Treatment of Chronic Delta Hepatitis With Lonafarnib, Ritonavir and Lambda Interferon

Phase 2

Completed

Conditions: Liver Disease
Hepatitis D

Interventions: Drug: Peg-interferon lambda
Drug: Lonafarnib
Drug: Ritonavir

Registration Number: NCT03600714

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

Brief Summary: Background:

Infection with hepatitis D virus leads to a chronic liver disease with no effective treatment. Lonafarnib has improved hepatitis D virus levels in blood, but the medication still needs more research. Ritonavir makes other drugs more effective and is used with lonafarnib to make it more effective. Lambda interferon stimulates the body s response to viruses. Researchers want to see if combining these drugs fights hepatitis D and helps the liver.

Objectives:

To see if combining lonafarnib, ritonavir, and lambda interferon is safe and effective to treat chronic hepatitis D infection.

Eligibility:

Adults at least 18 years old with chronic hepatitis D infection

Design:

Participants will be screened with a physical exam, medical history, and blood and urine tests.

Throughout the study, all participants will:

* Follow rules for medicine, food, and contraception

* Take hepatitis B medicine

* Have weight checked

* Have routine blood and urine tests

* Give stool samples

* Female participants will have pregnancy tests.

Participants will have 3 visits before treatment. They will repeat screening tests and have a heart test and liver scan.

Participants will have a 5-day inpatient stay. They will:

* Baseline blood and urine tests

* Have eye tests

* Answer health questions

* Have a liver sample taken and liver blood pressure measured. Participants will be sedated.

* Have reproductive tests

* Start the study drugs and have blood draws

Over 24 weeks of treatment, participants will:

-Take 2 study drugs by mouth every day and 1 as a weekly injection

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. Based on previous and ongoing clinical trials demonstrating effectiveness against HDV, we propose to treat 26 adult patients with chronic delta hepatitis using the combination of the farnesyltransferase inhibitor (FTI) lonafarnib (LNF), the protease inhibitor ritonavir (RTV) and peginterferon lambda-1a(lambda). In this phase 2a open label study, the safety and antiviral effects of triple therapy with LNF, RTV and lambda for a period of 6 months. After dosing, all patients will be monitored for 24 weeks off therapy. Nucleos(t)ide analogue therapy will be instituted/continued during this study to prevent the possibility of hepatitis B virus (HBV) reactivation/flare for the duration of participation in this clinical trial. Patients with quantifiable HDV RNA in serum will be enrolled. 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 alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, direct and total bilirubin, and albumin). At the end of the treatment, patients will be admitted to the clinical center and will undergo repeat liver biopsy and hepatic venous pressure gradient (HVPG) measurements, 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. This clinical trial is designed as a phase 2a study assessing the antiviral activity, safety and tolerance of fixed doses of lonafarnib, ritonavir and peginterferon lambda.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment	Peg-interferon lambda	Treatment with Lonafarnib, Ritonavir, and Peginterferon lambda
Treatment	Lonafarnib	Treatment with Lonafarnib, Ritonavir, and Peginterferon lambda
Treatment	Ritonavir	Treatment with Lonafarnib, Ritonavir, and Peginterferon lambda

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Discontinue Medication	24 weeks	Discontinuation of the medication before 24 weeks by the clinical team or patient will be considered a failure to tolerate the medicine.
Number of Participants With Decline of Hepatitis D Virus (HDV) RNA Viral Titer of >2 Logs	Baseline and 24 weeks	Decline of HDV RNA viral titer of \>2 logs from baseline at 24 weeks of therapy

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Reduction of Hepatic Venous Pressure Gradient (HVPG)	Baseline and 24 weeks after completing therapy	Reduction in hepatic venous pressure gradient (HVPG) measurements by \>25% of baseline OR normalization of HVPG (\<5 mm Hg) at 24 weeks after completing therapy
Number of Participants With Reduction in Histologic Inflammatory Scores (Modified HAI)	End of treatment and 24 weeks after completing therapy.	Reduction in histologic inflammatory scores (modified HAI) by at least two points with no progression in histologic fibrosis (Ishak) at week 24 post-treatment follow-up.
Number of Participants With Normalization of Serum ALT	End of therapy, and 12 and 24 weeks after completing therapy	Normalization of serum ALT (ALT \<20 in females and ALT \<31 in males) at the end of therapy, at week 12 of posttherapy follow-up and at week 24 of post-therapy follow-up, OR reduction in serum ALT by \>50% of baseline at week 12 of post therapy follow up and week 24 of post therapy follow up.
Number of Participants With Loss of HBsAg at Week 24	Week 24	Loss of HBsAg from the serum at week 24
Number of Participants With Loss of HBsAg at Week 12 Weeks After Completing Therapy	12 weeks after completing therapy	Loss of HBsAg from the serum at 12 weeks after completing therapy
Number of Participants With Loss of HBsAg at 24 Weeks After Completing Therapy	24 weeks after completing therapy	Loss of HBsAg from the serum at 24 weeks after completing therapy
Change in Quantitative Log HBsAg Levels From Baseline 24 Weeks After Completing Therapy	Baseline and 24 weeks after completing therapy	Change in quantitative log HBsAg levels at from baseline to 24 weeks after completing therapy
Change in Quantitative Log HBsAg Levels From Baseline to Week 24	Baseline and week 24	Change in quantitative log HBsAg levels at from baseline to week 24
Number of Participants With Sustained Virologic Response	12 and 24 weeks after completing therapy	Undetectable HDV RNA at both 12 and 24 weeks post treatment follow-up visits
Number of Participants With Reduction in Fibroscan Transient Elastography Values	Baseline and 24 weeks	Reduction in Fibroscan transient elastography values by \>25% of baseline at end of therapy.