Titrating-Dose of Lonafarnib in Combination With Ritonavir

Study Overview
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Brief Summary
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A phase 2, open-label study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of titrating-dose lonafarnib/ritonavir in patients chronically infected with hepatitis delta virus (HDV)

Detailed Description
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This is a Phase 2 study of 24 weeks of treatment with a dose-titration regimen of lonafarnib/ritonavir in up to 15 patients chronically infected with HDV: lonafarnib starting at 50 mg twice daily (BID) in combination with ritonavir 100 mg BID and escalating lonafarnib as tolerated. The duration of the study for each patient is approximately 13 months (up to 4 weeks for screening, 24 weeks of treatment, 4 weeks for the primary follow-up visit, and monthly safety follow-up visits for 5 months thereafter). The 6-month follow-up after the last dose of study drug is designed to allow evaluation of the clinical and virologic course after completion of the 24-week Treatment Period.

Official Title
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A Phase 2, Open-Label Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Activity of a Titrating-Dose Lonafarnib/Ritonavir in Patients Chronically Infected With Hepatitis Delta Virus

Conditions
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Chronic Delta Hepatitis

Intervention / Treatment
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* Drug: lonafarnib
* Drug: Ritonavir


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female, 18 to 65 years of age, inclusive Chronic HDV infection documented by a positive HDV antibody (Ab) test of at least 6 months duration and detectable HDV ribonucleic acid (RNA) by quantitative polymerase chain reaction (qPCR) at study entry Liver biopsy demonstrating evidence of chronic hepatitis Willingness to practice appropriate contraception Key Exclusion Criteria: Previous use of lonafarnib Co-infected with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) Active jaundice defined by total bilirubin level >2.0 mg/dL and known not to have Gilbert's disease Decompensated liver disease or cirrhosis, history of bleeding esophageal varices, ascites, or hepatic encephalopathy Serum creatinine concentration ≥1.5 times upper limit of normal (ULN) Evidence of another form of viral hepatitis (not including hepatitis B virus or HCV) or another form of liver disease Evidence of hepatocellular carcinoma Use of alfa interferon, either interferon alfa-2a or interferon alfa-2b, or peginterferon alfa-2a within 2 months before the start of screening Concomitant use of any of the following: Medications or foods that are known moderate or strong inducers or inhibitors of CYP3A4 or CYP2C19 Drugs known to prolong the PR interval or QT interval of the electrocardiogram Receipt of systemic immunosuppressive therapy within the 3 months before start of screening Statins, due to inhibition of mevalonate synthesis, which reduces protein prenylation Medications contraindicated in the prescribing information for ritonavir

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lonafarnib/ritonavir<br>Lonafarnib starting at 50 mg BID in combination with ritonavir 100 mg BID and escalating to lonafarnib 75 mg BID and then 100 mg BID as tolerated. The duration of the study for each patient is 6 months of treatment and 6 months follow-up. | Drug: lonafarnib<br>* antiviral farnesyltransferase inhibitor<br>* Other names: Sarasar;Drug: Ritonavir<br>* Cytochromes P450 3A4 inhibitor used to boost lonafarnib<br>* Other names: Norvir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in Mean Hepatitis D Virus (HDV) Ribonucleic Acid (RNA) Titer | Change from baseline to Week 24 in mean HDV RNA titer following dose escalating from lonafarnib 50 mg BID to 75 mg BID and to 100 mg BID, all boosted with ritonavir 100 mg BID. | Baseline and Week 24 (6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With 1 Log Reduction From Baseline by Timepoint | Number of patients with at least 1 log reduction in HDV RNA from baseline by dose level and timepoint | Baseline and Week 1, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 20, or Week 24 |