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

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)

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.

Study Overview

• Status: Completed
• Conditions: Hepatitis Delta Virus
• Intervention / Treatment: Drug: Lonafarnib; Drug: Ritonavir; Drug: PEG IFN-alfa-2a; Drug: Placebo Lonafarnib; Drug: Placebo Ritonavir

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 407
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sue Speyer; Phone Number: 650-272-6138; Email: DLIVR@eigerbio.com

Study Locations

• Belgium
  • Antwerpen, Belgium, 2060
    • ZNA Stuivenberg
  • Bruxelles, Belgium, 1070
    • Cliniques Universitaires de Bruxelles Hopital Erasme
  • Bruxelles, Belgium, 1020
    • C.H.U. Brugmann
  • Edegem, Belgium, 2650
    • Universitair Ziekenhuis Antwerpen
  • Liège, Belgium, 4000
    • CHU Sart Tilman
• Bulgaria
  • Sofia, Bulgaria, 1431
    • UMHAT "Sv. Ivan Rilski", EAD
  • Sofia, Bulgaria, 1407
    • Acibadem City Clinic Tokuda Hospital Ead
  • Sofia, Bulgaria, 1431
    • UMHAT "Alexandrovska" EAD
  • Stara Zagora, Bulgaria, 6000
    • Medical Center "Nov Rehabilitatsionen Tsentar", EOOD
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary
  • Ontario
    • Toronto, Ontario, Canada, M6H 3M1
      • Toronto Liver Centre
    • Toronto, Ontario, Canada, M5G 2C4
      • University Health Network
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre/Glen Site / Royal Victoria Hospital
• France
  • Alpes Maritimes
    • Nice Cedex 3, Alpes Maritimes, France, 06200
      • CHU Nice - Hôpital de l'Archet 2
  • Bas Rhin
    • Strasbourg Cedex, Bas Rhin, France, 67098
      • CHU Strasbourg - Hopital Hautepierre
  • Gironde
    • Pessac, Gironde, France, 33604
      • CHU Bordeaux - Hopital Haut-Leveque
  • Hauts De Seine
    • Clichy cedex, Hauts De Seine, France, 92110
      • Hopital Beaujon
  • Isere
    • La Tronche, Isere, France, 38043
      • CHU de Grenoble - Hôpital Nord
  • Rhone
    • Lyon, Rhone, France, 69004
      • Centre Hospitalier de la Croix Rousse
  • Seine Saint Denis
    • Bondy, Seine Saint Denis, France, 93140
      • Hôpital Jean Verdier
  • Val De Marne
    • Villejuif, Val De Marne, France, 94804
      • Hopital Paul Brousse
• Germany
  • Berlin, Germany, 13353
    • Charite - Campus Virchow-Klinikum
  • Berlin, Germany, 10439
    • Zentrum für Infektiologie Berlin Prenzlauer Berg GmbH
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf
  • Baden Wuerttemberg
    • Freiburg, Baden Wuerttemberg, Germany, 79106
      • Universitaetsklinikum Freiburg
    • Tuebingen, Baden Wuerttemberg, Germany, 72076
      • Universitaetsklinikum Tuebingen
  • Hessen
    • Frankfurt, Hessen, Germany, 60590
      • Goethe Universität Frankfurt Am Main
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hannover
  • Nordrhein Westfalen
    • Essen, Nordrhein Westfalen, Germany, 45147
      • Universitaetsklinikum Essen
• Greece
  • Athens, Greece, 11527
    • General Hospital of Athens Laiko
• Israel
  • Afula, Israel, 18101
    • Haemek Medical Center
  • Beer-Sheva, Israel, 84001
    • Soroka University Medical Center
  • Haifa, Israel, 34362
    • The Lady Davis Carmel Medical Center
  • Haifa, Israel, 3109601
    • Rambam Health Care Center
  • Jerusalem, Israel, 91031
    • Shaare Zedek Medical Center
  • Jerusalem, Israel, 9112001
    • Hadassah University Hospital - Ein Kerem
  • Nahariya, Israel, 2210001
    • Galilee Medical Center
  • Ramat Gan, Israel, 52363
    • Chaim Sheba Medical Center
• Italy
  • Brescia, Italy, 25123
    • Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia (Presidio Spedali Civili)
  • Foggia, Italy, 71100
    • Azienda Ospedaliero Universitaria Ospedali Riuniti di Foggia
  • Messina, Italy, 98124
    • Azienda Ospedaliera Universitaria Policlinico G. Martino
  • Milano, Italy, 20122
    • Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
  • Milano, Italy, 20162
    • Azienda Socio Sanitaria Territoriale Niguarda (Grande Ospedale Metropolitano Niguarda)
  • Modena, Italy, 1355
    • Universita di Modena e Reggio Emilia. Nuovo Ospedale civil
  • Napoli, Italy, 80131
    • Azienda Ospedaliera Universitaria "Federico II"
  • Parma, Italy, 43100
    • Azienda Ospedaliero Universitaria di Parma
  • Pisa, Italy, 56124
    • Azienda Ospedaliero Universitaria Pisana
  • Roma, Italy, 00133
    • Azienda Ospedaliera Universitaria Policlinico Tor Vergata
  • Torino, Italy, 10126
    • Azienda Ospedaliera Citta Della Salute E Della Scienza Di Torino
  • Foggia
    • San Giovanni Rotondo, Foggia, Italy, 71013
      • IRCCS Ospedale Casa Sollievo della Sofferenza
  • Milano
    • Rozzano, Milano, Italy, 20089
      • Istituto Clinico Humanitas
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, MD-2025
    • Rtl Sm Srl
  • Chisinau, Moldova, Republic of, 2025
    • ISMP Spitalul Clinic Republican "Timofei Mosneaga"
• Mongolia
  • Ulaanbaatar, Mongolia, 14230-0054
    • The Liver Center
• New Zealand
  • Grafton, New Zealand, 1023
    • Auckland City Hospital
• Pakistan
  • Karachi, Pakistan, 74800
    • The Aga Khan University
• Romania
  • Bucuresti, Romania, 021105
    • Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"
  • Bucuresti, Romania, 022328
    • Institutul Clinic Fundeni
  • Bucuresti, Romania, 010719
    • S.C MedLife S.A
  • Bucuresti, Romania, 010825
    • Spitalul Universitar de Urgenta Militar Central "Dr. Carol Davila"
  • Bucuresti, Romania, 030303
    • Fundatia "Dr. Victor Babes"
  • Cluj-Napoca, Romania, 400006
    • Spitalul Clinic Judetean de Urgenta Cluj Napoca
• Russian Federation
  • Chelyabinsk, Russian Federation, 454052
    • Clinic of the Ministry of health of the South Ural state medical UNIVERSITY Russia, 2 infectious diseases Department.
  • Krasnodar, Russian Federation, 350000
    • Krasnodar specialized clinical infectious diseases hospital
  • Moscow, Russian Federation, 121170
    • Modern Medicine Clinic, LLC
  • Moscow, Russian Federation, 127083
    • H-Clinic, LLC
  • Moscow, Russian Federation, 127473
    • National medical research center Phthisiopulmonology and infectious diseases of the Ministry of health of the Russian Federation
  • Novosibirsk, Russian Federation, 630099
    • Healthy Family, LLC
  • Pyatigorsk, Russian Federation, 357502
    • Clinica UZI 4D, LLC
  • Samara, Russian Federation, 443011
    • Medical University "Reaviz"
  • Samara, Russian Federation, 443063
    • Hepatolog, LLC
  • Stavropol, Russian Federation, 355017
    • State Budgetary Educational Institution of Higher Profesional Education "Stavropol State Medical University" of MoH
  • Yakutsk, Russian Federation, 677005
    • Office for treatment of patients with viral hepatitis GBU Sakha (Yakutia) "Yakut Republican clinical hospital"
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Valencia, Spain, 46026
    • Hospital Universitari I Politecnic La Fe
• Sweden
  • Falun, Sweden, 79182
    • Falu Lasarett
  • Huddinge, Sweden, 14157
    • Karolinska Universitetssjukhuset Huddinge
  • Malmö, Sweden, 205 02
    • Skanes universitetssjukhus
• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital Bern, Hepatologie, Bauchzentrum, INO- A, Ms. Kathrin Husi
• Taiwan
  • Changhua, Taiwan, 50004
    • Changhua Christian Hospital
  • Chia-Yi City, Taiwan, 600
    • Chia-Yi Christian Hospital
  • Kaohsiung, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Kaohsiung, Taiwan, 824
    • Kaohsiung Chang Gung Memorial Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
  • Taoyuan County, Taiwan, 333
    • Chang Gung Memorial Hospital, Linkou
• Turkey
  • Diyarbakir, Turkey, 21280
    • Dicle University, Medical Faculty
  • Istanbul, Turkey
    • Koc University Hospital
  • Izmir, Turkey, 35100
    • Ege University Medical Faculty
• Ukraine
  • Kharkiv, Ukraine, 61039
    • Hospital of the state institution "National Institute of Therapy named after L.T. Maloi of the National Academy of Medical Sciences of Ukraine"
  • Kyiv, Ukraine, 02091
    • Medical Center 'Ok!Clinic+' of International Institute of Clinical Research LLC
  • Kyiv, Ukraine, 01135
    • Medical Center "Harmony of Beauty", LLC
  • Kyiv, Ukraine, 03035
    • Medical Center "Preventclinic", LLC
  • Poltava, Ukraine, 36011
    • Municipal Enterprise "Poltava Regional Clinical Infectious Hospital of Poltava Regional Council"
  • Sumy, Ukraine, 40000
    • University Hospital of Sumy State University
  • Vinnytsia, Ukraine, 21029
    • Municipal non-profit enterprise " Vinnytsia city clinical hospital No. 1"
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, E1 1BB
      • Royal London Hospital
  • Strathclyde
    • Glasgow, Strathclyde, United Kingdom, G12 0YN
      • Gartnavel General Hospital
• United States
  • California
    • Fresno, California, United States, 93701
      • UCSF Fresno
    • Los Angeles, California, United States, 90057
      • Asia Pacific Liver Center
    • Los Angeles, California, United States, 90036
      • Ruane Clinical Research Group Inc.
    • Palo Alto, California, United States, 94303
      • Stanford University
    • Sacramento, California, United States, 95817
      • University of California Davis Health System
    • Sacramento, California, United States, 95825
      • Kaiser Permanente Medical Center Sacramento
  • Connecticut
    • New Haven, Connecticut, United States, 06510-3206
      • Yale University Medical Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Schiff Center for Liver Disease
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics
  • Maryland
    • Bethesda, Maryland, United States, 20814
      • National Institutes of Health
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • New York
    • New York, New York, United States, 10029
      • Mt. Sinai Hospital
    • New York, New York, United States, 11016
      • NYU Langone Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • Oklahoma
    • Norman, Oklahoma, United States, 73071
      • Central Sooner Research
  • Texas
    • Dallas, Texas, United States, 75390-8857
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Baylor St. Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.

2. 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.
3. Serum ALT > 1.3 x upper limit of the normal range (ULN) and < 10 x ULN.
4. Baseline liver biopsy demonstrating evidence of chronic hepatitis.
5. ECGs demonstrating no acute ischemia or clinically significant abnormality.
6. Normal dilated retinal examination.

Exclusion Criteria:

General Exclusions

1. Previous use of LNF within 12 months.
2. Current or previous history of decompensated liver disease.
3. Co-infected with human immunodeficiency virus or hepatitis C virus (HCV) by detectable HIV RNA and HCV RNA, respectively.
4. Evidence of significant portal hypertension.
5. Current evidence or history of ascites requiring diuretics or paracentesis, or hepatic encephalopathy.
6. History of hepatocellular carcinoma.

7. Patients with any of the following:

   • Current eating disorder
   • Evidence of alcohol substance use disorder.
   • Drug abuse within the previous 6 months before screening.

8. 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.
9. Other significant medical condition that may require intervention during the study.
10. Any condition that may impact proper absorption.
11. 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.
12. Use of heparin or warfarin.
13. Systemic antibiotics, antifungals, or antivirals for treatment of active infection other than HBV.
14. Receipt of systemic immunosuppressive therapy.
15. History or evidence for any intolerance or hypersensitivity to LNF, RTV, PEG IFN-alfa-2a, tenofovir or entecavir.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; Lonafarnib 50 mg BID + Ritonavir 100 mg BID	Drug: Lonafarnib; Lonafarnib (LNF) 50 mg BID; Other Names: LNF; Sarasar; EBP994; Drug: Ritonavir; Ritonavir (RTV) 100 mg BID; Other Names: Norvir; RTV
Experimental: Group 2; Lonafarnib 50 mg BID + Ritonavir 100 mg BID + PEG IFN alfa-2a 180 mcg QW	Drug: Lonafarnib; Lonafarnib (LNF) 50 mg BID; Other Names: LNF; Sarasar; EBP994; Drug: Ritonavir; Ritonavir (RTV) 100 mg BID; Other Names: Norvir; RTV; Drug: PEG IFN-alfa-2a; PEG IFN alfa-2a 180 mcg QW; Other Names: Pegasys; pegylated interferon-alfa
Active Comparator: Group 3; placebo Lonafarnib + placebo Ritonavir + PEG IFN-alfa-2a 180 mcg QW	Drug: PEG IFN-alfa-2a; PEG IFN alfa-2a 180 mcg QW; Other Names: Pegasys; pegylated interferon-alfa; Drug: Placebo Lonafarnib; Placebo; Drug: Placebo Ritonavir; Placebo
Placebo Comparator: Group 4; placebo Lonafarnib + placebo Ritonavir	Drug: Placebo Lonafarnib; Placebo; Drug: Placebo Ritonavir; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Eiger BioPharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2018
• Primary Completion (Actual): October 6, 2022
• Study Completion (Actual): March 24, 2023

Study Registration Dates

• First Submitted: October 18, 2018
• First Submitted That Met QC Criteria: October 23, 2018
• First Posted (Actual): October 25, 2018

Study Record Updates

• Last Update Posted (Actual): April 14, 2023
• Last Update Submitted That Met QC Criteria: April 13, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; Hepatitis; Hepatitis D; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Immunologic Factors; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Interferons; Interferon-alpha; Peginterferon alfa-2a; Interferon alpha-2; Ritonavir; Lonafarnib
• Other Study ID Numbers: EIG-LNF-011

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No