, 
25th quartile, 75th quartile, minimum, and maximum). 
The primary efficacy analysis will compare the treatment group differences in means of the 
Lambda dose groups against each other using an analysis of covariance model (ANCOVA) 
with treatment group as a covariate. The difference in the mean differences for each 
comparison will be calculated and reported along with their 95% confidence intervals (CIs). 
The primary analyses will be performed for the randomized, MITT, and treatment completion 
populations. 
8.2. 
Efficacy exploratory endpoints 
Additional efficacy analyses will evaluate the following endpoints for the randomized 
populations: 
• 
Virologic response rate at Week 48: Proportion of patients with HDV RNA below 
LLOQ at Week 48 (EOT) 


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• 
DVR rate: Proportion of patients with HDV RNA below LLOQ 24 weeks after 
Week 48 (Week 72) 
• 
Virologic response rate at 12 weeks post-treatment (Week 60): Proportion of patients 
with HDV RNA below LLOQ 12 weeks after Week 48 (Week 60) 
• 
Virologic response rate at 48 weeks post-treatment (Week 96): Proportion of patients 
with HDV RNA below LLOQ 48 weeks after Week 48 (Week 96) 
• 
Sustained virologic response rate at 12 weeks post-treatment (SVR-12): Proportion of 
patients with HDV RNA below the LLOQ at Week 48 (EOT) and 12 weeks after 
Week 48 (Week 60) 
• 
Sustained virologic response rate at 24 weeks post-treatment (SVR-24): Proportion of 
patients with HDV RNA below the LLOQ at Week 48 (EOT) and 24 weeks after 
Week 48 (Week 72) 
• 
Sustained virologic response rate at 48 weeks post-treatment (SVR-48): Proportion of 
patients with HDV RNA below the LLOQ at Week 48 (EOT) and 48 weeks after 
Week 48 (Week 96) 
• 
Proportion of patients with virologic failure, defined as any of the following 
occurring during or post-treatment: (a) serum HDV RNA increases at least 1 log10 
above the nadir value on two consecutive visits in patients who are on Lambda 
treatment; (b) serum HDV RNA detectable by qPCR (≥ LLOQ) in patients who had 
undetectable HDV RNA (< LLOQ) during therapy (breakthrough) or during the 
follow-up period (relapse); or (c) serum HDV RNA ≤ 1 log10 reduced from the 
baseline value through EOT (virologic non-response). 
• 
Change from baseline in HDV viral load 
• 
Change from baseline in HBV viral load 
• 
Change from baseline in HBsAg levels 
• 
Proportion of patients with clearance of HBsAg, where clearance is defined as 
undetectable HBsAg by current quantitative HBsAg assay 
• 
Proportion of patients with change from baseline in HBsAg categories on log10 scale 
(<0.25, 0.25 to <0.5, 0.5 to <0.75, 0.75 to <1, 1 to <1.25, 1.25 to <1.5, and ≥ 1.5) by visit 


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• 
Proportion of patients within each HBsAg category (<100 IU/mL, 100 to <200 IU/mL, 
200 to <500 IU/mL, 500 to <1000 IU/mL, 1000 to <2000 IU/mL, 2000 to <10,000 IU/mL, 
≥10,000 IU/mL) at each of the following times: Weeks 12, 24, and 48; at 12 and 
24 weeks after EOT (Weeks 60 and 72) 
• 
Proportion of patients with clearance of HBsAg at Weeks 12, 24, or 48 during the 
treatment period; at 12 and 24 weeks after EOT (Weeks 60 and 72) 
• 
Change from baseline in Fibroscan results at Week 48 (EOT) and 24 weeks after EOT 
(Week 72) 
• 
Change from baseline in ALT at Week 48 (EOT), 24 weeks after EOT (Week 72), and 
48 weeks after EOT (Week 96) 
• 
Proportion of patients with ALT normalization (i.e., ALT ≤ ULN) at Week 48 (EOT), 
24 weeks after EOT (Week 72), and 48 weeks after EOT (Week 96). Note: A patient 
who has baseline ALT ≤ ULN cannot qualify for assessment of ALT normalization. 
Therefore, two separate analyses will be performed: (a) patients with baseline 
ALT ≤ ULN will be included in the denominator and considered “non-responders” 
in the proportion calculation, and (b) patients with baseline ALT ≤ ULN will be 
excluded altogether from the proportion calculation. 
All exploratory efficacy endpoints will be analyzed in the randomized population. The 
following endpoints will also be analyzed in the MITT population and the treatment 
completion population: 
• 
Change from baseline in HDV viral load at Week 48 
• 
Change from baseline in HDV viral load at Week 72 
• 
Virologic response rate at Week 48 
• 
DVR rate 
• 
SVR-24 rate 
Each proportion endpoint will be presented as the frequency and percentage for each 
treatment group along with the exact 95% CI. The difference in the proportions will be 
presented along with the exact 95% CI. 


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The change from baseline endpoints by visit for all visits will be presented as longitudinal 
plots of the mean change from baseline by visit and treatment group with error bars 
representing the associated 95% CIs. In addition, boxplots will also be shown by visit and 
treatment group. 
Change in ALT at Week 48 (EOT), 24 weeks after EOT (Week 72), and 48 weeks after EOT 
(Week 96) will be shown as a lab shift table with baseline vs. Week 48, Week 72, and Week 96 
(as applicable) categorized ALT values (< 2×ULN, ≥ 2×ULN and ≤ 5×ULN, > 5×ULN and 
≤ 10×ULN, > 10×ULN). 
8.3. 
Sensitivity analyses 
The following sensitivity analyses will be performed: 
• 
DVR and SVR accounting for HDV RNA level at baseline: The DVR and SVR 
endpoints will also be performed in randomized population and treatment 
completion population excluding patients with HDV RNA level below LLOQ at 
baseline from the denominator of each proportion calculation. 
• 
DVR and SVR accounting for virologic failure: The DVR and SVR endpoints will also 
be performed in the randomized population and treatment completion population 
excluding responders with virologic failure from the numerator of each proportion 
calculation (see Section 8.2 for the definition of virologic failure). 
8.4. 
Interim analyses and data monitoring 
The study will have interim data snapshots for review and presentation. 
8.5. 
Multiplicity 
As there are no formal statistical tests and all analyses are descriptive, interim analyses will 
not require multiplicity adjustments. 


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9. 
Safety summaries 
9.1. 
Adverse events 
Adverse events (AEs) will be coded by the most current version of MedDRA at the time of the 
database lock for the final analysis and summarized by system organ class, preferred 
term (PT), and worst National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE version 4.03) grade per patient. Adverse events will be summarized by 
patient, not event.  
Investigators will assess the relationship of each AE to study drug. The relationship of each AE 
to study drug will be categorized as not related, unlikely related, possibly related, probably 
related, and definitely related.  
All AE presentations will summarize treatment-emergent adverse events (TEAEs), defined as 
AEs with onset on or after first dose date or onset prior to first dose date but with worsened 
grade on or after first dose date. AEs without a severity rating that are reported 
post-randomization will be considered treatment-emergent. Presentations will include all AEs 
up to 28 days after the last dose of study treatment. All SAEs and deaths will be summarized, 
i.e., no window will be applied to SAEs and deaths. 
The following presentations of TEAEs will be generated:  
• 
SAEs 
• 
All AEs 
• 
AEs ≥Grade 3 in severity 
• 
AEs related to study drug (i.e., AEs classified as possibly, probably, and definitely 
related) 
• 
AEs leading to treatment discontinuation 
• 
AEs of special interest: flu-like symptoms (PT), musculoskeletal symptoms 
(PTs: arthralgia, myalgia, and back pain), constitutional symptoms (PTs: fatigue and 
asthenia), neurologic symptoms (PTs: headache and dizziness), psychiatric 
symptoms (PTs: depression, irritability, and insomnia). In addition, a sensitivity 


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analysis will be performed to assess flulike symptoms by presence of ≥2 of the 
following PTs: pyrexia, chills, arthralgia, and myalgia. 
All adverse events will be listed with MedDRA coding, onset and resolution dates, 
seriousness, severity, relationship, actions, and outcome. 
9.2. 
Deaths 
The number of patients who died will be summarized by treatment group. A by-patient listing 
of deaths including death date, cause of death, and relationship to study treatment. 
9.3. 
Vital signs 
Vital signs (blood pressure, heart rate, temperature, and respiratory rate) are collected 
according to the schedule in Section 3.3. These data may be analyzed using summary statistics 
on changes from baseline or distribution of worst on-study value based on CTCAE grade. 
Figures rather than tabular presentation may be used if appropriate. 
9.4. 
Laboratory parameters 
Presentations will include all laboratory data after a patient discontinues from the study. A 
by-patient listing of laboratory parameters will be provided. 
9.4.1. 
Hematology 
The following will be summarized by treatment group as worst CTC grade on-treatment per 
patient and as shift table of worst on-treatment CTC grade compared to baseline CTC grade 
per patient: hemoglobin, platelets, WBCs, ANC, and lymphocyte count.  
ANC is defined as WBC x(%PMN +%Bands) x 10, where PMN refers to the 
polymorphonuclear cell family and includes neutrophils, basophils, and eosinophils. 


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9.4.2. 
Serum chemistry 
The following will be summarized by treatment group as worst CTC grade on-treatment per 
patient and as shift table of worst on-treatment CTC grade compared to baseline CTC grade 
per patient: ALT, AST, alkaline phosphatase, total bilirubin, and creatinine. 
9.4.3. 
Electrolytes 
The following will be summarized by treatment group as worst CTC grade on-treatment per 
patient and as shift table of worst on-treatment CTC grade compared to baseline CTC grade 
per patient: sodium (high and low), potassium (high and low), calcium (high and low), and 
magnesium (high and low). 
9.4.4. 
Hepatic function and ALT flares 
The number of patients with the following laboratory abnormalities from on-treatment 
evaluations will be summarized by treatment group: 
• 
ALT or AST >5 x ULN, >10 x ULN and >20 x ULN 
• 
Total bilirubin >2 x ULN 
• 
Concurrent (within 1 day) ALT or AST >5 x ULN and total bilirubin >2 x ULN 
• 
Concurrent (within 30 days) ALT or AST >5 x ULN and total bilirubin >2 x ULN 
The following scatterplots will be produced for the following hepatic laboratory parameters: 
• 
Total bilirubin peak vs. AST peak 
• 
Total bilirubin peak vs. ALT peak  
ALT flares are events of special interest. ALT flare definitions are specific to study periods as 
follows: 
• 
On-treatment ALT flare is defined as an ALT measurement >2 × baseline and 
>10 × ULN occurring between the start of study treatment and the end of study 
therapy plus 10 days.  
• 
Post-treatment ALT flare is defined as an ALT measurement >2 × reference and 
>10 x ULN occurring between the end of study treatment plus 11 days to the end of 


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off-treatment follow-up, where the reference is the minimum of the baseline and last 
ALT value up to the end of study treatment plus 10 days.  
Summaries of ALT flares will be presented separately for the on-treatment and follow-up 
periods. The number and percent of patients with one or more ALT flare will be summarized 
by treatment group. Graphical longitudinal displays of ALT flares with HDV RNA changes 
may also be presented.  
Among patients with ALT flares, the number and percent of patients with and without 
concurrent post-baseline laboratory abnormalities (occurring ± 30 days of an ALT flare, 
regardless of study period) will also be summarized. The post-baseline concurrent laboratory 
abnormalities of interest include: 
• 
INR >2 x ULN or prothrombin time  >1.5 x ULN 
• 
Total bilirubin >2.5 x ULN 
Patients with missing ALT data in a given period will be excluded from the analysis.   
9.5. 
Immunogenicity analyses 
Immunogenicity results will be summarized for patients in the safety population who have at 
least one post-baseline test result. Patients who have detectable anti-Lambda antibodies at 
baseline will be assessed for an on-study increase in antibody titer. Patients who lack 
detectable anti-Lambda antibodies at baseline will be assessed for the development of an 
on-study antibody response (anti-drug antibody seroconversion). 
For patients with antibodies at baseline, the number and percent of patients who have 
measurable (defined as ≥5-fold) increases in titer will be reported by treatment group. The 
number and percent of patients who develop anti-drug antibodies to Lambda will be 
summarized by treatment group and scheduled visit. The following will be summarized: 
• 
Incidence of patients who seroconverted (only patients without antibodies at 
baseline); 


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• 
Incidence of patients with neutralizing and non-neutralizing antibodies for patients 
who seroconvert. 
10. 
References 
1. 
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. Statistical principles for clinical trials (E9). ICH 
Harmonized Tripartite Guideline; 1998. 
2. 
Analytikjena. RoboGene HDV RNA quantification kit 2.0. 2017: https://www.analytik-
jena.com/fileadmin/content/products/02_Kits/RoboGene_HDV_RNA_Quantification_Kit
_2_0/Manual_RoboGene_HDV_RNA_Quantification_Kit_2_0_CE.pdf. 
3. 
SAS, Version 9.1, Cary NC: SAS Institute; 2002. 


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11. 
Appendix: Important protocol deviations 
Exhibit 3 shows the important protocol deviations pertaining to the inclusion and exclusion criteria 
as well as on-study important protocol deviations. 


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Exhibit 3. Important protocol deviations 
Protocol requirement 
Programmable 
Important deviation from criterion 
Inclusion criteria: 
 
 
Willing and able to comply with study procedures and provide 
written informed consent 
No 
 
Male or female, 18 to 65 years of age, inclusive 
Yes 
Patient’s baseline age was not between 18 to 65 
years, inclusive. 
Chronic HDV infection of at least 6 months' duration 
documented by a positive HDV Ab test; detectable and 
quantifiable HDV RNA by qPCR at study entry 
Yes 
Patient did not have documented chronic HDV 
infection, defined as at least 6 months’ duration by 
positive HDV Ab test. 
Serum ALT > ULN and <10 × ULN at screening 
Yes 
Patient did not have a baseline serum ALT > ULN 
and < 10 × ULN. 
ECG demonstrating no acute ischemia or clinically significant 
abnormality and a QTcF <450 ms for male patients and <460 ms 
for female patients 
Yes 
Patient had a baseline ECG showing a clinically 
significant abnormality. 
TSH and/or free T4 within 0.8 to 1.2 × ULN, or adequately 
controlled thyroid function as assessed by the investigator 
Yes 
Patient had a baseline TSH or free T4 that is >1.2 
times the normal limit. 
Dilated retinal examination ≤1 year before screening: For 
patients with diabetes, hypertension, or other risk factors for 
retinal disease, performed by a licensed ocular specialist; for all 
other patients, a normal retinal examination as assessed by the 
investigator or a licensed ocular specialist 
Yes 
Patient had an abnormal retinal examination 
finding at baseline or did not have a baseline 
retinal examination performed. 
(continued) 


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Exhibit 3. Important protocol deviations, continued 
Protocol requirement 
Programmable 
Important deviation from criterion 
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 
through 90 days after the last dose of study medication. Female 
patients of childbearing potential are all those except patients 
who are surgically sterile, who have medically documented 
ovarian failure, or who are at least one year postmenopausal. 
Yes 
Female patient did not have evidence of a 
negative serum or urine pregnancy test. 
Willing and able to provide written informed consent 
No 
 
Willing and able to comply with all study procedures 
No 
 
Exclusion criteria: 
 
 
Participation in a clinical trial with, or use of, any 
investigational agent within 30 days of start of screening, or 
treatment with IFNs or immunomodulators within 12 months 
of start of screening 
Yes 
Patient had prior treatment with an IFN therapy 
or regimen within 30 days of start of screening. 
Previous use of Lambda. Patients who previously participated 
in a clinical trial of Lambda but are confirmed to have received 
placebo or other non-Lambda IFNs are allowed. 
Yes 
Patient had prior treatment with Lambda. 
History or evidence of any intolerance or hypersensitivity to 
IFNs or other substances contained in the study medication. 
No 
 
Female patients who are pregnant or breastfeeding. Male 
patients must confirm that their female sexual partners are not 
pregnant. Female patients must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of hCG) within 24 hours prior to the start of 
investigational product. 
Yes 
Female patient did not have evidence of a 
negative serum or urine pregnancy test. 
(continued) 


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Exhibit 3. Important protocol deviations, continued 
Protocol requirement 
Programmable 
Important deviation from criterion 
Current or previous history of decompensated liver disease 
No 
 
Co-infected with HIV or HCV 
Yes 
Patient was HIV-positive at screening. 
Patient was HCV-positive at screening. 
Past history or current evidence of decompensated liver disease 
No 
 
Evidence of significant portal hypertension; current presence or 
history of variceal bleeding 
No 
 
Current evidence or history of ascites requiring diuretics or 
paracentesis, or hepatic encephalopathy 
No 
 
Patients with any of the following abnormalities at screening: 
platelet count <90,000 cells/mm3; WBC count <3,000 cells/mm3; 
ANC <1,500 cells/mm3; hemoglobin <11 g/dL for women and 
<12 g/dL for men; serum creatinine concentration ≥1.5 × ULN; 
or CrCl <50 mL/min by Cockroft-Gault 
Yes 
Patient had one of the following abnormalities at 
screening: (a) platelet count <90,000 cells/mm3, (b) 
WBC count <3,000 cells/mm3, (c) ANC <1,500 
cells/mm3, (d) hemoglobin <11 g/dL for women 
and <12 g/dL for men, (e) serum creatinine 
concentration ≥1.5 x ULN, or (f) CrCl <50 mL/min 
by Cockroft-Gault. 
Evidence of another form of viral hepatitis or another form of 
liver disease 
No 
 
History of hepatocellular carcinoma 
Yes 
Patient had a history of hepatocellular carcinoma. 
Patients with any of the following: current eating disorder or 
alcohol abuse; excessive alcohol intake; alcohol use that will 
interfere with study conduct; or drug abuse within the previous 
6 months before the screening visit with the exception of 
cannabinoids and their derivatives 
No 
 
(continued) 


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Exhibit 3. Important protocol deviations, continued 
Protocol requirement 
Programmable 
Important deviation from criterion 
Prior history or current evidence of any of the following: 
immunologically mediated disease; retinal disorder or 
clinically relevant ophthalmic disorder; any malignancy 
within five years before screening; cardiomyopathy or 
significant ischemic cardiac or cerebrovascular disease; 
chronic pulmonary disease associated with functional 
impairment; pancreatitis; severe or uncontrolled 
psychiatric disorder; active seizure disorder; or bone 
marrow or solid organ transplantation 
No 
 
Other significant medical condition that may require 
intervention during the study. 
No 
 
Therapy with an immunomodulatory agent; IFN-α (IFN 
alfa-2a or IFN alfa-2b, or pegylated IFN alfa-2a or 
alfa-2b); cytotoxic agent, or systemic corticosteroids 
within 12 months before screening 
No 
 
Use of telbivudine within three months before screening 
or during the study 
Yes 
Patient received telbivudine within 3 months prior to 
screening. 
Current use of Heparin or Coumadin 
Yes 
Patient received Heparin or Coumadin within 3 months 
prior to screening. 
Received blood products within 30 days prior to study 
randomization 
No 
 
Use of hematologic growth factors within 30 days prior 
to study randomization 
No 
 
Systemic antibiotics, antifungals, or antivirals for 
treatment of active infection other than HBV within 
14 days of study randomization 
No 
 
(continued) 


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Exhibit 3. Important protocol deviations, continued 
Protocol requirement 
Programmable 
Important deviation from criterion 
Any prescription or herbal product that is not approved 
by the investigator 
No 
 
Long-term treatment (>2 weeks) with agents that have a 
high risk for nephrotoxicity or hepatotoxicity, should be 
discussed with the medical monitor 
No 
 
Receipt of systemic immunosuppressive therapy within 
the three months before start of screening 
No 
 
On-study criteria: 
 
 
Randomization vs. treatment 
Yes 
Patient received an incorrect study treatment, i.e., a 
treatment that is not what the patient was randomized to 
receive. 
Randomization vs. treatment 
No 
Patient manually identified in protocol deviation 
spreadsheet who was randomized to 180 mcg but was 
moved to the 120 mcg group before receiving their first 
dose of study drug. 
Anti-HDV therapy 
Yes 
Patient received alternative anti-HDV therapy. 
Anti-HBV therapy 
Yes 
Patient did NOT receive one of the following medications 
from Day 1 to end of study: entecavir or tenofovir 
(continued) 


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Exhibit 3. Important protocol deviations, continued 
Protocol requirement 
Programmable 
Important deviation from criterion 
Dose interruption, reduction, and discontinuation 
criteria, as defined in Section 5.4.3 of the protocol 
Yes 
Patient’s dose was NOT reduced after any of the 
following events: 
• 
ANC ≥ 500/mm3 and < 750/mm3: reduce to DR1 
• 
Platelets < 50,000: reduce to DR2 
Patient’s dose was NOT interrupted after any of the 
following events: 
• 
ANC < 500/mm3 
• 
ALT (or AST) ≥ 15 × ULN  
and 
total bilirubin (TBILI) and/or INR < Grade 2 
• 
TBILI > 2.5 × ULN 
and 
DB > 3 × ULN 
Patient’s treatment was NOT discontinued after any of the 
following events: 
• 
ANC < 500/mm3 occurred and did not resolve 
within 4 weeks 
• 
ANC < 500/mm3 recurred at DR2 
• 
Two consecutive occurrences of platelets < 25,000 
ALT (or AST) ≥ 15 × ULN  
and 
TBILI and/or INR < Grade 2  
occurred and did not resolve within 4 weeks 
(continued) 


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E:\Proj\Eiger\Lambda\SAP\EIG-LMD-001_SAP_Final_v3.docx\AA 
Exhibit 3. Important protocol deviations, continued 
Protocol requirement 
Programmable 
Important deviation from criterion 
 
 
• 
Two consecutive occurrences of 
ALT (or AST) ≥ 5×ULN 
and 
TBILI and/or INR ≥ Grade 2 
• 
TBILI > 2.5 × ULN 
and 
DB > 3 × ULN 
occurred and did not resolve within 2 weeks 
• 
TBILI > 2.5 × ULN 
and 
DB > 3 × ULN 
recurred at DR2 
• 
All of the following occurred simultaneously: 
o 
ALT > 10 × ULN 
o 
ALT > 5 × baseline or nadir, whichever is lower 
o 
Total bilirubin > 5 × ULN 
o 
INR > 1.5 × ULN confirmed with local 
confirmation 
Efficacy labs 
Yes 
Patient did not have the following at baseline and Weeks 
12, 24, 48, and 72: 
• 
HDV RNA levels  
• 
ALT values 
• 
HBsAg, HBsAb, HBeAg, and HBeAb levels. 
Patient did not have Fibroscan results at baseline and 
Weeks 48 and 72.