Study of the Efficacy and Safety of Lonafarnib / Ritonavir With and Without Pegylated Interferon -Alfa-2a

Study Overview
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Brief Summary
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Two LNF-containing regimens will be evaluated in the D-LIVR Phase 3 study: (1) LNF/RTV/PEG IFN-alfa-2a and (2) LNF/RTV. Each of these arms will have efficacy endpoints that measure clinical benefit with regard to viral suppression and alanine aminotransferase (ALT) normalization. For each LNF-containing regimen, a composite endpoint of EOT (48 weeks) virologic response and ALT normalization will be used. Virologic response will be defined as a 2 log10 IU/mL reduction from baseline.

Detailed Description
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This partially double-blind, randomized study will employ a matrix (factorial) design to evaluate the efficacy and safety of LNF 50 mg/RTV 100 mg twice per day (BID) with and without PEG IFN-alfa-2a 180 mcg once-weekly (QW) for 48 weeks compared to no treatment (placebo LNF and placebo RTV) in patients chronically infected with hepatitis delta virus (HDV) and receiving anti-HBV (hepatitis B virus) nucleos(t)ide maintenance therapy. Approximately 400 patients will be randomized with an allocation ratio of 7:5:2:2 All patients will receive/maintain background anti-HBV nucleos(t)ide therapy with entecavir or tenofovir for at least 12 weeks prior to initiating study therapy. All patients who complete 48 weeks of treatment will have a liver biopsy for histology assessment at EOT and will be followed for an additional 24 weeks off study treatment.

Official Title
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A Phase 3, Matrix Design, Partially Double-Blind, Randomized Study of the Efficacy and Safety of 50 mg Lonafarnib/100 mg Ritonavir BID With and Without 180 mcg PEG IFN-alfa-2a for 48 Weeks Compared With PEG IFN-alfa-2a Monotherapy and Placebo Treatment in Patients Chronically Infected With Hepatitis Delta Virus Being Maintained on Anti-HBV Nucleos(t)Ide Therapy (D-LIVR)

Conditions
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Hepatitis Delta Virus

Intervention / Treatment
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* Drug: Lonafarnib
* Drug: Ritonavir
* Drug: PEG IFN-alfa-2a
* Drug: Placebo Lonafarnib
* Drug: Placebo Ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic HDV infection for at least 6 months in duration, documented by a positive HDV antibody test and HDV RNA ≥ 500 IU/mL. Note: All genotypes of HDV permitted. Demonstrable suppression of HBV DNA following at least 12 weeks of anti-HBV nucleos(t)ide treatment with entecavir or tenofovir prior to initiating therapy. Serum ALT > 1.3 x upper limit of the normal range (ULN) and < 10 x ULN. Baseline liver biopsy demonstrating evidence of chronic hepatitis. ECGs demonstrating no acute ischemia or clinically significant abnormality. Normal dilated retinal examination. Exclusion Criteria: General Exclusions Previous use of LNF within 12 months. Current or previous history of decompensated liver disease. Co-infected with human immunodeficiency virus or hepatitis C virus (HCV) by detectable HIV RNA and HCV RNA, respectively. Evidence of significant portal hypertension. Current evidence or history of ascites requiring diuretics or paracentesis, or hepatic encephalopathy. History of hepatocellular carcinoma. Patients with any of the following: Current eating disorder Evidence of alcohol substance use disorder. Drug abuse within the previous 6 months before screening. Prior history or current evidence of any of the following: Immunologically mediated disease, Retinal disorder or clinically relevant ophthalmic disorder, Any malignancy within 5 years before screening, Cardiomyopathy or significant ischemic cardiac or cerebrovascular disease, Chronic pulmonary disease, Pancreatitis or colitis, Severe or uncontrolled psychiatric disorder. Other significant medical condition that may require intervention during the study. Any condition that may impact proper absorption. Therapy with an immunomodulatory agent, IFN-α (eg, IFN alfa-2a or IFN-alfa-2b, or pegylated IFN-alfa-2a or alfa 2b), cytotoxic agent, or chronic systemic corticosteroids within 12 months of screening. Use of heparin or warfarin. Systemic antibiotics, antifungals, or antivirals for treatment of active infection other than HBV. Receipt of systemic immunosuppressive therapy. History or evidence for any intolerance or hypersensitivity to LNF, RTV, PEG IFN-alfa-2a, tenofovir or entecavir.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Lonafarnib 50 mg BID + Ritonavir 100 mg BID | Drug: Lonafarnib<br>* Lonafarnib (LNF) 50 mg BID<br>* Other names: LNF;Drug: Ritonavir<br>* Ritonavir (RTV) 100 mg BID<br>* Other names: RTV;|
| Experimental: Group 2<br>Lonafarnib 50 mg BID + Ritonavir 100 mg BID + PEG IFN alfa-2a 180 mcg QW | Drug: Lonafarnib<br>* Lonafarnib (LNF) 50 mg BID<br>* Other names: LNF;Drug: Ritonavir<br>* Ritonavir (RTV) 100 mg BID<br>* Other names: RTV;Drug: PEG IFN-alfa-2a<br>* PEG IFN alfa-2a 180 mcg QW<br>* Other names: pegylated interferon-alfa;|
| Active Comparator: Group 3<br>placebo Lonafarnib + placebo Ritonavir + PEG IFN-alfa-2a 180 mcg QW | Drug: PEG IFN-alfa-2a<br>* PEG IFN alfa-2a 180 mcg QW<br>* Other names: pegylated interferon-alfa;Drug: Placebo Lonafarnib<br>* Placebo<br>Drug: Placebo Ritonavir<br>* Placebo<br>|
| Placebo Comparator: Group 4<br>placebo Lonafarnib + placebo Ritonavir | Drug: Placebo Lonafarnib<br>* Placebo<br>Drug: Placebo Ritonavir<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the composite virologic and biochemical response rate at end-of-treatment (EOT) in patients who receive LNF 50 mg/RTV 100 mg BID vs patients who receive placebo. |  | 48 weeks | 
| To compare the composite virologic and biochemical response rate at EOT in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW vs patients who receive placebo. |  | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the histologic response rate at EOT in patients who receive LNF 50 mg/RTV 100 mg BID vs patients who receive placebo. |  | 48 weeks | 
| To compare the histologic response rate at EOT in patients who receive LNF 50 mg/RTV 100 mg BID with PEG IFN-alfa-2a 180 mcg QW vs patients who receive placebo. |  | 48 weeks | 
| To evaluate the health-related quality of life (HRQL) over a 48-week treatment period in patients who receive LNF 50 mg/RTV 100 mg BID vs placebo. |  | 48 weeks | 
| To evaluate the HRQL over a 48-week treatment period in patients who receive LNF 50 mg/RTV 100 mg BID/PEG IFN-alfa-2a 180 mcg QW vs placebo. |  | 48 weeks | 
| To evaluate the Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] over a 48-week treatment period in patients who receive LNF 50 mg/RTV 100 mg BID vs placebo. |  | 48 weeks | 
| To evaluate the Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] over a 48-week treatment period in patients who receive LNF 50 mg/RTV 100 mg BID/PEG IFN-alfa-2a 180 mcg QW vs placebo. |  | 48 weeks |