Treatment of Chronic Delta Hepatitis With Lonafarnib and Ritonavir
Condition: Hepatitis D
MeSH terms: Hepatitis A; Hepatitis D; Hepatitis D, Chronic; Hepatitis
Intervention: Lonafarnib; Ritonavir; Placebo
Intervention description: prenylation inhibitor to be administered daily at doses of 50 mg, 75 mg or 100 mg.; 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.; Placebo
Intervention MeSH terms: Ritonavir; Lonafarnib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Delta Hepatitis; Hepatitis D; Liver Disease; Hepatitis D Virus; Chronic Hepatitis

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).
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Age 18 years or above, male or female.

               2. Serum alanine or aspartate aminotransferase (ALT or AST) activities above the
                  upper limit of normal (ALT greater than or equal to 20 or AST greater than or
                  equal to 20 U/L in females and ALT greater than or equal to 30 or AST greater
                  than or equal to 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. In total, the participant and their partner must
             utilize two forms of contraception and one method must include a barrier method.

          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 hepatitis c virus
             (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 viral RNA or antigen 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 cytochrome p450, family 3, subfamily A (CYP3A)
             inhibitors and inducers.

         14. Use of any prescription, nonprescription or natural medicine (herbal) medications
             unless the use of medication is medically necessary with appropriate monitoring.

         15. 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.

         16. Clinically significant baseline EKG abnormalities.

         17. Uncontrolled elevated triglycerides.

         18. History of pancreatitis as a result of hypertriglyceridemia.

         19. Inability to understand or sign informed consent.

         20. Any other condition, which in the opinion of the investigators would impede the
             patient s participation or compliance in the study.