Lonafarnib for Chronic Hepatitis D

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )
ClinicalTrials.gov Identifier:
NCT01495585
First received: December 16, 2011
Last updated: July 1, 2014
Last verified: June 2014
  Purpose

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 Intervention Phase
Hepatitis D
Drug: Lonafarnib
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Treatment of Chronic Delta Hepatitis With Lonafarnib

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • The primary endpoint of therapy will be an improvement in quantitative serum HDV RNA levels after 28 days of lonafarnib therapy. [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Several secondary endpoints will be measured, including side effects, ALT levels, and symptoms. [ Time Frame: 7 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 14
Study Start Date: December 2011
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Lonafarnib
    Commercially approved products used to test the research hypothesis
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 > 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01495585

Contacts
Contact: Vanessa Haynes-Williams, R.N. (301) 451-7007 vhaynes@mail.nih.gov
Contact: Theo Heller, M.D. (301) 402-7147 theoh@intra.niddk.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Theo Heller, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )
ClinicalTrials.gov Identifier: NCT01495585     History of Changes
Other Study ID Numbers: 120046, 12-DK-0046
Study First Received: December 16, 2011
Last Updated: July 1, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Hepatitis
Delta
Treatment
Lonafarnib
Hepatitis D

Additional relevant MeSH terms:
Hepatitis D
Hepatitis
Hepatitis A
Hepatitis, Chronic
Hepatitis D, Chronic
Hepatitis, Viral, Human
Virus Diseases
RNA Virus Infections
Liver Diseases
Digestive System Diseases
Enterovirus Infections
Picornaviridae Infections

ClinicalTrials.gov processed this record on July 26, 2014