- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01495585
Lonafarnib for Chronic Hepatitis D
July 18, 2016 updated by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Treatment of Chronic Delta Hepatitis With Lonafarnib
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....
Study Overview
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 Type
Interventional
Enrollment (Actual)
14
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Maryland
-
Bethesda, Maryland, United States, 20892
- National Institutes of Health Clinical Center, 9000 Rockville Pike
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
INCLUSION CRITERIA:
- Age 18 years or above, male or female.
- 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.
- Presence of anti-HDV in serum.
- 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).
- Presence of HDV antigen in liver tissue or HDV RNA in serum.
- Written informed consent.
EXCLUSION CRITERIA:
- 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.
- 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.
- 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.
- Systemic immunosuppressive therapy within the previous 2 months.
- 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).
- Active substance abuse, such as alcohol, inhaled or injection drugs within the previous year.
- Evidence of hepatocellular carcinoma.
- Evidence of concurrent hepatitis C infection with positive serum HCV RNA.
- Any experimental therapy apart from pegylated interferon within 6 months prior to enrollment.
- Diagnosis of malignancy in the five years prior to the enrollment with exception granted to superficial dermatologic malignancies.
- Evidence of HIV co-infection; HIV (Omega) antibody positivity on serum testing.
- Concurrent usage of statins as these drugs inhibit mevalonate synthesis which reduces protein prenylation.
- Concurrent usage of moderate and strong CYP3A inhibitors and inducers.
- Inability to understand or sign informed consent.
- Any other condition, which in the opinion of the investigators would impede the patient s participation or compliance in the study.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Placebo
Placebo control
|
Placebo control
|
Experimental: Group 1
lonafarnib 100mg
|
Commercially approved products used to test the research hypothesis
|
Experimental: Group 2
lonafarnib 200mg
|
Commercially approved products used to test the research hypothesis
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Change in Quantitative Serum HDV RNA Levels After 28 Days of Lonafarnib Therapy.
Time Frame: 28 days
|
28 days
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
ALT Levels
Time Frame: 7 months
|
7 months
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Kefalakes H, Koh C, Sidney J, Amanakis G, Sette A, Heller T, Rehermann B. Hepatitis D Virus-Specific CD8+ T Cells Have a Memory-Like Phenotype Associated With Viral Immune Escape in Patients With Chronic Hepatitis D Virus Infection. Gastroenterology. 2019 May;156(6):1805-1819.e9. doi: 10.1053/j.gastro.2019.01.035. Epub 2019 Jan 18.
- 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. doi: 10.1128/JVI.72.11.9303-9306.1998.
- Rizzetto M, Ponzetto A, Forzani I. Hepatitis delta virus as a global health problem. Vaccine. 1990 Mar;8 Suppl:S10-4; discussion S21-3. doi: 10.1016/0264-410x(90)90207-3.
- Rosina F, Rizzetto M. Treatment of chronic type D (delta) hepatitis with alpha interferon. Semin Liver Dis. 1989 Nov;9(4):264-6. doi: 10.1055/s-2008-1040521. No abstract available.
- Koh C, Canini L, Dahari H, Zhao X, Uprichard SL, Haynes-Williams V, Winters MA, Subramanya G, Cooper SL, Pinto P, Wolff EF, Bishop R, Ai Thanda Han M, Cotler SJ, Kleiner DE, Keskin O, Idilman R, Yurdaydin C, Glenn JS, Heller T. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect Dis. 2015 Oct;15(10):1167-1174. doi: 10.1016/S1473-3099(15)00074-2. Epub 2015 Jul 16.
Helpful Links
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
December 1, 2011
Primary Completion (Actual)
April 1, 2015
Study Completion (Actual)
April 1, 2015
Study Registration Dates
First Submitted
December 16, 2011
First Submitted That Met QC Criteria
December 16, 2011
First Posted (Estimate)
December 20, 2011
Study Record Updates
Last Update Posted (Estimate)
August 31, 2016
Last Update Submitted That Met QC Criteria
July 18, 2016
Last Verified
July 1, 2016
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 120046
- 12-DK-0046 (Other Identifier: NIH Clinical Center)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Yes
IPD Plan Description
De-identified data with outside collaborators
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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