Clinical trial NCT02527707: Titrating-Dose of Lonafarnib in Combination With Ritonavir
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Delta Hepatitis
Lead sponsor: Eiger BioPharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Hannover Medical School
First posted: 2015-08-19
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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 ribonucleic acid (RNA) by quantitative polymerase chain reaction (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 human immunodeficiency virus (HIV) or hepatitis C virus (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 (not including hepatitis B virus or HCV) 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 interval or QT interval of the electrocardiogram
   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

Primary outcomes:
measure: Change From Baseline to Week 24 in Mean Hepatitis D Virus (HDV) Ribonucleic Acid (RNA) Titer
timeFrame: Baseline and Week 24 (6 months)
Secondary outcomes:
measure: Number of Patients With 1 Log Reduction From Baseline by Timepoint
timeFrame: Baseline and Week 1, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 20, or Week 24
Other outcomes:
Locations:
Study officials:
affiliation: Hannover Medical School
name: Heiner Wedemeyer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.