Treatment of Chronic Delta Hepatitis With Lonafarnib and Ritonavir

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).

Study Overview

• Status: Completed
• Conditions: Hepatitis D
• Intervention / Treatment: Other: Placebo; Drug: Lonafarnib; Drug: Ritonavir

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; Lonafarnib/Ritonavir at 50 mg/100 mg daily for 24 weeks followed by 24 weeks of off therapy follow-up.	Drug: Lonafarnib; prenylation inhibitor to be administered daily at doses of 50 mg, 75 mg or 100 mg.; Drug: Ritonavir; 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.
Experimental: Group 2; Lonafarnib/Ritonavir at 75 mg/100 mg daily for 24 weeks followed by 24 weeks of off therapy follow-up.	Drug: Lonafarnib; prenylation inhibitor to be administered daily at doses of 50 mg, 75 mg or 100 mg.; Drug: Ritonavir; 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.
Experimental: Group 3; Lonafarnib/Ritonavir at 100 mg/100 mg daily for 24 weeks followed by 24 weeks of off therapy follow-up.	Drug: Lonafarnib; prenylation inhibitor to be administered daily at doses of 50 mg, 75 mg or 100 mg.; Drug: Ritonavir; 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.
Experimental: Group 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.	Other: Placebo; Placebo; Drug: Lonafarnib; prenylation inhibitor to be administered daily at doses of 50 mg, 75 mg or 100 mg.; Drug: Ritonavir; 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.
Experimental: Group 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.	Other: Placebo; Placebo; Drug: Lonafarnib; prenylation inhibitor to be administered daily at doses of 50 mg, 75 mg or 100 mg.; Drug: Ritonavir; 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.
Experimental: Group 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.	Other: Placebo; Placebo; Drug: Lonafarnib; prenylation inhibitor to be administered daily at doses of 50 mg, 75 mg or 100 mg.; Drug: Ritonavir; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Decline of Hepatitis Delta Virus (HDV) RNA Quantitative Measurements of >2 Logs From Baseline at 12 Weeks of Treatment	The number of participants who experienced a > 2 log IU/mL decline in serum HDV RNA at 12 weeks of treatment	12 weeks
Number of Participants With Decline of HDV RNA Quantitative Measurement of > 2 Logs From Baseline at 24 Weeks of Treatment	The number of participants who experienced a > 2 log IU/mL decline in serum HDV RNA levels at 24 weeks of treatment	24 weeks

Collaborators and Investigators

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

Publications and helpful links

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.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: July 29, 2015
• Primary Completion (Actual): February 23, 2017
• Study Completion (Actual): February 23, 2017

Study Registration Dates

• First Submitted: July 29, 2015
• First Submitted That Met QC Criteria: July 29, 2015
• First Posted (Estimate): July 30, 2015

Study Record Updates

• Last Update Posted (Actual): September 25, 2018
• Last Update Submitted That Met QC Criteria: August 27, 2018
• Last Verified: February 23, 2017

More Information

Terms related to this study

• Keywords: Hepatitis D; Chronic Hepatitis; Liver Disease; Hepatitis D Virus; Delta Hepatitis
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis D; Hepatitis D, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Lonafarnib
• Other Study ID Numbers: 150170; 15-DK-0170

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No