Lonafarnib for Chronic Hepatitis D

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01495585
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 3
• Duration (Months): 40
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Background:

• Chronic hepatitis D is a severe disease of the liver caused by infection with the hepatitis D virus. The hepatitis D virus can only infect a person who also has hepatitis B; therefore, people with delta hepatitis have both hepatitis B and hepatitis D virus infection. Most people with hepatitis D eventually develop cirrhosis, which causes scarring and damage to the liver. There is currently no effective treatment for chronic hepatitis D.

• Lonafarnib is a drug that was originally designed to treat different types of cancer. It may be able to prevent the hepatitis D virus from reproducing itself. However, it has not been tested on people with hepatitis D. Researchers want to study different doses of lonafarnib to see how they affect virus levels and other symptoms of hepatitis D.

Objectives:

• To test the safety and effectiveness of lonafarnib as a treatment for chronic hepatitis D.

Eligibility:

• Individuals at least 18 years of age who have chronic hepatitis D.

Design:

• Participants will be screened with a medical history and physical exam. They will have blood and urine tests, eye exams, and imaging studies of the liver and gall bladder. A liver biopsy may also be performed.

• Participants will receive either lonafarnib or placebo twice a day for 28 days. For the first 3 days, participants will stay in the hospital to have frequent blood tests. Participants will have four more clinic visits (on days 7, 14, 21, and 28) for blood and urine tests. Eye exams and heart function tests will also be given. Men may be asked to provide sperm samples for further testing.

• After the 28 days of treatment, participants will stop taking the drug or placebo. They will have regular followup visits for up to 6 months after stopping treatment....

Condition or Disease	Intervention/Treatment	Phase
Hepatitis D	Drug: Lonafarnib; Other: Placebo	Phase 2

Detailed Description

Chronic delta hepatitis is a serious form of chronic liver disease caused by infection with the hepatitis D virus (HDV), a small RNA virus that requires farnesylation of its major structural protein (HDV antigen) for replication. We propose to treat between 12 and 14 patients with chronic delta hepatitis using the farnesyltransferase inhibitor (FTI) lonafarnib for a duration of twenty-eight days. Farnesyltransferase inhibitors have not been used in the therapy of delta hepatitis. Patients with HBsAg and HDV RNA in serum, elevated aminotransferases, or moderate-to-severe chronic hepatitis and HDV antigen on liver biopsy will be enrolled. Before receiving therapy, patients will be monitored for at least three months with regular testing for alanine aminotransferase (ALT) levels and will undergo Clinical Center admission for medical evaluation and percutaneous liver biopsy. Two dosing groups of lonafarnib will be assessed, with a placebo cohort in each group. At each clinic visit, patients will be questioned about side effects and symptoms, 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 two-week intervals, for a period of 28 days, patients will also be tested for HBsAg, anti-HBs, HBV DNA, and prothrombin time. At the end of 28 days of 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 an improvement in quantitative serum HDV RNA levels after 28 days of lonafarnib therapy. The primary safety endpoint will be the ability to tolerate the drug at the prescribed dose for the 4 week duration. Several secondary endpoints will be measured, including side effects, ALT levels, and symptoms. Therapy will be stopped for intolerance to lonafarnib (which will be carefully defined). This study is designed as a phase 2a study assessing the safety, tolerance and antiviral activity of two dose levels of lonafarnib, a farnesyltransferase inhibitor.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Treatment of Chronic Delta Hepatitis With Lonafarnib
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo control	Other: Placebo; Placebo control
Experimental: Group 1 lonafarnib 100mg	Drug: Lonafarnib; Commercially approved products used to test the research hypothesis
Experimental: Group 2 lonafarnib 200mg	Drug: Lonafarnib; Commercially approved products used to test the research hypothesis

Outcome Measures

Primary Outcome Measures

1. Change in Quantitative Serum HDV RNA Levels After 28 Days of Lonafarnib Therapy. [28 days]

Secondary Outcome Measures

1. ALT Levels [7 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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 > 41 or AST > 31 U/L) on an average of three determinations taken during the previous 6 months. The mean of the three determinations will be defined as baseline levels.

3. Presence of anti-HDV in serum.

4. Evidence of chronic hepatitis on liver biopsy done within the previous 12 months with a necroinflammatory score in histology activity index of at least 5 (out of a maximum of 18) and at least 1 for hepatic fibrosis (out of a maximum of 6).

5. Presence of HDV antigen in liver tissue or HDV RNA in serum.

6. Written informed consent.

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 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.

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 apart from pegylated interferon 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 (Omega) antibody positivity on serum testing.

12. Concurrent usage of statins as these drugs inhibit mevalonate synthesis which reduces protein prenylation.

13. Concurrent usage of moderate and strong CYP3A inhibitors and inducers.

14. Inability to understand or sign informed consent.

15. Any other condition, which in the opinion of the investigators would impede the patient s participation or compliance in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Theo Heller, M.D., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Glenn JS, Marsters JC Jr, Greenberg HB. Use of a prenylation inhibitor as a novel antiviral agent. J Virol. 1998 Nov;72(11):9303-6.
• Rizzetto M, Ponzetto A, Forzani I. Hepatitis delta virus as a global health problem. Vaccine. 1990 Mar;8 Suppl:S10-4; discussion S21-3. Review.
• Rosina F, Rizzetto M. Treatment of chronic type D (delta) hepatitis with alpha interferon. Semin Liver Dis. 1989 Nov;9(4):264-6. Review.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT01495585
• Other Study ID Numbers: 120046; 12-DK-0046
• First Posted: Dec 20, 2011
• Last Update Posted: Aug 31, 2016
• Last Verified: Jul 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Hepatitis; Delta; Treatment; Lonafarnib; Hepatitis D
• Additional relevant MeSH terms: Hepatitis A; Hepatitis D; Hepatitis; Lonafarnib

Study Results

Participant Flow

Pre-assignment Detail	In Group 1, participants were randomized either placebo or lonafarnib 100 mg. In Group2, participants were randomized into either placebo or lonafarnib 200 mg.

Arm/Group Title	Placebo	Lonafarnib 100 mg	Lonafarnib 200 mg
Arm/Group Description	Two placebo participants in Group1 and two placebo participants in Group 2. The two placebo participants in Group 1 received open label lonafarnib 200 mg.	6 participants were randomized to Lonafarnib 100 mg.	4 participants were randomized to Lonafarnib 200 mg.
Period Title: Overall Study
STARTED	4	6	4
Open Label Lonafarnib 200 mg	2	0	0
COMPLETED	4	6	4
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Lonafarnib 100 mg	Lonafarnib 200 mg	Total
Arm/Group Description	placebo control.	6 participants were randomized to Lonafarnib 100 mg.	4 participants were randomized to Lonafarnib 200 mg and two "Placebo" participants in Lonafarnib 100 mg arm received open label lonafarnib 200 mg .	Total of all reporting groups
Overall Participants	4	6	6	16
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	34	36	45	38
Sex: Female, Male (Count of Participants)
Female	2 50%	1 16.7%	2 33.3%	5 31.3%
Male	2 50%	5 83.3%	4 66.7%	11 68.8%
Body mass index (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	26.5	22.8	26.1	24.4
Pre-treatment mucleoside analogues (participants) [Number]
yes	1 25%	2 33.3%	2 33.3%	5 31.3%
no	3 75%	4 66.7%	4 66.7%	11 68.8%
Ethnic origin (participants) [Number]
Asian	2 50%	3 50%	3 50%	8 50%
White	1 25%	3 50%	3 50%	7 43.8%
African	1 25%	0 0%	0 0%	1 6.3%

Outcome Measures

1. Primary Outcome

Title	Change in Quantitative Serum HDV RNA Levels After 28 Days of Lonafarnib Therapy.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Group 1	Group 2
Arm/Group Description	placebo control. Group 1 placebo participants received open-label lonafarnib as group 2 participants. Each group consisted of 8 participants (6 lonafarnib ands 2 placebo).	lonafarnib 100 mg	lonafarnib 200 mg
Measure Participants	4	6	6
Mean (Standard Deviation) [log(IU/ml)]	-0.13 (0.14)	-0.73 (0.54)	-1.54 (0.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Group 1
	Comments	Student t-test was used on the change in serum log HDV RNA after 28 days of therapy with lonafarnib.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Group 2
	Comments	Student t-test was used on the change in serum log HDV RNA after 28 days of therapy with lonafarnib.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	ALT Levels
Time Frame	7 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Group 1	Group 2
Arm/Group Description	placebo control. Group 1 placebo participants received open-label lonafarnib as group 2 participants. Each group consisted of 8 participants (6 lonafarnib ands 2 placebo).	lonafarnib 100 mg	lonafarnib 200 mg
Measure Participants	4	6	6
Mean (Standard Deviation) [U/L]	18 (13)	4 (93)	29 (85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Group 1
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.96
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Group 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	7 months
Arm/Group Title	Placebo		Group 1		Group 2
Arm/Group Description	placebo control. Group 1 placebo participants received open-label lonafarnib as group 2 participants. Each group consisted of 8 participants (6 lonafarnib ands 2 placebo).		lonafarnib 100 mg		lonafarnib 200 mg
All Cause Mortality
	Placebo		Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		6/6 (100%)		6/6 (100%)
Gastrointestinal disorders
Nausea	1/4 (25%)	1	1/6 (16.7%)	2	5/6 (83.3%)	6
Diarrhoea	0/4 (0%)	0	3/6 (50%)	3	6/6 (100%)	6
Decreased appetite	0/4 (0%)	0	1/6 (16.7%)	1	5/6 (83.3%)	5
Abdominal bloating/dyspepsia	1/4 (25%)	1	1/6 (16.7%)	1	6/6 (100%)	6
Vomitting	0/4 (0%)	0	0/6 (0%)	0	3/6 (50%)	3
General disorders
Fatigue	0/4 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1
Headache	1/4 (25%)	1	1/6 (16.7%)	1	1/6 (16.7%)	1
Lightheadedness	1/4 (25%)	1	0/6 (0%)	0	0/6 (0%)	0
Metabolism and nutrition disorders
Weight loss > 2kg	0/4 (0%)	0	1/6 (16.7%)	1	6/6 (100%)	6
Reproductive system and breast disorders
Testicular pain	0/4 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.