Conditions: Hepatitis D
Keywords: Delta Hepatitis Hepatitis D Liver Disease Hepatitis D Virus Chronic Hepatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 22
Healthy volunteers: no

Brief summary:
Background:

\- Chronic hepatitis D is a liver disease caused by the hepatitis D virus (HDV). It can be severe and progressive. Most people with hepatitis D will develop scarring and damage to the liver. There is no FDA approved drug to treat chronic hepatitis D. Researchers want to know if the drugs lonafarnib and ritonavir can help people with chronic hepatitis D.

Objective:

\- To find out if treatment of hepatitis D with lonafarnib and ritonavir is safe and effective.

Eligibility:

\- People 18 years of age and older with chronic hepatitis D. They must not have HIV or other major illnesses.

Design:

* Participants will be screened with medical history, physical exams, and blood tests.
* Participants will have 24 weeks of treatment. They will then have 24 weeks of follow-up.
* Participants will be in 1 of 6 treatment groups. Those in each group will receive different doses of the study drugs. Some groups will start with placebo but will receive treatment after 3 months of placebo.
* Participants will also take drugs to treat hepatitis B.
* Participants will have many visits. These will include:
* One three-day stay at the Clinical Center
* Physical exams
* EKG: small sticky patches will be put on the chest, arms, and legs to trace heart rhythm
* Ultrasounds of the abdomen
* Urine and blood tests
* Stool samples
* Eye exams
* Evaluations by a reproductive endocrinologist (women) or urologist (men). Men may provide a sperm sample (optional).

Detailed description:
Chronic delta hepatitis is a serious form of chronic liver disease caused by infection with the hepatitis D virus (HDV), a small RNA virus that requires farnesylation of its major structural protein (HDV antigen) for replication. We propose to treat 21 adult patients with chronic delta hepatitis using the combination of the farnesyltransferase inhibitor (FTI) lonafarnib (LNF) and the protease inhibitor ritonavir (RTV). LNF has been shown to decrease serum quantitative HDV RNA in patients with chronic delta hepatitis infection, but dosing is limited by its side effects. RTV inhibits one of the cytochrome P-450 systems that metabolizes LNF leading to higher serum levels of LNF with minimal side effects. In this randomized, double-blinded, placebo-controlled study, there will be six groups of patients; Group 1(4 patients) will receive LNF/RTV 50/100 mg daily for 24 weeks, Group 2 (4 patients) will receive LNF/RTV 75/100mg daily for 24 weeks, Group 3 (4 patients) will receive LNF/RTV 100/100mg daily for 24 weeks, Group 4, 5 and 6 (3 patients for each group) will initially receive placebo for 12 weeks followed by either LNF/RTV 50/100 mg daily (3 patients) or LNF/RTV 75/100mg daily (3 patients) or LNF/RTV 100/100 mg daily (3 patients) for 12 weeks. After dosing, all patients will be monitored for 24 weeks off therapy. Nucleos(t)ide analogue therapy will be instituted during this study to prevent the possibility of hepatitis B virus reactivation/flare; Patients on pre-existing nucleos(t)ide analogues will be continued and patients not on pre-existing therapy will receive either entecavir or tenofovir for 48 weeks. Patients with quantifiable HDV RNA in serum and elevated aminotransferases will be enrolled. Before receiving therapy, patients will be evaluated for at least 3 visits with regular testing for HDV RNA quantitation and alanine aminotransferase (ALT) levels and will undergo Clinical Center admission for medical evaluation, timed blood draws and to start therapy. At each clinic visit, patients will be questioned about side effects, symptoms and quality of life, undergo focused physical examination, and have blood drawn for complete blood counts, HDV RNA, and routine liver tests (including ALT, aspartate aminotransferase , alkaline phosphatase, direct and total bilirubin, and albumin). At the end of the treatment, patients will undergo repeat physical examination, assessment of symptoms (using a symptom scale questionnaire), complete blood counts, routine liver tests, and hepatitis B and D viral markers. The primary therapeutic endpoint will be a decline of HDV RNA viral titer of 2 logs at the end of therapy. The primary safety endpoint will be the ability to tolerate the drugs at the prescribed dose for the full course of therapy. Several secondary endpoints will be measured, including side effects, ALT levels, maintained virological response, undetectable HDV RNA in the serum, loss of HBsAg and symptoms. Therapy will be stopped for intolerance to lonafarnib and/or ritonavir (which will be carefully defined). This clinical trial is designed as a phase 2a study assessing the antiviral activity, safety and tolerance of three different doses of lonafarnib and ritonavir.

Arms:
arm 1: Lonafarnib/Ritonavir at 50 mg/100 mg daily for 24 weeks followed by 24 weeks of off therapy follow-up. arm 2: Lonafarnib/Ritonavir at 75 mg/100 mg daily for 24 weeks followed by 24 weeks of off therapy follow-up. arm 3: Lonafarnib/Ritonavir at 100 mg/100 mg daily for 24 weeks followed by 24 weeks of off therapy follow-up. arm 4: Placebo for 12 weeks then Lonafarnib/Ritonavir at 50 mg/100 mg daily for 12 weeks followed by 24 weeks of off therapy follow-up. arm 5: Placebo for 12 weeks then Lonafarnib/Ritonavir at 75 mg/100 mg daily for 12 weeks followed by 24 weeks of off therapy follow-up. arm 6: Placebo for 12 weeks then Lonafarnib/Ritonavir at 100 mg/100 mg daily for 12 weeks followed by 24 weeks of off therapy follow-up.

Interventions: intervention 1: Lonafarnib intervention 2: Ritonavir intervention 3: Placebo
Intervention descriptions: intervention 1: prenylation inhibitor to be administered daily at doses of 50 mg, 75 mg or 100 mg. intervention 2: FDA approved drug for use of boosting other drugs. Will be used to boost Lonafarnib as they both use the same cytochrome P450 system. Will be administered at 100 mg daily. intervention 3: Placebo

Protocol document:
Prot_SAP_000.pdf: 
Heller 
HDV LNFR4 
January 24, 2018 
1 
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY 
DISEASES 
 
DATE: January 24, 2018 
 
 
CLINICAL PROTOCOL NO.: 15-DK-0170 
 
 
 
 
 
 
IND NO.: 113137 
IND SPONSOR:  NIDDK 
 
TITLE: Treatment of Chronic Delta Hepatitis with Lonafarnib and Ritonavir. 
 
SHORT TITLE: Lonafarnib and Ritonavir for Delta Hepatitis 
 
IDENTIFYING WORDS: Antiviral agents, Viral Hepatitis, Hepatitis D Virus, Delta 
Hepatitis, Chronic Hepatitis, Cirrhosis, Farnesyltransferase inhibitors, Lonafarnib, 
Prenylation inhibitors 
 
PRINCIPAL INVESTIGATOR: *Theo Heller, M.D. LDB, 10/9B16 402-7147 
 
LEAD ASSOCIATE INVESTIGATOR: *Christopher Koh, M.D., LDB: CRC, 5-2740, 
443-9402 
 
ASSOCIATE INVESTIGATORS:  
 
Barbara Rehermann, M.D., NIDDK/LDB: 10/9B16, 4961721 
 
  
 
 
 
ESTIMATED DURATION OF STUDY: 5 YEARS 
 
NUMBER AND TYPE OF PATIENTS: 21 patients with chronic delta hepatitis, ages 
greater than or equal to 18 years, both male and female. 
 
SUBJECTS OF STUDY: 
Number 
 
Sex 
 
 
Age Range 
 
Patients 
 
21 
 
Male & Female 
 
³ 18 years 
 
Volunteers 
 
None 
 
PROJECT USES IONIZING RADIATION: Yes, for medically indicated reasons only. 
PROJECT USES “DURABLE POWER OF ATTORNEY”: No 
 
OFF-SITE PROJECT:  No 
 
MULTI-INSTITUTIONAL PROJECT:  No 
 
* Designates investigators who can obtain consent. 
 
 
 
 
 
 


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HDV LNFR4 
January 24, 2018 
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HDV LNFR4 
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PRECIS 
 
Chronic delta hepatitis is a serious form of chronic liver disease caused by 
infection with the hepatitis D virus (HDV), a small RNA virus that requires farnesylation 
of its major structural protein (HDV antigen) for replication. We propose to treat 21 adult 
patients with chronic delta hepatitis using the combination of the farnesyltransferase 
inhibitor (FTI) lonafarnib (LNF) and the protease inhibitor ritonavir (RTV).  LNF has 
been shown to decrease serum quantitative HDV RNA in patients with chronic delta 
hepatitis infection, but dosing is limited by its side effects.  RTV inhibits one of the 
cytochrome P-450 systems that metabolizes LNF leading to higher serum levels of LNF 
with minimal side effects. In this randomized, double-blinded, placebo-controlled study, 
there will be six groups of patients; Group 1(4 patients) will receive LNF/RTV 50/100 
mg daily for 24 weeks, Group 2 (4 patients) will receive LNF/RTV 75/100mg daily for 
24 weeks, Group 3 (4 patients) will receive LNF/RTV 100/100mg daily for 24 weeks, 
Group 4, 5 and 6 (3 patients for each group) will initially receive placebo for 12 weeks 
followed by either LNF/RTV 50/100 mg daily (3 patients) or LNF/RTV 75/100mg daily 
(3 patients) or LNF/RTV 100/100 mg daily (3 patients) for 12 weeks.  After dosing, all 
patients will be monitored for 24 weeks off therapy.  Nucleos(t)ide analogue therapy will 
be instituted during this study to prevent the possibility of HBV reactivation/flare; 
Patients on pre-existing nucleos(t)ide analogues will be continued and patients not on 
pre-existing therapy will receive either entecavir or tenofovir for 48 weeks. Patients with 
quantifiable HDV RNA in serum and elevated aminotransferases will be enrolled. Before 
receiving therapy, patients will be evaluated for at least 3 visits with regular testing for 
HDV RNA quantitation and alanine aminotransferase (ALT) levels and will undergo 
Clinical Center admission for medical evaluation, timed blood draws and to start therapy. 
At each clinic visit, patients will be questioned about side effects, symptoms and quality 
of life, undergo focused physical examination, and have blood drawn for complete blood 
counts, HDV RNA, and routine liver tests (including ALT, AST, alkaline phosphatase, 
direct and total bilirubin, and albumin). At the end of the treatment, patients will undergo 
repeat physical examination, assessment of symptoms (using a symptom scale 
questionnaire), complete blood counts, routine liver tests, and hepatitis B and D viral 
markers. The primary therapeutic endpoint will be a decline of HDV RNA viral titer of 2 


Heller 
HDV LNFR4 
January 24, 2018 
4 
logs at the end of therapy.  The primary safety endpoint will be the ability to tolerate the 
drugs at the prescribed dose for the full course of therapy.  Several secondary endpoints 
will be measured, including side effects, ALT levels, maintained virological response, 
undetectable HDV RNA in the serum, loss of HBsAg and symptoms.  Therapy will be 
stopped for intolerance to lonafarnib and/or ritonavir (which will be carefully defined).   
This clinical trial is designed as a phase 2a study assessing the antiviral activity, safety 
and tolerance of three different doses of lonafarnib and ritonavir. 
 
 


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HDV LNFR4 
January 24, 2018 
5 
Background 
 
A. Chronic Delta Hepatitis 
 
The hepatitis D virus (HDV) is an incomplete RNA virus, which is composed of a 
1.7 kb single-stranded circular genomic RNA, virally encoded small and large delta 
antigens, and a surrounding lipid envelope.1 HDV only infects persons who are also 
infected with hepatitis B virus (HBV), because its lipid envelope is embedded with HBV 
surface antigen (HBsAg).2-5 The HBsAg envelope protein provided by HBV protects the 
HDV nucleocapsid antigen and provides a means for the virus to enter and exit the 
hepatocyte.   HBV and its antigens are not necessary for the replication of HDV once it 
has entered the cell, but they are necessary for spread of the infection to other cells, the 
development of acute and chronic hepatitis D and transmission of delta hepatitis to 
others.6     
 Delta hepatitis is the most severe and dreaded form of human viral hepatitis.  
HDV infection leads to chronic hepatitis in a high proportion of persons, is associated 
with progression to cirrhosis in 5 to 10 years in up to 80% of cases and poor outcomes.7  
Because of the unique nature of HDV and its requirement for the helper function of HBV 
infection, delta hepatitis occurs only in persons who also have hepatitis B.  HDV 
infection is found worldwide2 but most commonly in Central Africa, the Amazon Basin 
of South America, Mongolia, and in Eastern European countries.  In the United States, 
delta hepatitis is most common among immigrants from areas of the world where HDV 
infection is endemic and in persons who have multiple exposures to hepatitis, particularly 
injection drug users and persons with hemophilia who received blood products before 
1986.  Delta hepatitis occurs either as co-infection with acute hepatitis B or as super-
infection in patients with pre-existing chronic HBV infection.8 Hepatocellular carcinoma 
may develop as a complication of cirrhosis in some cases.9 The complications associated 
with hepatitis B and D are identical except that the progression to cirrhosis is more rapid 
in hepatitis D.  Thus, delta hepatitis shares epidemiological patterns and clinical features 
with hepatitis B, but tends to be more severe and more rapidly progressive. The 


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HDV LNFR4 
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6 
seriousness of chronic hepatitis D has led to attempts to develop therapies for this chronic 
viral infection. 
Currently, there is no satisfactory therapy for HDV infection, nor is there any 
FDA approved therapy.  Several studies have shown a lack of efficacy of nucleos(t)ide 
analogues used in chronic HBV infection for chronic HDV.10, 11 The American 
Association for the Study of Liver Diseases (AASLD) guidelines suggest therapy with 
alpha interferon for chronic HDV infection, however recent results have identified the 
need for alternative therapies.3, 4, 12-14 In a large multicenter randomized clinical trial, the 
Hep-Net/International Delta Hepatitis Intervention Trial (HIDIT 1), sustained HDV RNA 
clearance with interferon based therapy with or without adefovir for 48 weeks was 
successful in only about a quarter of patients with chronic HDV infection.15 In a follow-
up study, HIDIT-2, which increased treatment duration up to 96 weeks with peginterferon 
plus tenofovir or placebo, more than one third of patients, experienced a post-treatment 
relapse.16 Additionally, the Liver Diseases Branch of the NIDDK has recently published 
its long-term peginterferon HDV study, which evaluated increasing the doses of 
peginterferon (up to 360 mcg/wk) for up to 5 years.  In this study, only 39% achieved the 
primary endpoint of histological improvement or loss of serum HDV and HBsAg at 3 
years and at the end of the study, only 23% seroconverted HBsAg.17 Thus, given the 
unsatisfactory results of interferon-based therapies against chronic HDV infection, 
alternative therapies have been sought.18  
More recently, in a phase 2a double-blinded, randomized, placebo-controlled 
clinical trial, the Liver Diseases Branch of the NIDDK has evaluated the safety and utility 
of the prenylation inhibitor, Lonafarnib, in patients with chronic HDV (12-DK-0046).  
Compared to placebo, patients that received lonafarnib 100 mg BID for 28 days 
experienced a significant mean HDV RNA decline of 0.73 log (p=0.04) and patients who 
received lonafarnib 200 mg BID experienced a significant mean HDV RNA decline of 
1.54 logs (p=0.002)(unpublished data, manuscript in preparation).  
 
B. Prenylation Inhibitors 
Prenylation is a post-translational lipid modification that involves the covalent 
addition of either farnesyl or geranylgeranyl prenyl lipids derived from mevalonic acid to 


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HDV LNFR4 
January 24, 2018 
7 
conserved cysteine residues at or near the C-terminus of proteins.1 These reactions are 
catalyzed by farnesyltransferase (FTase) or the geranylgeranyltransferases (GGTases).6, 
19, 20 The substrate for FTase or GGTase I is a characteristic tetrapeptide found in the 
amino acid sequence of the protein referred to as a CXXX box motif (where C is a 
cysteine and X is one of the last three amino acids at the C-terminus of the protein).19 The 
effect of prenylation is to promote membrane association of the modified protein.  
Prenylation also plays a major role in protein-protein interactions.1, 19 
The novel idea of prenylation inhibition was originally developed as a therapeutic 
approach for cancer, as exemplified by the farnesyltransferase inhibitor (FTI) BZA-5B to 
prevent prenylation of the farnesylated oncogene RAS.1 Various phase I/II/III trials in 
oncology with FTIs have revealed a favorable side effect profile, with good safety and 
relative lack of toxicity, and ease of administration as they are taken orally.6, 20  
 
 
C. Prenylation Inhibitors in Chronic Delta Hepatitis 
Prenylation plays a vital role in the viral life cycle of HDV, which allows for 
therapeutic opportunities for eradication.  The HDV genome has a single open-reading 
frame that can encode two proteins: a small or a large delta antigen.  The large delta 
antigen differs from the small one by having an additional 19 amino acids on its C-
terminus. The production of small and large delta antigens is dependent upon editing of 
the HDV RNA to change the stop codon which ends the production of small delta antigen 
and allows “read through” to the next stop codon which produces the large delta antigen.  
The small delta antigen is essential for genome replication, whereas the large delta 
antigen (LHDAg) performs other functions such as transactivation of various genes and 
mediation of assembly and release of HBsAg-enveloped particles6.  In both cell-free 
translation reactions and in intact cells, it has been shown that the LHDAg is subject to 
prenylation.1, 20 Genetic disruption of the CXXX box prevents prenylation of LDHAg and 
its ability to interact with, and form secreted particles with, HBsAg.19   Thus, prevention 
of prenylation is a reasonable approach to blocking the HDV life cycle.  Use of 
prenylation inhibitors has been evaluated with success in vitro in cell culture as well as in 
vivo in a mouse model of HDV replication.1, 6, 19, 20   


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HDV LNFR4 
January 24, 2018 
8 
Initial studies in mice with the FTI BZA-5B in HDV have shown it to be a potent 
inhibitor of large delta antigen prenylation and able to specifically inhibit the prenylation-
dependent production of HDV virus-like particles in a dose-dependent manner.1 
Continued evaluation with both BZA-5B and FTI-277 revealed no effect on general 
protein synthesis; however, there was significant prenylation inhibition on the production 
of complete, infectious HDV virions.20 More recently, in an in vivo mouse model of 
HDV, these compounds were able to completely clear HDV viremia to below the limit of 
detection.6 These results demonstrate that prenylation inhibitors can indeed effectively 
inhibit HDV viremia and may prove to be an important therapeutic target in patients with 
hepatitis D infection.  Lonafarnib is an orally bioavailable tricyclic farnesyltransferase 
inhibitor that is metabolized by the cytochrome P-450 (3A4) system and has been shown 
to have anti-tumor activity in various phase I, II and III trials and anti-HDV properties in 
preclinical models.   
Recently, the Liver Diseases Branch of the NIDDK completed a phase 2A 
randomized, double-blinded placebo-controlled trial evaluating Lonafarnib for 28 days in 
the patients with chronic HDV (12-DK-0046).  In this first-in-human study for patients 
with chronic HDV infection, compared to placebo, patients who received lonafarnib 100 
mg orally twice daily experienced a 0.73 log IU/ml decline of HDV RNA in serum 
(p=0.04) and patients who received lonafarnib 200 mg orally twice daily experienced a 
1.54 log IU/ml decline of HDV RNA in serum (p=0.002) (Figure 1).  Mean lonafarnib 
serum concentrations significantly correlated with mean change HDV RNA from 
baseline to the end of therapy (R2=0.76, p<0.0001) (Figure 2). As expected, since 
lonafarnib works on host machinery, there was no evidence of viral resistance. In the 
lonafarnib 100 mg BID group, side effects included mild nausea (25%), diarrhea (37.5%), 
anorexia (12.5%), and abdominal bloating (12.5%). In the lonafarnib 200 mg BID group, 
side effects included nausea (75%), diarrhea (75%), anorexia (62.5%), dyspepsia (75%), 
vomiting (37.5%), mean weight loss of 4kg (75%).  There were no grade 3 or 4 adverse 
events nor serious adverse events (unpublished data, manuscript in preparation). Because 
of weight loss, as well as other gastrointestinal side effects, in the patients who received 
the higher dose of lonafarnib, it is intended to use the lower dose of lonafarnib with 
ritonavir (to boost serum levels) and avoid the gastrointestinal side effects of the higher 


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HDV LNFR4 
January 24, 2018 
9
dose. 
Fig.1 HDV RNA decline after 28 days of therapy 
 
Fig.2 Correlation between serum lonafarnib levels with change in serum 
HDV RNA. 
 
Placebo
100mg BID 
200mg BID
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
Log HDV RNA Decline 
IU/mL
p=0.04
p=0.01
p=0.002
Lonafarnib Dose
0.13
0.73
1.54
0
1000
2000
3000
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
 Mean Serum Lonafarnib Concentration (ng/mL)
Mean Change HDV RNA From 
Baseline to Day 28 (log IU/mL)
r2=0.78


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HDV LNFR4 
January 24, 2018 
10 
 
 D. Concomitant use of Ritonavir (Booster effect) 
Through inhibition of metabolic enzymes including cytochrome P-450 CYP3A4 
and drug transporters, ritonavir has been utilized as a booster mechanism to increase the 
bioavailability of concomitant drugs.21 Ritonavir has historically been used in HIV as a 
booster to enhance the bioavailability and efficacy of other protease inhibitors to yield 
increased and improved penetration into HIV reservoirs. This effect is achieved through 
ritonavir’s ability to inhibit the cytochrome P450 CYP3A4 enzyme, thereby reducing the 
metabolism of concomitant administered protease inhibitors leading to changes their 
pharmacokinetic parameters, including area under the curve (AUC), maximum 
concentration, minimum concentration and half life.22 The use of ritonavir as a 
therapeutic booster in patients with chronic liver disease and chronic hepatitis B and/or C 
have been evaluated successfully in multiple previous studies.23-27 In hepatitis C, one 
such successful example of the use of ritonavir with Danoprevir, which successfully 
enhanced the pharmacokinetic parameters of Danoprevir, thus allowing a lower dose of 
danoprevir and enabling higher plasma trough concentrations with lesser exposure to 
Danoprevir.28-30 Ritonavir significantly inhibited Danoprevir metabolism, including the 
production of reactive metabolites, which reduced the risk of alanine aminotransferase 
elevation that was observed with high dose unboosted Danoprevir.31 In chronic HDV 
infection, there are no published studies to date evaluating ritonavir as a therapeutic 
booster.  However, given that the metabolism of lonafarnib is mediated via CYP3A4 (the 
same enzyme that ritonavir inhibits), one would expected to see enhanced 
pharmacokinetic parameters at lower doses as compared to monotherapy with 
lonafarnib.32 In a recently completed small proof-of-concept dose finding study in 
Ankara, Turkey (LOWR-HDV-1), the combination of lonafarnib 100 mg twice daily and 
ritonavir 100 mg daily has resulted in a mean HDV RNA decline of >2 log IU/mL (range, 
2.37 to >5) with normalization of ALT after 5 weeks of therapy in 2 of 3 patients 
(unpublished results).  The combination of lonafarnib and ritonavir was well tolerated 
and safe for 8 weeks and serum lonafarnib concentrations were greatly increased with 
ritonavir (approximately 3x) compared to lonafarnib monotherapy at the same dose.  
In an ongoing follow-up study in Ankara, Turkey (LOWR-HDV-2) that is 
evaluating differing doses of lonafarnib and ritonavir (LNF/RTV 100/50 mg twice daily, 


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HDV LNFR4 
January 24, 2018 
11 
LNF/RTV 100/100 mg once daily, LNF/RTV 150/100 mg once daily and LNF/RTV 
100/100 mg twice daily) for 3 months, preliminary results show a mean HDV RNA 
decline >1.5 log IU/ml in 8 patients after 1 month of therapy. Notably, in this ongoing 
study, the dosing of LNF/RTV 100/100 mg once daily has shown a continuous HDV 
RNA decline with a mean decline of  >3log HDV RNA IU/ml (unpublished results). This 
evidence suggests that ritonavir could be used as a pharmacokinetic booster of lonafarnib 
as it appears to optimize the pharmacokinetic profile of lonafarnib while allowing for a 
lower dose (with less side effects) and still maintaining the antiviral activity of 
lonafarnib. 
 
E.  Interaction between HBV and HDV during Therapy 
Patients with chronic delta hepatitis have both HDV and HBV infection, yet most 
patients with delta hepatitis have detectable serum HBsAg with negative HBeAg, and 
have low levels of HBV DNA in serum.  It seems that HDV replication competes with, 
and inhibits HBV replication.  An important consideration, however, is that therapeutic 
inhibition of one virus may be accompanied by an increase in replication of the other.  
At the present time, a 4 to 6 month course of alpha interferon therapy is an 
approved therapy of chronic hepatitis B.33, 34 Therapy is recommended only for patients 
with elevated serum aminotransferase activity chronic hepatitis on liver biopsy and either 
HBeAg or high levels of HBV DNA in serum.  Pegylated interferon alfa-2a has also been 
approved for treatment of chronic HBV in the United States and has been suggested to 
have similar or slightly improved efficacy with more convenient administration then 
standard alpha interferon.34 The recommended treatment duration with peginterferon alfa- 
2a in patients with chronic HBV is for 48 weeks.34  The Liver Disease Branch of the 
NIDDK has studied the effects of long-term therapy of peginterferon alfa-2a in the 
treatment of patients with chronic delta hepatitis for a median of 140 weeks. The results 
showed only 39% of the patients responded to therapy with three seroconverting 
HBsAg.17  
 Other approved therapies for chronic hepatitis B include oral 
nucleoside/nucleotide analogues: lamivudine (Epivir-HBV, 3TC), adefovir dispivoxil 
(bis-POM PMEA, Hepsera), tenofovir disoproxil fumarate (Viread), entecavir 


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HDV LNFR4 
January 24, 2018 
12 
(Baraclude), and L-deoxythymidine (Telbivudine/LdT, Tyzeka). Currently, Entecavir or 
Tenofovir are considered first line therapies for chronic hepatitis B. 34  These agents are 
potent inhibitors of the HBV polymerase and reduce serum levels of HBV DNA, which is 
usually followed by improvements in serum aminotransferase levels and liver histology.  
Lamivudine monotherapy has been evaluated in chronic hepatitis D by the Liver 
Diseases Branch (95-DK-199) 35 and by investigators in Europe36 and shown to be 
without beneficial effect.  Lamivudine resulted in rapid decreases in HBV DNA levels 
(which were low to begin with) but had no effect on HDV RNA levels, serum 
aminotransferase levels, or histology.  Similarly, short-term combination therapy of alpha 
interferon and lamivudine has been found to be largely ineffective.37 A possible use of 
lamivudine in chronic delta hepatitis, however, is the uncommon patient with high levels 
of HBV DNA.  The pattern of high HBV DNA levels despite chronic delta hepatitis is 
found in approximately 20% of patients with this disease seen at the Clinical Center of 
the NIH.  In these patients, inhibition of HBV may be important particularly because 
suppression of HDV RNA may be followed by rises in HBV DNA levels.  In this current 
study, clinically approved nucleoside analogues for chronic HBV infection will be used.   
 
F. Role of intestinal microbiome in chronic liver diseases 
With increasing appreciation of the gut-liver axis, the role of the intestinal 
microbiome and bacterial translocation on the pathogenesis of liver disease and its 
progression including inflammation and fibrosis has been a recent focus of investigators.  
In patients with chronic hepatitis B, investigators have described extensive 
differences between patients with and without cirrhosis regarding the fecal microbiota 
community and altered composition of intestinal Bifidobacterium with a shift from 
beneficial species to opportunistic pathogens in patients with cirrhosis.38, 39 Further 
studies have described that the existence of cirrhosis (regardless of etiology) is associated 
with microbial dysbiosis and changes in intestinal microbial composition.  Specifically, 
in patients with cirrhosis, pathogenic species appear to be more likely to translocate 
across the gut wall 40.  
In addition to the data in cirrhotic patients, emerging data suggests bacterial 
translocation (BT) may occur at earlier stages of compensated liver disease and can also 


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HDV LNFR4 
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13 
contribute to progression of liver disease. Kupffer cells (KC) express Toll-like Receptors 
(TLRs) that are highly sensitive to lipopolysacharide LPS-triggered TLR activation. 
Additionally, KC, are also potent activators of hepatic stellate cells (HSC) which play a 
vital role in hepatic fibrogenesis. 41 In an in vivo mouse model, Seki et al reported a 
mechanism that promotes the pro-fibrogenic response where LPS binds to TLR-4 on the 
HSC which, in turn, leads to KC chemotaxis as well as to sensitization of HSC to TGF-β 
signaling.42 Henao-Mejia and Elinav in another landmark study described that bacterial 
translocation through TLR-4 and TLR-9 dependent pathways drove non-alcoholic fatty 
liver disease (NAFLD) and its progression to steatohepatitis.43 These and other studies 
outline the role of microbial products in activation of key intracellular events involved in 
liver inflammation and fibrosis, thus conceptually establishing a link between BT to the 
portal system and liver disease progression. Other studies have also suggested that BT to 
the systemic circulation may occur in earlier stages of liver fibrosis. 44, 45 In the serum of 
chronic hepatitis B and C patients in different stages of liver fibrosis, elevated levels of 
soluble CD14 (sCD14), a macrophage-derived marker of LPS bioreactivity were 
identified. 46 In addition, evidence of portosystemic shunting and decreased Kupffer cell 
function was described in pre-cirrhotic HCV patients using highly sensitive quantitative 
liver function tests and SPIO-MRI imaging respectively47, 48. 
Microbiome diversity and bacterial translocation in chronic HDV patients has not 
been described in the literature. We plan to assess the fecal microbiota diversity and its 
bacterial translocation in chronic hepatic D (HDV) and their changes during treatment 
with lonafarnib and ritonavir. The initial focus would be to recapitulate the findings of 
dysbiosis seen in other liver diseases in patients with HDV. 
 
Hypothesis And Aims 
 
Therapy with lonafarnib and ritonavir will lead to a significant decline in hepatitis 
D virus levels. 
 
Assessment of Response To Therapy: 
Primary Therapeutic End Point: 


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HDV LNFR4 
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14 
Decline of HDV RNA quantitative measurements of >2 logs from baseline at 12 
and 24 weeks of therapy with lonafarnib and ritonavir. 
Primary Safety End Point: 
The ability to tolerate lonafarnib and ritonavir at different doses for 12 and 24 
weeks of therapy. Discontinuation of the medication by the clinical team or patient will 
be considered a failure to tolerate the medicine. 
 
Secondary End Points: 
1. Undetectable HDV RNA in serum by quantitative measurements at 
the end of therapy.  
2. Sustained undetectable HDV RNA in serum at weeks 12 and 24 
post treatment follow up.  
3. Comparison of serologic HDV RNA decline between different 
doses of lonafarnib.  
4. Comparison HDV RNA decline between 12 and 24 weeks of 
therapy at the differing doses. 
5. Normalization of serum ALT (ALT <20 or AST <20 U/L in 
females and ALT <31 or AST <31 U/L in males) at the end of 
therapy, at week 12 of post-therapy follow-up and at week 24 of 
post-therapy follow-up.  
6. Comparison of ALT changes between different doses of 
lonafarnib.  
7. Loss of HBsAg from the serum at the end of therapy, at week 12 of 
post-therapy follow-up and at week 24 of post-therapy follow-up.  
8. Changes in symptom scale measurements and quality of life 
before, during and after therapy. 
9. Seroconversion of HBsAg at the end of therapy, at week 12 of 
post- therapy follow up and at week 24 of post-therapy follow-up. 
10. Changes in the fecal microbiome before and after treatment. 
11. Comparison of fecal microbiome analysis between different 
groups. 
 


Heller 
HDV LNFR4 
January 24, 2018 
15 
Protocol 
 
This is a randomized, double-blinded, placebo-controlled study treating 21 adult 
patients with chronic delta hepatitis with different doses of lonafarnib plus ritonavir for 
12 weeks and 24 weeks. All patients will be monitored with quantitative HDV RNA and 
HBV DNA levels as well as routine safety measures and liver function tests. 
 
A. Entry Criteria 
 
Inclusion Criteria: 
1. Age 18 years or above, male or female. 
2. Serum alanine or aspartate aminotransferase activities above the upper limit of 
normal (ALT ≥20 or AST ≥20 U/L in females and ALT ≥30 or AST ≥30 U/L in 
males) on an average of three determinations taken during the previous 6 months 
at the NIH clinical center.  The mean of the three determinations will be defined 
as “baseline” levels. 
3. Presence of anti-HDV in serum. 
4. Presence of quantifiable HDV RNA in serum. 
 
Exclusion Criteria: 
1. Decompensated liver disease, defined by bilirubin >4mg/dL, albumin <3.0 
gm/dL, prothrombin time >2 sec prolonged, or history of bleeding esophageal 
varices, ascites or hepatic encephalopathy. Laboratory abnormalities that are not 
thought to be due to liver disease may not necessarily require exclusion. Patients 
with ALT levels greater than 1000 U/L (>25 times ULN) will not be enrolled but 
may be followed until three determinations are below this level. 
2. Pregnancy, active breast-feeding, or inability to practice adequate contraception, 
in women of childbearing potential or in spouses of such women. Adequate 
contraception is defined as vasectomy in men, tubal ligation in women, or use of 
two barrier methods such as condoms and spermicide combination, birth control 
pills, an intrauterine device, Depo-Provera, or Norplant. 


Heller 
HDV LNFR4 
January 24, 2018 
16 
3. Significant systemic or major illnesses other than liver disease, including, but not 
limited to, congestive heart failure, renal failure (eGFR <50 ml/min), organ 
transplantation, serious psychiatric disease or depression (only if felt to be at high 
risk by the NIH psychiatric consultation service), and active coronary artery 
disease. 
4. Systemic immunosuppressive therapy within the previous 2 months.  
5. Evidence of another form of liver disease in addition to viral hepatitis (for 
example autoimmune liver disease, primary biliary cirrhosis, primary sclerosing 
cholangitis, Wilson disease, alcoholic liver disease, nonalcoholic steatohepatitis 
(but not steatosis), hemochromatosis, or alpha-1-antitrypsin deficiency). 
6. Active substance abuse, such as alcohol, inhaled or injection drugs within the 
previous year. 
7. Evidence of hepatocellular carcinoma. 
8. Evidence of concurrent hepatitis C infection with positive serum HCV RNA. 
9. Any experimental therapy or pegylated interferon therapy within 6 months prior 
to enrollment. 
10. Diagnosis of malignancy in the five years prior to the enrollment with exception 
granted to superficial dermatologic malignancies. 
11. Evidence of HIV co-infection; HIV 1/2 antibody positivity on serum testing. 
12. Concurrent usage of statins as these drugs inhibits mevalonate synthesis, which 
reduces protein prenylation. 
13. Concurrent usage of moderate and strong CYP3A inhibitors and inducers. 
14. Concurrent usage of alpha 1 adrenoreceptor antagonist, antiarrhythmic, pimozide, 
sildenafil, sedative and hypnotics, ergot and St. John’s Wort due to possible effect 
of ritonavir on hepatic metabolism of these drugs resulting in potentially life 
threatening side effects.  
15. Clinically significant baseline EKG abnormalities. 
16. Uncontrolled elevated triglycerides. 
17. History of pancreatitis as a result of hypertriglyceridemia. 
18. Inability to understand or sign informed consent. 


Heller 
HDV LNFR4 
January 24, 2018 
17 
19.  Any other condition, which in the opinion of the investigators would impede the 
patient’s participation or compliance in the study. 
 
B. Initial Evaluation: 
Before admission to the NIH Clinical Center to start therapy, patients will undergo 
evaluations for eligibility in this protocol (Table 1).  These evaluations will include at 
least 3 visits within 6 months of starting therapy with regular testing for HDV RNA and 
HBV DNA quantitation and alanine aminotransferase (ALT) levels.  These eligibility 
evaluations (except reproductive hormone assessments and consultations) will be 
performed under the liver diseases branch omnibus protocol 91-DK-0214 (Evaluation of 
patients with liver disease).  The reproductive hormone assessments and consultations 
will be performed under this protocol after informed consent has been obtained (Table 1).  
During the eligibility evaluations, patients will undergo a thorough explanation of this 
protocol, provided this protocol’s consent for review, and provided multiple opportunities 
to ask questions about this study. This will be documented in the patient’s chart. Testing 
performed for clinically related purposes or research related purposes are defined in 
Table 1 testing descriptions.  If found to be eligible, the patient will be consented to this 
protocol and will be admitted to the NIH Clinical Center and undergo the following 
evaluation shortly before starting therapy: 
C. History and physical examination. 
D. Concomitant medication query (including dose and indication for each).  
Documentation of concomitant medication, which may be CYP3A, 2C9, and P-gp 
substrates, will be performed. 
E. A standard symptom questionnaire [which focuses on fatigue and abdominal 
pain], which provides information on categorical presence of symptoms as well as 
their severity, pattern and frequency (Appendix 1). 
F. Blood tests.  These include complete blood count (CBC with differential and 
platelet count), prothrombin time (PT), partial thromboplastin time (PTT), 
sedimentation rate (ESR), reticulocyte count, plasma haptoglobin level, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), direct and total serum 
bilirubin, albumin, total protein, lactate dehydrogenase (LDH), creatine 


Heller 
HDV LNFR4 
January 24, 2018 
18 
phosphokinase (CK), sodium, chloride, bicarbonate, potassium, blood urea 
nitrogen, creatinine, glucose, magnesium, uric acid, calcium, phosphorus, 
cholesterol, triglycerides, iron and iron-binding capacity (transferrin), ferritin, 
immunoglobulin levels, thyroid stimulating hormone (TSH), antinuclear antibody 
(ANA), alpha fetoprotein (AFP), rheumatoid factor, cryoglobulins, hepatitis B 
surface antigen (HBsAg), antibody to HBsAg (Anti HBs), antibody to hepatitis B 
core antigen (anti HBc), hepatitis B e antigen (HBeAg), antibody to HBeAg (anti 
HBe), hepatitis B virus DNA (HBV DNA), antibody to hepatitis D antigen (anti 
HDV), hepatitis D virus RNA (HDV RNA), anti-HCV, HCV RNA, and anti-
HAV.  HBV DNA, HCV RNA and HDV RNA will be tested by polymerase chain 
reaction (PCR). The research laboratory of Dr. Jeffrey S. Glenn at Stanford 
University will perform all HDV RNA testing for this protocol.  This test is not 
commercially available.  An additional 50 ml of whole blood will be collected for 
immunological studies and 7 ml of serum will be collected and stored at -20° C. 
Women of childbearing potential will have a pregnancy test.  
G. In males, AM levels of inhibin B, luteinizing hormone (LH), total and free 
testosterone, and follicle stimulating hormone (FSH) will be obtained.  These can 
be obtained after informed consent has been obtained either during the pre-
treatment visits or at the time of inpatient admission to start therapy. 
H. In females, AM levels of luteinizing hormone (LH), estradiol, progesterone, 
antimullerian hormone, follicle-stimulating hormone (FSH), 
dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), 
testosterone, sex hormone binding globulin (SHBG) and 17-hydroxyprogesterone 
(17-OHP) will be obtained. These can be obtained after informed consent has 
been obtained either during the pre-treatment visits or at the time of inpatient 
admission to start therapy. 
I. A reproductive endocrinology or urological consultation for evaluation of current 
and future reproductive potential, the potential of reversibility in the event that 
reproductive toxicity occurs, and guidance on potential barrier methods will be 
obtained. Sperm samples will be obtained, wherever possible, based on the 
recommendations of the consult. These baseline examinations will be performed 


Heller 
HDV LNFR4 
January 24, 2018 
19 
after informed consent has been obtained either during the pretreatment 
evaluation visits or during the inpatient admission to start therapy. Sperm 
sampling will be offered and if obtained, given that the normal spermatogenesis 
cycle is 90 days, a repeat sperm sample (if available) will be evaluated at 90 days 
after therapy has been completed. Patients will also be provided the opportunity to 
store sperm or eggs at an outside facility of their own choosing and at their own 
cost prior to starting therapy. 
J. Female subjects of reproductive potential and female partners of male subjects 
must use two reliable forms of contraception (e.g. oral contraceptive plus barrier 
method) from the start of the study until 6 months from the end of lonafarnib and 
ritonavir dosing. 
K. Pharmacokinetic drug levels of lonafarnib and ritonavir will be obtained at time 0, 
30 minutes, 1 hour, and 2 hours after the initial dose has been administered.  A 
pre-dose drug level, prior to scheduled dosing, will also be obtained at 48 hours 
and at 72 hours. Pharmacokinetic drug levels of lonafarnib and ritonavir will also 
be obtained at each outpatient visit to correlate viral levels with drug levels. 
L. An abdominal ultrasound will be performed. 
M. An electrocardiogram (EKG) in digital format will be performed. 
N. A detailed baseline ophthalmology exam including retinal photography will be 
performed either during the pretreatment evaluation visits or during the inpatient 
admission to start therapy.  
 
C. Randomization 
All patients who are determined eligible and provide written informed consent 
will then be randomized by a set of random numbers held in the Pharmaceutical 
Development Service (PDS) into either one of six groups. Both the investigators and the 
patient will be blinded as to specific results of this randomization (groups 1, 2, 3, 4, 5 or 
6) until the final patient has completed the 24-week treatment period. The randomization 
code will be blocked so that equal numbers of patients will be randomized to each group. 
Randomization will not be stratified due to the small sample size.   
 


Heller 
HDV LNFR4 
January 24, 2018 
20 
D. Treatment 
The treatment design of this study entails 6 groups (1-6) of patients (Figure 3).  A 
total of 21 patients will be enrolled and patients will be randomized into one of six 
groups. Group 1 will consist of 4 patients and will receive lonafarnib and ritonavir at a 
dose of 50/100 mg once daily orally for 24 weeks.  Group 2 will consist of 4 patients and 
will receive lonafarnib and ritonavir at a dose of 75/100 mg once daily orally for 24 
weeks.  Group 3 will consist of 4 patients and will receive lonafarnib and ritonavir at a 
dose of 100/100mg once daily orally for 24 weeks.  Group 4, 5 and 6 will consist of 3 
patients in each group and will receive placebo for the initial 12 weeks followed by 
lonafarnib and ritonavir at either the 50/100 mg dose (total of 3 patients) or the 75/100 
mg dose (total of 3 patients) or the 100/100 mg dose (total of 3 patients) for 12 weeks 
(Figure 3). In each group, after completing the first 24 weeks of the study, patients will 
be followed off anti-HDV therapy for 24 weeks as described in Table 1. Eiger 
BioPharmaceuticals, Inc will supply the lonafarnib and ritonavir.  
After the eligibility evaluations completed under protocol 91-DK-0124  (as 
described above and in Table 1), eligible patients will be consented to this protocol and 
will be randomized to start therapy in one of six groups as described above and in figure 
3. At the start of therapy, patients will be admitted to the Clinical Center, for duration of 
72 hours, for induction of therapy, observation for side effects, administration of the 
medication, and timed blood draws to facilitate analysis of virological response kinetics.  
During the 72-hour admission, frequent blood sampling will be performed 
(0,6,12,18,24,36,48 and 72 hours) to assess initial viral kinetics in response to therapy, to 
have baseline immunological analysis, pharmacokinetic analysis and an 
electrocardiogram.  
To prevent the possibility of a hepatitis B flare, all patients will be treated with 
either entecavir or tenofovir (which are first-line nucleos(t)ide analogues recommended 
by the AASLD and EASL) for a duration of 48 weeks (24 weeks of entacavir or tenofovir 
+ lonafarnib/ritonavir for group 1-3, 12 weeks of entacavir or tenofovir+placebo  
followed by 12 weeks of entacavir or tenofovir + lonafarnib/ritonavir for 12 weeks for 
group 4-6 and 24 weeks of entacavir or tenofovir during the post-therapy monitoring 
phase for all groups). In patients who are not on nucleos(t)ide analogues prior to entering 


Heller 
HDV LNFR4 
January 24, 2018 
21 
this study, they will be started on a nucleos(t)ide analogue at least 2 weeks before dosing 
of lonafarnib/ritonavir or placebo so that steady state has been reached prior to instituting 
HDV therapy (to reduce the risk of a hepatitis B flare). Patients will be informed about 
the possible adverse effects of these medications during their pretreatment clinic visits 
and via the package insert that is provided the medication.  Patients will also be offered 
multiple opportunities to ask questions about these medications during their clinic visits. 
For patients started on nucleos(t)ide analogue therapy (as a result of their participation in 
this protocol) the medication will be administered under this protocol after the consent 
has been signed. If therapy for HBV has been started (a nucleos(t)ide analogue(s)) prior 
to enrolling in this study, the specific nucleos(t)ide(s) analogue will be continued. The 
currently approved nucleoside analogues for hepatitis B include: lamivudine, adefovir, 
tenofovir, entecavir and telbivudine.34    
After induction of therapy, as mentioned above, patients will be treated as 
outpatients and followed on a regular basis in the outpatient clinic at the NIH Clinical 
Center (See below and Table 1). Compliance with drug dosing will be monitored through 
either patient diaries or assessments noted in the medical record at outpatient visits.  
Therapy will be stopped for intolerance to lonafarnib and/or ritonavir (which is carefully 
defined in table 3). Patients who stop therapy due to intolerance, self-discontinue therapy 
or drop out from the study will be considered as treatment failures. 
At 12 and 24 weeks of dosing (therapy or placebo+therapy), patients will undergo 
a thorough evaluation including an updated history and physical examination, multiple 
blood tests, urine tests, symptoms and quality of life questionnaires, EKG testing, 
virological testing, ophthalmologic exam with retinal photography and reproductive 
medicine consultation.  After the final patient completes 24 weeks of dosing, all patients 
and physicians will be unblinded and patients will be told which group they participated 
in.  Once the final patient has completed treatment and followed for at least 24 weeks off 
of therapy, the results of the overall study will be made to the participants.  
 
 


Heller 
HDV LNFR4 
January 24, 2018 
22
"#$%&'!()!*+%,-!.'/#$0!
•! Group 1: LNF/RTV 50/100mg once daily (4 patients). 
•! Group 2: LNF/RTV 75/100mg once daily (4 patients). 
•! Group 3: LNF/RTV 100/100mg once daily (4 patients). 
•! Group 4: Placebo for 12 weeks followed by LNF/RTV 50/100mg once daily for 
12 weeks (3 patients). 
•! Group 5: Placebo for 12 weeks followed by LNF/RTV 75/100mg once daily (3 
patients). 
•! Group 6: Placebo for 12 weeks followed by LNF/RTV 100/100mg once daily (3 
patients). 
 
12"3140565&0#7!
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LNF/RTV 50/100 mg 
/
'' /
1 
LNF/RTV 50/100 mg 
Off Therapy 
'' /
LNF/RTV 100/100mg 
3 
LNF/RTV 100/100mg 
Off Therapy 
Off Therapy 
/
LNF/RTV 75/100mg 
2 
LNF/RTV 75/100mg 
Off Therapy 
Placebo 
4 
LNF/RTV 50/100 mg 
Off Therapy 
Placebo 
5 
LNF/RTV 75/100mg 
Off Therapy 
Placebo 
6 
LNF/RTV 100/100mg 


Heller 
HDV LNFR4 
January 24, 2018 
23 
E. Monitoring during therapy: 
After the 72-hour admission to start therapy, patients will be seen in the outpatient 
clinic, interviewed and have blood tests taken at regular intervals during and after therapy 
(Table 1). At each time point, an acceptable deviation would include +/-3 days.  
Opthalmologic examination with retinal photography and reproductive medicine 
consultation will be performed at week 12 and week 24 during therapy and end of the 
study. AM reproductive hormone evaluations (LH, FSH estradiol, progesterone, AMH, 
DHEA, DHEAS, Androstenedione, Testosterone and Free Testosterone, SHBG and 17-
OHP for females and inhibin B, LH, FSH, Free and total testosterone levels for males) 
will be obtained monthly. At week 24, therapy will be stopped and patients will undergo 
an updated history and physical exam, viral kinetics, immunological analysis, 
pharmacookinetic analysis, and electrocardiogram. The timing of blood specimens, 
physical examinations and special evaluations is provided in Table 1.    Routine blood 
tests will include complete blood count and differential, serum acute care panel, mineral 
panel, lipid panel, hepatic panel (ALT, AST, alkaline phosphatase, LDH, CPK, direct and 
total bilirubin, albumin, total protein, amylase, lipase, electrolytes, calcium, phosphate, 
glucose, blood urea nitrogen, magnesium, creatinine, and uric acid). Virologic 
assessments will include HDV RNA (a stored serum sample will be kept and viral RNA 
levels done in batches) HBsAg, anti-HBs, HBeAg, anti-HBe and HBV DNA levels.  
“Extended Visit I” blood tests will include prothrombin time, and a pregnancy test in 
females of reproductive age.  “Extended visits II” blood tests will include ophthalmologic 
examination with retinal photography, reproductive medicine consultation, and AM 
reproductive hormone levels (LH, FSH, estradiol, progesterone, AMH, DHEA, DHEAS, 
Androsetenedione, Testosterone, SHBG, 17-OHP for females and inhibin B, LH, FSH, 
free and total testosterone for males) will be collected as shown in Table 1. 
Pharmacokinetic (PK) drug levels of lonfarnib and ritonavir (pre-dose) will be drawn on 
every visit while on therapy (weeks 1-24) and at weeks 1, 2, 4, 8, 12, 16, 20 and 24 after 
cessation of therapy as shown in Table 1. Blood will be drawn for immunological 
analysis while on therapy on as shown in Table 1. When appropriate, blood will be drawn 
in pediatric tubes and the amount of blood that will be drawn from adult patients (i.e., those 
persons 18 years of age or older) for research purposes shall not exceed NIH Clinical Center 


Heller 
HDV LNFR4 
January 24, 2018 
24 
rules over any eight-week period.  Patients will also undergo electrocardiogram (EKG) 
evaluations collected in digital format on every visit while on therapy, due to the rare 
instances of asymptomatic bradycardia, PR prolongation49 and QT/QTc interval 
prolongation described in oncologic trials with use of lonafarnib.49, 50  In the rare event 
that diabetes mellitus should develop during participation in this study an endocrinology 
consultation will be obtained as needed. At specified outpatient visits during therapy 
(Table 1), patients will be asked about their symptoms, fill out a symptoms and quality of 
life questionnaire and will undergo assessment of vital signs and medication diaries.  
HBV DNA will be tested at the NIH Clinical Center utilizing the COBAS 
Ampliprep/COBAS Taqman HBV v2.0 test, which is an FDA approved assay intended 
for the use as an aid in the management of chronic HBV infection.  HDV RNA testing 
will be done by quantitative PCR.  Samples will be collected at baseline and at each 
sampling time point to enable resistance monitoring and analysis and viral kinetics. The 
latter will include determination of baseline isolate sequence analysis to enable 
identification and monitoring of changes in viral genome sequences as a function of 
treatment duration. Analysis of drug-treated patients will enable an assessment of 
background genomic variability. Any clinical evidence of breakthrough or rebound 
(defined as a greater than 1 log increase above an observed viral load nadir) will prompt a 
more in-depth analysis that will focus first on the region encoding the CXXX box, as 
changes in the prenylation substrate sequence represent a logical potential mechanism of 
escape from prenylation-inhibiting drugs such as lonafarnib. Because other unanticipated 
mechanisms of resistance could theoretically be operative, however, we would anticipate 
also performing full genome sequencing to enable maximally unbiased assessment for 
candidate resistance mutations. We will also have the ability to engineer any identified 
candidate resistance mutation back into an HDV vector competent for in vitro replication, 
in order to confirm that the mutation is indeed causative of any suspected decreased 
sensitivity to lonafarnib. 30-50 ml of serum will also be obtained at the initial evaluation 
and end of the study for immunologic studies.  The immunologic studies will be done in 
the Liver Diseases Branch of the NIH by Barbara Rehermann MD.   
 
F. Post Treatment Monitoring 


Heller 
HDV LNFR4 
January 24, 2018 
25 
After therapy at week 24, patients will be monitored on an outpatient basis and 
followed off-therapy for follow-up and blood testing at 1, 2, 4, 8, 12, 16, 20, and 24 
weeks.  At each time point, an acceptable deviation would include +/- 5 days. The timing 
of blood specimens, physical examinations and special evaluations in provided in Table 
1.  Routine blood tests will include complete blood count and differential, serum acute 
care panel, mineral panel, hepatic panel (ALT, AST, alkaline phosphatase, LDH, CPK, 
direct and total bilirubin, albumin, total protein, electrolytes, calcium, phosphate, glucose, 
blood urea nitrogen, magnesium, creatinine, and uric acid).  Virologic assessments will 
include HDV RNA (a stored serum sample will be kept and viral RNA levels done in 
batches)  HBsAg, anti-HBs, HBeAg, anti-HBe and HBV DNA levels. Thereafter, patients 
will be followed in the usual fashion by the Liver Diseases Branch under protocol 91-
DK-0214. As interferon is the only approved therapy for HDV, if a patient has been 
previously treated with interferon, there is no additional therapy to be offered.  It is not 
planned to routinely offer interferon to all patients after participating in this study.  
However, if a prolonged HDV flare with significant liver damage is demonstrated, rescue 
therapy with interferon will be offered.  Although it is not clear if delaying interferon 
therapy for 9 months will have adverse events, patients will be made aware of the option 
of obtaining standard of care therapy prior to enrollment. 
 
G. Monitoring of Subjects who Discontinue Therapy 
Patients in whom therapy is stopped early or who discontinue treatment on their 
own will initially be followed in the same manner as those who do not respond as defined 
in the protocol.  After treatment is discontinued, the specific blind will be broken for the 
patient, and the patient will be followed for at least 24 weeks with visits to the outpatient 
clinic as specified in Table 1.  Thereafter, patients will be followed on an unscheduled 
basis under protocol 91-DK-0214 as is typical for patients who have participated in 
studies done by the Liver Diseases Branch. 
 
H. Fecal microbiome and Bacterial Translocation (BT) analysis 
With the recent introduction of highly sensitive analytical methods, the ability to 
meticulously describe the intestinal microbiome in health and disease has allowed for 


Heller 
HDV LNFR4 
January 24, 2018 
26 
identification of fecal microbial dysbiosis.  More recently, investigators have begun 
evaluating associations between the fecal microbiome and bacterial translocation in 
chronic liver disease, advanced liver disease and its potential contribution in poor 
outcomes in liver disease.  
 
In this study, for research related purposes, we plan to utilize pyro-sequencing 
techniques to survey microbial diversity in patients’ fecal samples. Stool microbial 
analysis will be performed in the research laboratory of Dr. Jeffrey S. Glenn at Stanford 
University in addition to the primary investigator’s research laboratory.  Patients may 
refuse the microbiome portion of the study and still participate in other portions of this 
study.  Prior to stool sample collection, all the patients will continue their routine diets.  
Those who have taken antibiotics, probiotics or have routine yogurt consumption for 30 
days may be excluded from the microbiota analysis. At each visit, a specific medication 
history (including prescription and OTC medications) and dietary recordings (appendix 
2) will be taken. Samples (stool and serum) will be elicited at the time points shown in 
Table 2 and stored in -80C for future analysis. 
At the time of analysis, we intend to evaluate the relationship between specific 
microbiome maps and the occurrence of BT. In addition, species homology between 
blood and fecal samples will be determined by deep sequencing.  
 
Bacterial DNA will be extracted from patient serum and stool using QIAamp 
DNA mini kit (Qiagen) according to the manufacturer’s protocol. Patients’ dietary history 
of the day prior to stool sample collection and any changes made in medication use since 
screening visit will be recorded.  Polymerase chain reaction (PCR) for a conserved region 
of the 16S rRNA gene will be performed with two universal primers, forward primers 
(27F-Bac, 5’-AGAGTTTGATCMTGGCTCAG-3’) and reverse primers (543R-Bac, 5’-
ATTACCGCGGCTGCTGGC-3’) to detect and identify the bacterial DNA. For each 
sample, uniquely barcoded universal primers will be used for multiplexing. Amplified 
PCR products will be analyzed by agarose gel electrophoresis and then be pooled for 
pyrosequencing. Amplicons will undergo deep sequencing to be performed at SAIC-
Frederick Inc. Sequences with a minimum length of 200 bp will be analyzed using 
mothur (version 1.21.0) for 16S rRNA gene sequence analysis. Taxonomic classification 
will be done using the RDP Classifier and phylogenetic tree will be generated using the 


Heller 
HDV LNFR4 
January 24, 2018 
27 
Clearcut program. Stool samples will be collected at the beginning of study, every 4 
weeks, at the end of treatment week 24 and every 4 weeks of post treatment. (Table  2) 
Blood will be drawn and used to measure microbial cell wall products, (LPS, 
peptidoglycan and beta-D-glucan), host response markers and selected cytokines. This 
blood samples will be collected whenever we collect the stool sample. (Table 2). 
 
 


Heller 
HDV LNFR4 
January 24, 2018 
28 
Table 1: Design of Study 
Study Visit 
HDV Therapy 
(RTV/LNF or 
Placebo) 
HBV Therapy° 
MD Visit 
RN Visit 
Extended Visit 
I 
Extended 
Visit II 
AM 
Reproductive 
Blood 
Virologic & PK 
Assessment 
Comments 
PreTx 
Visit 
1⌃ 
 
 
* 
 
* 
* (To be 
completed 
once at one 
of these 
visits) 
 
* 
Extended visit 
II can be done 
any of pre visit 
or during first 
admission. 
Visit should be 
<6 months of 
starting 
therapy. 
PreTx 
Visit 2⌃ 
 
 
* 
 
  
 
* (To be 
complet
ed once 
at one 
of these 
visits 
after 
consent 
is 
signed) 
* 
Visit should be 
<6 months of 
starting 
therapy. 
Immunologic 
evaluation 
PreTx 
Visit 3⌃ 
 
 
* 
 
  
* 
Symptom & 
QOL 
Questionnaire, 
Consent Form, 
visit should be 
<6 months of 
starting 
therapy. 
Admit: 
Day 0-4 
*  
* 
*  
* 
* 
Admission, 
EKG, Start 
Therapy, 
symptoms & 
QOL 
Questionnaire, 
immunologic 
evaluation 
Outpt 
Wks: 
4, 8,12, 
16,20* 
 
 
* 
 
 
* 
 
 
* 
 
 
 
* 
 
 
 
* 
 
 
* 
QOL 
Questionnaire, 
EKG, 
immunologic 
evaluation 
Outpt 
Wks: 
1, 2, 3* 
* 
* 
 
* 
 
 
 
* 
EKG, 
symptoms & 
QOL 
Questionnaire 
Outpt 
Wk: 
* 
* 
* 
 
* 
* 
* 
* 
QOL 
Questionnaire, 


Heller 
HDV LNFR4 
January 24, 2018 
29 
 
 
 
 
 
Post Therapy Follow-up  
Study Visit 
HDV Therapy 
(RTV/LNF or 
Placebo) 
HBV Therapy 
MD Visit 
RN Visit 
Extended Visit 
I 
Extended 
Visit II 
AM  
Reproductive 
blood work 
Virologic & PK 
Assessment 
Comments 
Week 1* 
None 
* 
 
* 
 
 
 
* 
Symptom & 
QOL 
Questionnaire 
Week 2* 
None 
* 
 
* 
 
 
 
* 
Symptom & 
QOL 
Questionnaire 
Week 4* 
None 
* 
* 
* 
* 
 
* 
* 
Symptom & 
QOL 
Questionnaire, 
Immunologic 
evaluation 
Week 8* 
None 
* 
* 
* 
* 
 
* 
* 
Symptom & 
QOL 
Questionnaire, 
immunologic 
evaluation 
Week 
12* 
None 
* 
* 
* 
* 
 
* 
* 
Symptom & 
QOL 
Questionnaire 
Week 
16* 
None 
* 
* 
* 
* 
 
 
* 
Symptom & 
QOL 
Questionnaire, 
immunologic 
evaluation 
Week 
20* 
None 
* 
* 
* 
* 
 
 
* 
Symptom & 
QOL 
Questionnaire 
Week 
24* 
None 
* 
* 
* 
* 
* 
* 
* 
Symptom & 
QOL 
Questionnaire 
 
Actual visit may vary +/-3 days on week 1 & 2 and +/-5 days between weeks 4 
through 24. 
24* 
EKG, 
immunologic 
evaluation 
Actual visit may vary +/- 3 days. 


Heller 
HDV LNFR4 
January 24, 2018 
30 
° Patients on preexisting nucleos(t)ide analogues will be maintained on therapy throughout the 
study.  Those not on nucleos(t)ide analogues for HBV will be started two weeks before dosing of 
lonafarnib/ritonavir or placebo.  
⌃ PreTx visits 1,2 & 3 will be performed under protocol 91-DK-0214. Reproductive 
endocrine testing will be performed under this protocol after informed consent has been 
obtained. 
 
Physician visit includes review of diary, vital signs, review of symptoms, interim 
medical history, physical examination, symptom questionnaire, urinalysis, and routine 
blood tests for acute care panel (chem-7), mineral panel (albumin, magnesium), hepatic 
panel (ALT, AST, alkaline phosphatase, direct and total bilirubin), complete blood count 
with differential, and total protein.  These tests are clinical blood tests utilized to monitor 
response to therapy and safety.  
Extended Visit I includes prothrombin time and thyroid function tests.  Women of 
childbearing age will have a pregnancy test.  These tests are clinical blood tests utilized to 
monitor response to therapy and safety. 
Extended Visit II includes ophthalmologic exam, retinal photography, reproductive 
medicine consultation.  These examinations are clinical examinations utilized to monitor 
safety.  
AM reproductive blood work AM hormone levels of (LH, FSH, estradiol, progesterone, 
AMH, DHEA, DHEAS, Androstenedione, Testosterone, Free testosterone, SHBG, 
17_OHP for females and inhibin B, LH, FSH, free and total testosterone for males).  
These tests are clinical blood tests utilized to monitor safety.  
Immunological evaluation includes blood to be drawn (30-50 ml) for laboratory 
assessment.  The blood obtained for testing in this evaluation is for research related 
testing. 
Virologic and PK Assessment includes: HDV RNA and HBV DNA qualitative tests via 
polymerase chain reaction assay (PCR) or a quantitative PCR (qPCR) for viral titer.  
HBV virologic characterization including HBsAg, HBeAg and HBeAb will also be 
performed.  This testing is for clinical purposes to monitor response to therapy and safety.  
One red top tube (10 mL) will be obtained and stored in -80 for pharmacokinetic (PK) 
analysis of lonafarnib and ritonavir.  This blood obtained for PK testing is for research 
related testing. 
Symptom and Quality of Life questionnaire will be administered on several occasions, 
before, during and after 12 weeks of treatment and in subsequent off treatment follow-up 
visits for 24 weeks.  The data obtained from these questionnaires are for research related 
purposes. 
Start therapy includes blood drawn immediately before and then 6, 12, 18, 24, 48, 72 
hours after the first dose of LNF/RTV for measurement of HDV RNA 
 
 


Heller 
HDV LNFR4 
January 24, 2018 
31 
Table 2. Time points for collection of samples for Microbiome & Bacterial 
Translocation Analysis 
Time 
Therapy 
Blood and stool 
sample for bacterial 
translocation and 
blood sample for 
cytokines 
Baseline Time = 0 
None 
* 
On Tx Week 
4,8,12,16,20 
Lonafarnib+Ritonavir 
* 
End of Tx Week 24  Lonafarnib+Ritonavir 
* 
Post Tx week 4, 
8,12, 16, 20, 24 
None 
* 
An acceptable deviation for collection of these samples is +/- 3 days. 
All microbiome related testing is intended for research purposes. 
 
 
I. Immunologic Analysis 
Chronic delta hepatitis is characterized by a lymphomononuclear infiltrate of the 
liver.  The relative composition of this cellular infiltrate (HDV-specific T cells versus 
HBV-specific T cells versus nonspecific bystander cells), the antigenic targets within HDV 
that are recognized by these T cells and the contribution of the HDV-specific T cell 
response to disease progression are not known.   
We aim to define the HDV-specific T cell response in blood samples of HDV/HBV-
coinfected patients in the chronic stage of disease prior to treatment. Peripheral blood 
mononuclear cells (PBMC) will be isolated from blood samples.  The HDV-specific CD4 
and CD8 T cell response to recombinant delta antigen will be assessed by measuring 
cytokines (IFNg, TNFa, IL-2) by multicolor flow cytometry and enzyme-linked 
immunospot assays.  Individual responses will be mapped with 41 overlapping peptides 
spanning the delta antigen and minimal optimal epitopes will be defined.  The quality and 
strength of the HDV-specific T cell response will be compared to the quality and strength 
of the HBV core and surface antigen-specific response. 
We also plan to take advantage of the fact that the prenylation inhibitor is a potent 
antiviral drug with no direct effect on the immune system.   We will also evaluate 
whether a reduction of HDV viral or antigen load determined by treatment with the 
prenylation inhibitor causes a qualitative or quantitative change of the T cell response in 


Heller 
HDV LNFR4 
January 24, 2018 
32 
the peripheral blood, and specifically, the emergence of HDV-specific memory T cells 
that we have identified in a rare case of a patient who spontaneously recovered from 
HDV infection (Heller, Rehermann, unpublished).    
 
J. Design of the Trial/Statistical considerations. 
This study is designed as a phase 2a FDA regulated clinical study evaluating the 
utility of combination therapy of lonafarnib and ritonavir in patients with chronic HDV 
infection. This study should show if HDV suppression is possible; assist in suggesting the 
lowest effective dose for viral suppression; and how well lonafarnib and ritonavir is 
tolerated. Thus assessment of virologic response is the primary therapeutic endpoint and 
safety/tolerability is the primary safety endpoint.    
Measurement of HDV RNA levels will be performed in batch and the treating 
physician or the investigator will not necessarily know the results until a patient may 
have finished treatment.   
In order to achieve a primary virologic response goal of a 2-log decline in HDV 
RNA in serum at end of 24 weeks of therapy, a total of 21 patients will be enrolled (4 
patient’s per 24 week treatment group and 3 patient’s per placebo + 12 week treatment 
group).  This allows for pooling of week 12 data between all dosing groups while also 
allowing for statistical adequacy in assessing therapy out to 24 weeks with a statistical 
power of 80%, an alpha of .05 and accounting for a 20% dropout rate.  
 
K. Hazards and Discomforts 
The hazards associated with this study are the following. 
1. The risks and discomforts of frequent phlebotomy.  To document stable levels of 
biochemical and serologic markers of chronic hepatitis and to monitor the effects 
and toxicities of the therapy, frequent blood sampling will be required.  Patients 
will have between 30-32 venipuncture during their course of participation.  The 
amount of blood that will be drawn from adult patients (i.e., those persons 18 years of 
age or older) for research purposes shall not exceed 10.5 mL/kg or 550 mL, 
whichever is smaller, over any eight-week period. 


Heller 
HDV LNFR4 
January 24, 2018 
33 
2. The risks and hazards of lonafarnib therapy.   Lonafarnib is an orally bio-
available tricyclic farnesyl transferase inhibitor that has been shown to have anti-
tumor activity in various phase I and II trials and anti-HDV properties in various 
preclinical models and a recently completed phase 2a clinical study performed at 
the NIH clinical center.51-53 Multiple phase 1 and 2 and 3 studies have been 
completed with lonafarnib alone or in combination with a variety of 
chemotherapeutic regimens. This has amounted to the administration of 
lonafarnib to >1600 subjects.    
 
In initial animal studies, lonafarnib was well tolerated and had no major end-
organ toxicities at repeated doses of 15 mg/kg up to 6 months in rats and 10 
mg/kg up to 1 year in monkeys; these doses result in systemic exposures that are 
less than those attained at a clinical dose of 200 mg twice per day (BID).  At 
higher doses, representing animal to human exposure multiples similar to that 
seen in humans at 200 mg BID, the key side effects included bone marrow 
suppression and testicular toxicity in rats and monkeys, lymphoid and kidney 
changes in rats, and diarrhea and electroretinographic changes in monkeys.  The 
no-effect doses for reproductive effects on fertility (10 mg/kg in rats) and embryo-
fetal development (15 mg/kg in rats and <10 mg/kg in rabbits) result in systemic 
exposures less than those attained at a clinical dose of 200 mg BID.   The no-
effect dose for peri- and postnatal development in rats was >20 mg/kg, the highest 
dose evaluated.  Lonafarnib was not mutagenic or clastogenic.   
 
Metabolism studies conducted in vitro have shown that cytochrome P450 
enzymes, CYP3A4, and CYP3A5, were mainly responsible for the oxidative 
metabolism of lonafarnib.  This metabolism was studied extensively in vivo and 
the principle metabolic pathways were similar in rats, monkeys and humans and 
primarily involved oxidation or dehydrogenation, and combinations of these two 
processes.  No metabolites specific to humans were detected in vitro or in vivo. 
The main route of excretion was fecal, with urinary excretion representing <2% of 
the administered dose.  Lonafarnib also causes mixed induction/inhibition of 


Heller 
HDV LNFR4 
January 24, 2018 
34 
hepatic drug-metabolizing enzymes in rats and monkeys when administered once 
daily for 3 months in toxicology studies.  In vitro studies in human liver 
microsomes showed that lonafarnib inhibited the activity of CYP3A4 and, to a 
lesser extend CYP2C9.  Neither of these systems is used in the metabolism of 
currently approved drugs to treat HBV.  Multiple co-administered doses of the 
P450 inhibitor ketoconazole resulted in a 5-fold increase in exposure to 
lonafarnib. 
 
In clinical studies, phase 1 dose-finding studies have shown that doses ranging 
from 25 mg to 200 mg twice daily (BID) are safe and well tolerated.  Doses of 
100, 200 and 300 mg BID have been employed in various phase II studies 
involving solid tumors and hematologic malignancies.50, 54, 55 In the initial dose-
finding phase 1 trial, minor hematologic and non-hematologic side effects were 
seen.50 The hematologic side effects included transient reversible neutropenia and 
transient reversible thrombocytopenia.  At doses of less than 200 mg twice daily, 
these grade 1 toxicities (NCI common toxicity criteria) were seen in 3 of 12 
patients.50 At the 200 mg twice-daily dose level, no toxicities were seen.  At 
higher doses, 300 mg BID and 400 mg BID, 2 of 6 individuals experienced grade 
4 dose limiting toxicities of neutropenia and 1 of 6 experienced grade 4 dose 
limiting toxicity of thrombocytopenia during a median treatment duration of 40 
days.50  
 
The major non-hematologic side effects that were observed were gastrointestinal 
and consisted of diarrhea, nausea, vomiting and anorexia which were mild and did 
not require intervention (grade 1 and 2) within the 200 mg twice daily group. 
Other toxicities that were observed included grade 1 or 2 elevation of liver 
enzymes; reversible grade 1 or 2 elevated plasma creatinine levels. At the higher 
doses of 300-400 mg twice daily, toxicities observed included; transient fever 
(grade 2), asymptomatic sinus bradycardia (55 beats/min) resolving at the end of 
therapy, reversible (grade 3) neurocortical toxicity consisting of disorientation and 
confusion.50 During the above-mentioned phase 1 study, no toxicity greater than 


Heller 
HDV LNFR4 
January 24, 2018 
35 
grade 1 in both hematologic and non-hematologic categories was recorded at the 
200 mg twice-daily administration level.50  
Subsequent phase II studies, at doses of 200 mg twice daily, have replicated 
similar grade 1 and 2 side effects of; diarrhea, nausea, vomiting, dyspepsia, 
anorexia, asthenia, fever/infection, hemorrhage, increase of serum creatinine, 
increased liver function tests and rash.55, 56 In the first study, patients were treated 
for a median duration of 185 days55, 56 Currently, there are various phase I, II and 
III investigational studies ongoing (www.clinicaltrails.gov) with no significant 
safety alerts (www.fda.gov).  
 
Although it is not specified if patients with pre-existing advanced liver disease 
were excluded in the above-mentioned clinical trials with lonafarnib, specific data 
on dosing in liver patients and side-effect profile in them are not available. In our 
recently completed, first-in-humans, proof-of-concept study evaluating lonafarnib 
in patients with chronic HDV infection, lonafarnib was administered at doses of 
100 mg BID and 200 mg BID in a total of 12 patients.  During this study, patients 
underwent digitized electrocardiography (at baseline, weekly while on therapy 
and weeks 1 and 2 after stopping therapy), ophthalmologic examination with 
retinal photography (at baseline, end of therapy and 24 weeks post-therapy) and 
evaluations (specialist consultations, serologic testing and transvaginal 
ultrasounds on day 3 of menstrual cycle for females) for reproductive toxicity (at 
baseline, end of therapy and 24 weeks post-therapy). No patients were found to 
have any significant changes in these parameters at any time during participation 
in this study. Regarding symptoms encountered in this study, side effects of 
lonafarnib included mild nausea (25%), diarrhea (37.5%), anorexia (12.5%), and 
abdominal bloating (12.5%) in the lonafarnib 100mg bid group. In the lonafarnib 
200 mg BID group, nausea (75%), diarrhea (75%), anorexia (62.5%), dyspepsia 
(75%), vomiting (37.5%) and mean weight loss of 4kg (75%) were found. There 
were no grade 3 or 4 adverse events or serious events.  
 


Heller 
HDV LNFR4 
January 24, 2018 
36 
As there are no HDV-specific therapies, lonafarnib appears to potentially be the 
first direct acting anti-HDV agent by compromising the RNA replication complex 
through inhibition of prenylation at the level of the farnesyl transferase.  A risk 
associated with the use of direct acting antiviral agents would be the development 
of resistance by the virus. However, because prenylation is a host function not 
coded for by the HDV genome, the risk of resistance development could be 
mitigated. As proof of absence of viral resistance with prenylation inhibitors in 
HDV, population-based sequencing of LDAg (codons 115-215) at baseline, end 
of therapy and 24 weeks after end of therapy was performed in our recently 
completed study (12-DK-0046).  Analysis at these time points revealed no 
changes in viral sequences thus confirming the absence of viral resistance.  
An additional risk that may be encountered with the therapy of HDV includes an 
increase in liver function tests during and after therapy, the risk of a flare in HBV 
(≥2 log increase and a total HBV DNA over 2,000 IU/mL) as the HDV viral load 
goes down, and an increase in HDV viral load after therapy is ended.  Flares in 
liver function tests are not uncommon with the start of treatment of HBV disease 
and necessitate a careful and frequent review of liver function tests.  We will treat 
all the patients with nucleoside analogues for HBV, the selection being made by 
the investigator based on the subject’s condition and history of prior anti-HBV 
therapy. It should also be noted, that lonafarnib has undergone extensive analysis 
and has exhibited neither synergy nor antagonism in combination with the 5 
available HBV antiviral medications. A flare in HDV viral load after termination 
of lonafarnib will be monitored closely and interferon therapy may be started as 
determined by the investigator.  It should be noted that when interferon is used for 
HDV it is typically given for a year, and cessation of therapy may be associated 
with flares of HDV.  
3. The risks and hazards of Ritonavir therapy. Ritonavir is an orally bio-available 
protease inhibitor, which was used as a pharmacokinetic booster 
(coadministration of 100mg Ritonavir) of second protease inhibitor or other 
retroviral agents. In this study, ritonavir will be used as a pharmacokinetic booster 
of Lonafarnib. The most common side effects (>10%) of ritonavir are nausea, 


Heller 
HDV LNFR4 
January 24, 2018 
37 
diarrhea, vomiting, altered sense of taste (taste perversion), abdominal pain, 
arthralgia, back pain, cough and loss of appetite. If it is used more than 60 days, 
there is increased in cholesterol, triglycerides, and blood sugar, potentially 
resulting in the development of diabetes mellitus. The increase in cholesterol and 
triglycerides can occur within one week of taking this medication. Lipid profile 
should be monitor prior to initiating therapy and at periodic intervals during 
therapy. After the completion of the study, cholesterol and triglyceride levels 
should return to baseline. 
a) Elevation of AST/ALT can exceed 5 times the upper limit of normal, clinical 
hepatitis and jaundice in patients receiving Ritonavir alone or in combination 
with other antiretroviral drugs. 49 Dosage adjustment is not necessary in 
patients who have mild (Child- Pugh Class A) to moderate (Child-Pugh Class 
B) hepatic impairment. There is no safety data available for severe (Child- 
Pugh Class C) hepatic impairment patients. Ritonavir is not recommended in 
patients who have severe hepatic impairment. As we are not going to enroll 
decompensated liver disease patients, it should not be a problem. 49 
b) Pancreatitis has been observed in those who developed hypertriglyceridemia. 
If clinical symptoms or laboratory abnormalities (increased serum amylase or 
lipase), pancreatitis should be considered. Patients should be evaluated and 
Ritonavir should be discontinued if a diagnosis of pancreatitis is made.49 
c) Allergic reaction/Hypersensitivity including urticarial, mild skin eruptions, 
bronchospasm and angioedema have been reported. Cases of anaphylaxis, 
toxic epidermal necrolysis, Stevens-Johnson syndrome have also been 
reported. We will discontinue treatment if severe reactions develop. 
d) Prolong PR interval in some patients. Post-marketing cases of second or 
third degree atrioventricular block have been reported in patients. The effect 
on PR interval of co-administrating with other drugs that prolong PR interval 
(calcium channel blockers, beta blockers, digoxin and atazanavir) has not been 
studied. But caution should be undertaken when co-administration of 
Ritonavir with these drugs, especially with those drugs metabolized by 
CYP3A. 


Heller 
HDV LNFR4 
January 24, 2018 
38 
Metabolism of Ritonavir is mainly through cytochrome P450 CYP3A4. 21 
Concurrent usage of other moderate and strong CYP3A inhibitors and inducers 
will lead to change in plasma concentration of concomitant medications, resulting 
prolonged therapeutic or adverse effects. Patients who are taking these 
medications should be excluded.  
4. The risks of the combination of Lonafarnib and Ritonavir. Aside from the small 
proof-of-concept Turkish study (mentioned above) evaluating three patients with 
this combination regimen for chronic HDV infection, this is the first study 
utilizing the combination of lonafarnib and ritonavir for 12 weeks therapy for 
chronic HDV infection.  In the three patients that received this combination the 
regimen was reported to be safe and well tolerated. Thus, we do not anticipate 
additional significant side effects aside from each drug’s individual side effect 
profile mentioned above. 
5. The risks of the combination of Lonafarnib, Ritonavir and HBV therapy. The 
risks of the combination of lonafarnib, ritonavir and a nucleos(t)ide analogues are 
not known.  In the small proof-of-concept Turkish study (mentioned above) a 
single patient on a nucleos(t)ide analogue was administered lonafarnib and 
ritonavir.  This patient did not experience any additional side effects that could be 
attributed to the use of a nucleos(t)ide analogue in combination with lonfarnib and 
ritonavir.  During the NIDDK study 12-DK-0046, 5 of 14 patients were on 
nucleos(t)ide analogues while on lonafarnib monotherapy.  During this 28 day 
study, there were no additional side effects that could be attributed to the use of a 
nucleos(t)ide analogue in combination with lonafarnib.  Ritonavir has been used 
in combination with nucleos(t)ide analogues in HIV approved therapies and is 
thought to be safe. Nucleos(t)ide analogues for hepatitis B function through a 
different mechanism of action and have different pharmacokinetics and side effect 
profile.  As such, it is believed that there is no added risk of the combination of 
lonafarnib, ritonavir and a nucleos(t)ide analogue for hepatitis B.     
 
L. Adverse Events and Modification of Dose of Prenylation Inhibitor and 
Ritonavir. 


Heller 
HDV LNFR4 
January 24, 2018 
39 
Patients will be monitored for side effects.  The use of statins will be prohibited 
during the course of the study as are the use of moderate and strong CYP3A inhibitor and 
inducers.  Discontinuation of lonafarnib + ritonavir or placebo will be based upon the 
scoring of adverse events as shown in table 3. After discontinuation, the patient’s 
grouping will be unblinded so that the investigators are aware of the therapy and dose so 
that additional blinded patients can be closely monitored. The scoring of toxicity will be 
performed from the CTCAE Version 4.03 with modifications for leukocytes, platelets, 
prothrombin time, partial thromboplastin time, ALT, AST and bilirubin.  These variables 
have been modified because the National Cancer Institute (NCI) designed the original 
version with use for cancer trials and not for clinical trials in liver disease.  The modified 
version to be utilized for this clinical trial accounts for accepted variations of liver tests 
used in various other liver disease clinical trials by the Liver Diseases Branch. Factors 
that will lead to discontinuation of lonafarnib and ritonavir include pregnancy, any grade 
3  or any grade 4 adverse events or any adverse event, which, in the opinion of the 
investigator, places the patient at increased risk.  Drug discontinuation may also be based 
on individual clinical presentations of each subject.  For example, AST and ALT values 
will be evaluated in the context of each individual’s baseline values.  Rather than 
utilizing specific cutoff values, which may not be in the best interest of each subject, if 
the investigator identifies a significant elevation in liver related laboratory tests which 
may jeopardize the patient’s safety, the drug may be discontinued.  If the female becomes 
pregnant, the patient’s obstetrician will be provided with the standard of care guidelines 
to prevent HBV transmission.  Lonafarnib and ritonavir will not be restarted unless 
another cause for the abnormality or symptom is found. 
 
 


Heller 
HDV LNFR4 
January 24, 2018 
40 
Table 3.  Scoring of toxicity for dose modification.  Scoring of toxicity from the 
CTCAE Version 4.03, with modifications for leukocytes, platelets, prothrombin time, 
partial thromboplastin time, ALT, AST and bilirubin.  Normal ranges for values at the 
NIH Clinical Center are used. 
 
Scoring of toxicity for dose modification 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
Allergic reaction/ 
hypersensitivity 
(including drug fever) 
Allergic reaction 
Transient 
flushing or 
rash; drug 
fever <38 C 
(<100.4 F) 
Rash; 
flushing; 
urticarial; 
dyspnea; 
drug fever 
>38 C 
(>100.4 F) 
Symptomatic 
bronchospasm, 
with or without 
urticarial; 
parenteral 
medication(s) 
indicated; allergy-
related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
Anorexia 
Anorexia 
Loss of 
appetite 
without 
alteration in 
eating habits 
Oral intake 
altered 
without 
significant 
weight loss 
or 
malnutrition; 
oral 
nutritional 
supplements 
indicated 
Associated with 
significant weight 
loss or malnutrition 
(e.g., inadequate 
oral caloric and/or 
fluid intake); IV 
fluids, tube 
feedings or TPN 
indicated 
Life 
threatening 
consequences 
Death 
Nausea 
Nausea 
Loss of 
appetite 
without 
alteration in 
eating habits 
Oral intake 
decreased 
without 
significant 
weight loss, 
dehydration 
or 
malnutrition; 
IV fluids 
indicated <24 
hrs 
Inadequate oral 
caloric or fluid 
intake; IV fluids, 
tube feedings, or 
TPN indicated >24 
hrs 
Life 
threatening 
consequences 
Death 
Fatigue (asthenia, 
lethargy, malaise) 
Fatigue 
Mild fatigue 
over baseline 
Moderate or 
causing 
difficulty 
performing 
some ADL 
Severe fatigue 
interfering with 
ADL 
Disabling 
----- 
Diarrhea 
Diarrhea 
Increase of <4 
stools per day 
over baseline; 
mild increase 
Increase of 4-
6 stools per 
day over 
baseline; IV 
Increase of >6 
stools per day over 
baseline; 
incontinence; IV 
Life 
threatening 
consequences 
(e.g. 
Death 


Heller 
HDV LNFR4 
January 24, 2018 
41 
in ostomy 
output 
compared to 
baseline 
fluids 
indicated <24 
hrs; moderate 
increase in 
ostomy 
output 
compared to 
baseline; not 
interfering 
with ADL 
fluids >24 hrs; 
hospitalization; 
sever increase in 
ostomy output 
compared to 
baseline; 
interfering with 
ADL  
hemodynamic 
collapse) 
Distention/bloating, 
Abdominal 
Distention 
Asymptomatic 
Symptomatic, 
but not 
interfering 
with GI 
function 
Symptomatic 
interfering with GI 
function 
----- 
------- 
Vomiting 
Vomiting 
1 episode in 
24 hrs 
2-5 episodes 
in 24 hrs; IV 
fluids 
indicated <24 
hrs 
>5 episodes in 24 
hrs; IV fluids, or 
TPN indicated >24 
hrs 
Life 
threatening 
consequences 
Death 
Creatinine 
Creatinine 
>ULN – 1.5 X 
ULN 
> 1.5 – 2.0 X 
ULN 
> 2.0 – 6.0 X ULN 
>4.0 X ULN 
Death 
Glomerular Filtration 
Rate 
GFR 
<75-60% LLN 
<60-40% 
LLN 
<40% LLN, 
chronic dialysis not 
indicated 
Chronic 
dialysis or 
renal 
transplantation 
indicated 
Death 
Glucose, serum-low 
(hypoglycemia) 
Hypoglycemia 
<LLN – 55 
mg/dL 
<LLN – 3.0 
mmol/L 
<55 – 40 
mg/dL 
<3.0 – 2.2 
mmol/L 
<40-30 mg/dL 
<2.2-1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Triglyceride, serum- 
high 
(hypertriglyceridemia) 
Hypertriglyceridemia 
>ULN – 2.5 X 
ULN 
>2.5 – 5.0 X 
ULN 
>5.0 – 10 X ULN 
>10 X ULN 
Death 
Cholesterol, serum 
high 
(Hypercholesterolemia) 
Hypercholesterolemia >ULN - 300 
mg/dL; >ULN 
- 7.75 
mmol/L 
>300 - 400 
mg/dL; >7.75 
- 10.34 
mmol/L 
>400 - 500 mg/dL; 
>10.34 - 
12.92 mmol/L 
>500 mg/dL; 
>12.92 
mmol/L 
----- 
Pain – Headache 
Pain – Headache 
Mild pain not 
interfering 
with function 
Moderate 
pain; pain or 
analgesics 
interfering 
with 
function, but 
not 
interfering 
with ADL 
Severe pain; pain 
or analgesics 
severely interfering 
with ADL 
Disabling 
----- 
Pain – Abdominal 
Pain – Abdominal 
Mild pain not 
interfering 
with function 
Moderate 
pain; pain or 
analgesics 
Severe pain; pain 
or analgesics 
Disabling 
----- 


Heller 
HDV LNFR4 
January 24, 2018 
42 
interfering 
with 
function, but 
not 
interfering 
with ADL 
severely interfering 
with ADL 
Infection- Upper 
Airway NOS 
Infection – Upper 
Airway NOS 
Mild 
Moderate 
Severe 
Life – 
threatening; 
disabling 
Death 
Infection – 
Nasopharyngitis 
Infection – 
Nasopharyngitis 
Mild  
Moderate 
Severe 
Life-
threatening; 
disabling 
Death 
Hemoglobin 
Hemoglobin 
<LLN – 10.0 
g/dL 
<LLN – 6.2 
mmol/L 
<LLN – 100 
g/L 
< 10.0 – 8.0 
g/dL 
<6.2 – 4.9 
mmol/L 
<100 – 80 
g/L 
<8.0 – 6.5 g/dL 
<4.9 – 4.0 mmol/L 
<80 – 65 g/L 
<6.5 g/dL 
<4.0 mmol/L 
<65 g/L 
Death 
Leukocytes (total 
WBC) 
Leukocytes 
<2000/mm3 
<2.0 X 109/L 
<1500 – 
1000/mm3 
<1.5 – 1.0 X 
109/L 
<1000 – 500/mm3 
1.0 – 0.5 X 109/L 
<500/mm3 
<0.5 X 109/L 
Death 
Platelets 
Platelets 
<70,000/mm3 
-60,000/mm3 
<70.0 – 60.0 X 
109/L 
<60,000 – 
40,000/mm3 
<60.0 – 40.0 
X 109/L 
<40,000 – 
25,000/mm3  
<40.0 – 25.0 X 
109/L 
<25,000/mm3 
<25.0 X 109/L 
Death 
INR (International 
Normalized Ratio of 
prothrombin time) 
INR 
>1 – 1.5 X 
ULN 
>1.5 – 2 X 
ULN 
>2 X ULN 
------ 
----- 
PTT Partial 
Thromboplastin time) 
PTT 
>1 – 1.5 X 
ULN 
>1.5 – 2 X 
ULN 
>2 X ULN 
------ 
----- 
Bicarbonate, serum-
low 
Bicarbonate, serum-
low 
<LLN – 18 
mmol/L 
<18 – 15 
mmol/L 
<15-11 mmol/L 
<11 mmol/L 
Death 
Acidosis (metabolic or 
respiratory) 
Acidosis 
pH < normal, 
but >7.3 
----- 
pH <7.3 
pH <7.3 with 
life 
threatening 
consequences 
Death 
Alkaline Phosphatase 
(U/L) 
Alkaline Phosphatase 
>ULN – 2.5 X 
ULN 
>2.5 0 5.0 X 
ULN 
>5.0 – 20.0 X ULN 
>20.0 X ULN 
----- 
Bilirubin 
(hyperbilirubinemia) 
Bilirubin 
>ULN – 1.5 X 
ULN 
>1.5 – 3.0 X 
ULN 
>3.0 – 10.0 X ULN 
>10.0 X ULN 
----- 
Albumin, serum-low 
(hypoalbuminemia) 
Hypoalbuminemia 
<LLN – 3 
g/dL 
<LLN – 30 
g/L 
<3 – 2 g/dL 
<30 – 20 g/L 
<2 g/dL 
<20 g/L 
------ 
Death 
AST, SGOT (serum 
glutamic oxaloacetic 
transaminase) 
AST 
>3 – 5 X 
patient’s 
baseline 
values 
>5-10 X 
patient’s 
baseline 
values 
>10 – 20 X 
patient’s baseline 
values 
>20 X 
patient’s 
baseline 
values 
Death 


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HDV LNFR4 
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43 
ALT, SGPT (serum 
glutamic pyruvic 
transaminase) 
ALT 
>3-5 X 
patient’s 
baseline 
values 
>5-10 X 
patient’s 
baseline 
values 
>10 – 20 X 
patient’s baseline 
values 
>20 X 
patient’s 
baseline 
values 
Death 
Pancreatitis 
Pancreatitis 
 
Enzyme 
elevation or 
radiologic 
finding only 
Severe pain; 
vomiting; medical 
intervention 
indicated (e.g., 
analgesia, 
nutritional support) 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
 
 


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44 
M. Data and Safety Monitoring 
The Principal Investigator will function as the data and safety monitor and report 
any adverse events to the IRB.   The Principal and Associate Investigators in this protocol 
will monitor data and safety.  The Liver Diseases Branch, NIDDK, reviews data and 
safety weekly in clinical research rounds.  These rounds are separate from regular clinical 
rounds and consist of review of all study patients including flow sheets of major safety 
and efficacy measurements.  The rationale for not using an outside data and safety 
monitoring committee is that this is a small, single center study using medications with 
defined side effects and known safety concerns.  All measurements and tests are well 
established in clinical medicine. Yearly reports are made to the NIDDK/NIAMS IRB 
regarding safety and efficacy. 
 
N. Reporting of Adverse Events, Unanticipated Problems and Deviations 
Adverse events, protocol deviations, unanticipated problems (UP), , serious 
adverse events, sponsor and serious, are defined as described in NIH HRPP SOP 16 
(“Reporting Requirements for Unanticipated Problems, Adverse Events and Protocol 
Deviations.”). All adverse events occurring during the study, including those observed by 
or reported to the research team, will be recorded. Serious unanticipated problems, and 
serious protocol deviations, will be reported to the IRB, the Sponsor and CD as soon as 
possible but not more than 7 days after the PI first learns of the event. Not serious 
unanticipated problems will be reported to the IRB, the Sponsor and CD as soon as 
possible but not more than 14 days after the PI first learns of the event.  
Deaths will be reported to the Clinical Director and IRB within 7 days after the PI 
first learns of the event.   
The PI will immediately report Suspected Adverse Reactions (SARs) to the 
Sponsor according to the requirements of 21 CFR 312.64(b) and as agreed upon with the 
sponsor.  
Not serious protocol deviations will only be reported to the IRB and the Sponsor 
(within 14 days after the PI first learns of the event) if they represent a departure from NIH 
polices for the conduct of human subjects research, adversely affect the health care of the 
subject(s) or compromise the interpretation or integrity of the research. Non-serious 


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45 
protocol deviations that result from normal subject scheduling variations or technical issues 
associated with sampling that does not impact the health of the subject or the interpretation 
of the study data will not be reported. 
 
Adverse events that are clearly not related to the study procedures, such as those 
that occur prior to initiation of study related procedures, adverse events that are expected 
and thought to be related to the natural history of HDV or comorbidities will not be reported 
to the IRB or the Sponsor. If it is determined from the review of the aggregate data that an 
adverse event is occurring at a greater frequency or level of severity than previously 
expected, it constitutes a UP, and the problem will be reported to the IRB, the Sponsor and 
CD expeditiously.  All other study related adverse events, all unanticipated problems and 
all protocol deviations will be reported in aggregate to the IRB at the time of continuing 
review. ..   A summary of all suspected adverse reactions and study efficacy data will be 
provided yearly in annual reports to the Sponsor. Reports will be sent to the FDA, 
MEDWATCH program (telephone 1-800-FDA-1088; or via the internet at 
www.fda.gov/medwatch/index.html) and the Eiger Pharmaceuticals, the company that 
produces the prenylation inhibitor. 
 
O. Regulatory Requirements 
The IND associated with this study (113137), in which the NIDDK is the sponsor, 
is associated with lonafarnib.  The FDA has not requested an IND for the use of ritonavir 
in combination with lonafarnib. Study procedures will be subject to audits and/or 
monitoring visits by independent monitors and auditors to ensure compliance with the 
protocol and applicable regulatory requirements consistent with the NIH quality assurance 
program plan and applicable FDA guidelines.  Audit and/or monitoring visit results will be 
reported to the Principal Investigator for further reporting as appropriate.   Study 
documents and pertinent hospital or clinical records will be reviewed to verify that the 
conduct of the study is consistent with the protocol plan. 
 
P. Recruitment strategy 


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46 
We will advertise on the NIH web site and through letters sent to local physicians 
and clinics for patients.   
 
Q. Recruitment of Women, Minority Individuals and Children. 
Delta hepatitis is a rare disease in the general population.  The major risk factors 
are injection drug use and hemophilia.  It is rare to find the disease in childhood, the 
majority of children with delta hepatitis being immigrants from areas of the world where 
it is common (Eastern Europe, Amazon Basin).  In addition, hepatitis is often mild in 
children.  Finally, FTIs have not been adequately evaluated for safety and efficacy in 
children. We therefore do not plan to recruit children below the age of 18. 
Women are less likely to have HDV, as one of the risk factors, hemophilia is a disease of 
males.  Notwithstanding this, every effort will be made to  find both women and 
members of minorities with HDV.  To increase the representation of both women and 
minority individuals in this trial, we plan to advertise widely.  
 
R. Consent Process 
 
The investigational nature and research objectives of this trial will be carefully 
explained to the subjects during the preliminary visit evaluations and subjects will be 
offered multiple opportunities to ask protocol specific questions.  These discussions will 
be documented in the patient’s chart at each visit.  Additionally, a copy of the consent 
will be provided to the patient for review during the pretreatment visits prior to obtaining 
a signed informed consent before dosing.  Once a subject is determined to be eligible to 
participate in this study, they will be invited to complete the evaluations aforementioned 
in this protocol.  Consent will be obtained by the NIDDK principal investigator or one of 
the NIDDK associate investigators identified on the cover page.   
We do not plan or anticipate the enrollment of non-English speaking subjects; 
however they are not excluded from participation either. Should a non-English speaking 
subject be eligible for enrollment, IRB approval will be obtained for use of the short form 
consent process in the absence of a fully translated consent document as outlined in SOP 
12.9.1, under the provisions of 45 CFR 46.117(b)(2). IRB approval will be obtained 


Heller 
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47 
according to IRB guidance prior to obtaining informed consent from the potential study 
participant/s. 
 
S.  Research Use, Storage and Disposition of Human Subject’s Samples and Data. 
Patients will have serum and stool stored from selected time points during this 
study.  The serum specimens will be used for repeat virological testing and special tests 
as needed and the stool tests will be used for microbiome analysis.   Samples may be used 
to assess factors associated with response or non-response to therapy.    These samples 
will be tested in the Liver Diseases Branch or the routine clinical services of the Clinical 
Center.  Residual samples may be used for future research related to liver disease and its’ 
associated conditions.  If residual samples are evaluated by outside collaborators in the 
future, this will be done so only after all identifying data have been removed from all 
samples.   Dr. Jeffrey S. Glenn at Stanford University School of Medicine will perform 
all HDV RNA quantitative testing for this protocol. All samples sent to outside 
collaborators and Dr. Glenn will be numbered and a key to the number system will be 
stored and backed up by the principal investigator of this study.  Research records and 
data as well as sera will be stored indefinitely in our locked offices and freezers, the 
medical record department and the pathology department.  These materials will be 
protected and tracked by standard operating procedures in the medical record as well as a 
compulsive filing system in our locked offices and freezers.  There will be redundant 
storage of clinical information in the medical record department and our offices. 
Computer files will be maintained on password-protected computers and servers.  Serum 
samples will be processed and stored by the NIDDK core laboratory facility.  These 
samples will be stored in locked freezers inside locked rooms.  Access to these samples 
will require written approval from the Liver Diseases Branch chief, and will be recorded 
by the LDB and by the core laboratory.  This should minimize the risk of loss or 
destruction of information and specimens.  If that were to occur we would report it to the 
IRB.  We do not plan to destroy this personal medical information or research subject 
sera after completion of the study because it may be critically important for physicians 
(here or elsewhere) to have access to this information when caring for these patients in 
the future.  If requested, Eiger Biopharmaceuticals (who will be providing the Lonafarnib 


Heller 
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48 
and Ritonavir), will have access to the clinical data only after all personal identifiers have 
been removed.  They will also be included in all serious adverse event notifications. 
 
T. Risk/Benefit Assessment 
The research risk associated with this study is greater than minimal risk with potential 
prospect of direct benefit to the subject.  We expect to acquire generalizable knowledge 
about lonfarnib and ritonavir as a therapy of chronic delta hepatitis infection. 
 
 
 
 U. Study Alternatives 
 
Alternatives to the study may be offered at the NIH or at outside medical centers 
and are routine therapy with interferon for 12 months, being monitored on no therapy, or 
awaiting results of this or other studies of therapy of chronic delta hepatitis. 
Patients who choose to enroll in this clinical trial, if not previously treated, may 
delay therapy with interferon for up to 48 weeks.  For this reason, if a patient has 
advanced disease, the study investigators may choose to recommend treatment with 
interferon before enrollment (either by the Liver Diseases Branch under protocol 91-DK-
0214 or outside of the NIH). 
 
Q.  Remuneration/Compensation 
No compensation is offered to study participants. 
 
 
 
 
 


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49 
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52. 
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antiviral efficacy of the prenylation inhibitor lonafarnib. Hepatology 
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Ravoet C, Mineur P, Robin V, et al. Farnesyl transferase inhibitor (lonafarnib) in 
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Lonafarnib + Ritonavir for Chronic Hepatitis Delta  
 
Patient Name ________________________________ 
 
 
Enrollment Criteria 
 
No 
Criteria 
Yes/No 
Comment 
1 
Is patient 18 years or above? 
 
 
Age = _____  years 
2 
Is mean ALT level ≥30 U/L in males 
or ≥20 U/L in females?  
 
Or mean AST level ≥30 U/L in males 
or ≥20 U/L in females?? 
 
Mean ALT = 
 (______ + ______ + ______)=_______ 
Mean AST =  
(______ + ______ + ______)=_______ 
3 
Are 
anti-HDV 
and 
HDV 
RNA 
positive? 
 
Date of sample: ___/___/___ 
 
4 
Is consent form signed? 
 
Date of signature ___/___/___ 
 
 
The answers to these questions should 
all be yes for the patient to be enrolled 
in this study. 
 
 
 
 
 
 
 
 
 
The answers to the above questions are all yes.   
 
 
 
  ______________________________ 
Signature and Date


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54 
PRENYLATION INHIBITORS FOR CHRONIC HEPATITIS D 
 
Patient Name _______________________________ 
Exclusion Criteria 
 
No 
Criteria 
Yes/No 
Comment 
1 
Is ALT > 1000U/L?   
 
 
2 
Is serum bilirubin > 4 mg%? 
 
Bilirubin =  
3 
Is serum albumin < 3 gm%? 
 
Albumin = 
4 
Is protime > 2 seconds prolonged or 
INR >1.7? 
 
Protime = 
INR 
5 
Is there a history of bleeding 
varices, ascites or encephalopathy? 
 
 
6 
For 
females 
with 
childbearing 
potential: Is the patient pregnant, 
actively breast-feeding, or unable to 
practice birth control? 
 
Not applicable if patient has had a 
tubal ligation ____ 
7 
For males: Is the patient able to 
practice birth control? 
 
Not applicable if patient has had a 
vasectomy _____ 
8 
Are there significant other medical 
illnesses such as CHF, renal failure, 
transplant, 
psychiatric 
dx, 
and 
angina? 
 
 
9 
Has the patient been on systemic 
immunosuppressive therapy within 
the previous 2 months? 
 
 
10 
Does the patient have another form of 
liver disease in addition to coinfection 
of HBV and HDV? 
 
 
11 
Has the patient undergone any 
experimental therapy or pegylated 
interferon within 6 months prior to 
starting the study? 
 
 
12 
Has the patient had a diagnosis of 
malignancy within 5 years prior to 
enrollment with the exception of 
superficial 
dermatologic 
malignancies? 
 
 
13 
Has patient had active substance 
abuse in the last one year? 
 
Alcohol, inhaled or injection drugs 
14 
Does the patient have evidence of HIV 
co-infection? 
 
 
15 
Is AFP > 200 ng/ml and does the 
ultrasound/MRI/CT show evidence of 
a mass in the liver? 
 
AFP = _____  
US/MRI/CT date __/__/__ 


Heller 
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55 
16 
Is the patient currently on statin 
medications? 
 
 
17 
Is 
the 
patient 
currently 
on 
medications 
that 
would 
alter 
metabolism of ritonavir? 
 
Alpha-1-adrenoreceptor antagonist 
Antiarrythmic medications 
Pimozide 
Sildinafil 
Sedative and hynotics 
Ergot 
St. John’s Wort 
 
 
The answer to all of the above questions is no:   
 
 
 
_________________________________ 
 
                                     Signature and Date  
 
 
 
 


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56 
Appendix 1 
 
SYMPTOM SCALE: Delta Hepatitis 
 
Name:__________________________________ Date:(M/D/Yr)____/____/____   
 
Mark with an "x" the place on the lines below that best describes how you have 
felt during the past week.  
 
     None  
 
 
 
 
 
 
 
Worst ever           
 
Fatigue 
 
 
|____________________________________________________| 
 
Nausea 
 
 
|____________________________________________________| 
 
Diarrhea 
 
 
 
|____________________________________________________| 
 
Confusion 
 
|____________________________________________________| 
 
Loss of Appetite 
 
 
 
|____________________________________________________| 
 
Indigestion 
 
|____________________________________________________| 
 
In general, how do you feel overall? 
 
Very Good   
 
 
 
 
                
 Awful 
 
|____________________________________________________| 
 
Are you having side effects with Prenylation Inhibitor therapy? 
 
 
Yes ___ 
No ___ 
 
If yes, how much do these side effects interfere with your ordinary.. 
 
 
 
 
 
 
 
 
Not at all 
 
A little  
A lot      Extremely 
 
Responsibilities  
at home 
 
 
     
 
 
Ability to work 
 
Enjoyment of life   


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57 
Appendix 2 
 
Microbiome Monthly Intake Questionnaire: Delta Hepatitis 
 
Name: _________________________________ Date: (M/D/Yr) _____/______/______ 
 
 
1. Over past month, have you taken any new antibiotic medications prescribed by a doctor?
 
 
 
 
 
 
 
  
Yes [  ]           No [   ] 
 
 
If yes, when was the last time you took the antibiotic?   ________________ 
Name of antibiotic                ________________________________ 
 
 
Duration of treatment           _________________________________ 
    
2. Over past month, have you taken any probiotics?    
Yes [   ]          No  [   ] 
 
If yes, when was the last time you took probiotic?       _________________ 
 
         Name of probiotic                    _______________________________ 
 
         How long have you been taking probiotics?        _________________  
 
3. Over past month, have you eaten any yogurt?                        Yes [  ]          No  [  ] 
 
If yes, when was the last time you ate yogurt?     ______________________ 
           Name of yogurt                                          ______________________ 
           Does yogurt have probiotics in it?                     Yes [  ]          No  [  ]