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Titrating-Dose of Lonafarnib in Combination With Ritonavir (LOWR-4)

Primary Purpose

Chronic Delta Hepatitis

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
lonafarnib
Ritonavir
Sponsored by
Eiger BioPharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Delta Hepatitis

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

  1. Male or female, 18 to 65 years of age, inclusive
  2. Chronic HDV infection documented by a positive HDV antibody (Ab) test of at least 6 months duration and detectable HDV RNA by qPCR at study entry
  3. Liver biopsy demonstrating evidence of chronic hepatitis
  4. Willingness to practice appropriate contraception

Key Exclusion Criteria:

  1. Previous use of lonafarnib
  2. Co-infected with HIV or HCV
  3. Active jaundice defined by total bilirubin level >2.0 mg/dL and known not to have Gilbert's disease
  4. Decompensated liver disease or cirrhosis, history of bleeding esophageal varices, ascites, or hepatic encephalopathy
  5. Serum creatinine concentration ≥1.5 times upper limit of normal (ULN)
  6. Evidence of another form of viral hepatitis or another form of liver disease
  7. Evidence of hepatocellular carcinoma
  8. Use of alfa interferon, either interferon alfa-2a or interferon alfa-2b, or peginterferon alfa-2a within 2 months before the start of screening
  9. Concomitant use of any of the following:

    1. Medications or foods that are known moderate or strong inducers or inhibitors of CYP3A4 or CYP2C19
    2. Drugs known to prolong the PR or QT interval
    3. Receipt of systemic immunosuppressive therapy within the 3 months before start of screening
    4. Statins, due to inhibition of mevalonate synthesis, which reduces protein prenylation
    5. Medications contraindicated in the prescribing information for ritonavir

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    lonafarnib/ritonavir

    Arm Description

    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.

    Outcomes

    Primary Outcome Measures

    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.

    Secondary Outcome Measures

    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

    Full Information

    First Posted
    August 13, 2015
    Last Updated
    May 26, 2023
    Sponsor
    Eiger BioPharmaceuticals
    Collaborators
    Hannover Medical School
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02527707
    Brief Title
    Titrating-Dose of Lonafarnib in Combination With Ritonavir
    Acronym
    LOWR-4
    Official Title
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    May 2023
    Overall Recruitment Status
    Completed
    Study Start Date
    September 2015 (undefined)
    Primary Completion Date
    August 2016 (Actual)
    Study Completion Date
    February 9, 2017 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Eiger BioPharmaceuticals
    Collaborators
    Hannover Medical School

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    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
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Chronic Delta Hepatitis

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    15 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    lonafarnib/ritonavir
    Arm Type
    Experimental
    Arm Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    lonafarnib
    Other Intervention Name(s)
    EBP994, Sarasar
    Intervention Description
    antiviral farnesyltransferase inhibitor
    Intervention Type
    Drug
    Intervention Name(s)
    Ritonavir
    Other Intervention Name(s)
    Norvir
    Intervention Description
    Cytochromes P450 3A4 inhibitor used to boost lonafarnib
    Primary Outcome Measure Information:
    Title
    Change From Baseline to Week 24 in Mean Hepatitis D Virus (HDV) Ribonucleic Acid (RNA) Titer
    Description
    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.
    Time Frame
    Baseline and Week 24 (6 months)
    Secondary Outcome Measure Information:
    Title
    Number of Patients With 1 Log Reduction From Baseline by Timepoint
    Description
    Number of patients with at least 1 log reduction in HDV RNA from baseline by dose level and timepoint
    Time Frame
    Baseline and Week 1, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 20, or Week 24

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    65 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Heiner Wedemeyer, MD, PhD
    Organizational Affiliation
    Hannover Medical School
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    26189433
    Citation
    Koh C, Canini L, Dahari H, Zhao X, Uprichard SL, Haynes-Williams V, Winters MA, Subramanya G, Cooper SL, Pinto P, Wolff EF, Bishop R, Ai Thanda Han M, Cotler SJ, Kleiner DE, Keskin O, Idilman R, Yurdaydin C, Glenn JS, Heller T. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect Dis. 2015 Oct;15(10):1167-1174. doi: 10.1016/S1473-3099(15)00074-2. Epub 2015 Jul 16.
    Results Reference
    background
    PubMed Identifier
    29152762
    Citation
    Yurdaydin C, Keskin O, Kalkan C, Karakaya F, Caliskan A, Karatayli E, Karatayli S, Bozdayi AM, Koh C, Heller T, Idilman R, Glenn JS. Optimizing lonafarnib treatment for the management of chronic delta hepatitis: The LOWR HDV-1 study. Hepatology. 2018 Apr;67(4):1224-1236. doi: 10.1002/hep.29658. Epub 2018 Feb 19.
    Results Reference
    background
    PubMed Identifier
    34860418
    Citation
    Yurdaydin C, Keskin O, Yurdcu E, Caliskan A, Onem S, Karakaya F, Kalkan C, Karatayli E, Karatayli S, Choong I, Apelian D, Koh C, Heller T, Idilman R, Bozdayi AM, Glenn JS. A phase 2 dose-finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis. Hepatology. 2022 Jun;75(6):1551-1565. doi: 10.1002/hep.32259. Epub 2021 Dec 23.
    Results Reference
    background
    Links:
    URL
    http://eigerbio.com
    Description
    Eiger BioPharmaceuticals, Inc. company website

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    Titrating-Dose of Lonafarnib in Combination With Ritonavir

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