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

Hepatitis Delta Virus Clinical Trial

— D-LIVR  

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03719313
• Other study ID #: EIG-LNF-011
• Status: Completed
• Phase: Phase 3
• Start date: December 1, 2018
• Est. completion date: March 24, 2023

Study information

• Verified date: April 2023
• Source: Eiger BioPharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 407
• Est. completion date: March 24, 2023
• Est. primary completion date: October 6, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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-a (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.

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis D
• Hepatitis Delta Virus

Intervention

Drug:
• Lonafarnib
Lonafarnib (LNF) 50 mg BID
• Ritonavir
Ritonavir (RTV) 100 mg BID
• PEG IFN-alfa-2a
PEG IFN alfa-2a 180 mcg QW
• Placebo Lonafarnib
Placebo
• Placebo Ritonavir
Placebo

Locations

Country	Name	City	State
Belgium	ZNA Stuivenberg	Antwerpen
Belgium	C.H.U. Brugmann	Bruxelles
Belgium	Cliniques Universitaires de Bruxelles Hopital Erasme	Bruxelles
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Belgium	CHU Sart Tilman	Liège
Bulgaria	Acibadem City Clinic Tokuda Hospital Ead	Sofia
Bulgaria	UMHAT "Alexandrovska" EAD	Sofia
Bulgaria	UMHAT "Sv. Ivan Rilski", EAD	Sofia
Bulgaria	Medical Center "Nov Rehabilitatsionen Tsentar", EOOD	Stara Zagora
Canada	University of Calgary	Calgary	Alberta
Canada	McGill University Health Centre/Glen Site / Royal Victoria Hospital	Montreal	Quebec
Canada	Toronto Liver Centre	Toronto	Ontario
Canada	University Health Network	Toronto	Ontario
France	Hôpital Jean Verdier	Bondy	Seine Saint Denis
France	Hôpital Beaujon	Clichy cedex	Hauts De Seine
France	CHU de Grenoble - Hôpital Nord	La Tronche	Isere
France	Centre Hospitalier de la Croix Rousse	Lyon	Rhone
France	CHU Nice - Hôpital de l'Archet 2	Nice Cedex 3	Alpes Maritimes
France	CHU Bordeaux - Hôpital Haut-Lévêque	Pessac	Gironde
France	CHU Strasbourg - Hôpital Hautepierre	Strasbourg Cedex	Bas Rhin
France	Hôpital Paul Brousse	Villejuif	Val De Marne
Germany	Charite - Campus Virchow-Klinikum	Berlin
Germany	Zentrum für Infektiologie Berlin Prenzlauer Berg GmbH	Berlin
Germany	Universitaetsklinikum Essen	Essen	Nordrhein Westfalen
Germany	Goethe Universität Frankfurt Am Main	Frankfurt	Hessen
Germany	Universitaetsklinikum Freiburg	Freiburg	Baden Wuerttemberg
Germany	Universitaetsklinikum Hamburg-Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover	Niedersachsen
Germany	Universitaetsklinikum Tuebingen	Tuebingen	Baden Wuerttemberg
Greece	General Hospital of Athens Laiko	Athens
Israel	HaEmek Medical Center	Afula
Israel	Soroka University Medical Center	Beer-Sheva
Israel	Rambam Health Care Center	Haifa
Israel	The Lady Davis Carmel Medical Center	Haifa
Israel	Hadassah University Hospital - Ein Kerem	Jerusalem
Israel	Shaare Zedek Medical Center	Jerusalem
Israel	Galilee Medical Center	Nahariya
Israel	Chaim Sheba Medical Center	Ramat Gan
Italy	Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (Presidio Spedali Civili)	Brescia
Italy	Azienda Ospedaliero Universitaria Ospedali Riuniti di Foggia	Foggia
Italy	Azienda Ospedaliera Universitaria Policlinico G. Martino	Messina
Italy	Azienda Socio Sanitaria Territoriale Niguarda (Grande Ospedale Metropolitano Niguarda)	Milano
Italy	Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico	Milano
Italy	Universita di Modena e Reggio Emilia. Nuovo Ospedale civil	Modena
Italy	Azienda Ospedaliera Universitaria "Federico II"	Napoli
Italy	Azienda Ospedaliero Universitaria di Parma	Parma
Italy	Azienda Ospedaliero Universitaria Pisana	Pisa
Italy	Azienda Ospedaliera Universitaria Policlinico Tor Vergata	Roma
Italy	Istituto Clinico Humanitas	Rozzano	Milano
Italy	IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo	Foggia
Italy	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino
Moldova, Republic of	ISMP Spitalul Clinic Republican "Timofei Mosneaga"	Chisinau
Moldova, Republic of	Rtl Sm Srl	Chisinau
Mongolia	The Liver Center	Ulaanbaatar
New Zealand	Auckland City Hospital	Grafton
Pakistan	The Aga Khan University	Karachi
Romania	Fundatia "Dr. Victor Babes"	Bucuresti
Romania	Institutul Clinic Fundeni	Bucuresti
Romania	Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"	Bucuresti
Romania	S.C MedLife S.A	Bucuresti
Romania	Spitalul Universitar de Urgenta Militar Central "Dr. Carol Davila"	Bucuresti
Romania	Spitalul Clinic Judetean de Urgenta Cluj Napoca	Cluj-Napoca
Russian Federation	Clinic of the Ministry of health of the South Ural state medical UNIVERSITY Russia, 2 infectious diseases Department.	Chelyabinsk
Russian Federation	Krasnodar specialized clinical infectious diseases hospital	Krasnodar
Russian Federation	H-Clinic, LLC	Moscow
Russian Federation	Modern Medicine Clinic, LLC	Moscow
Russian Federation	National medical research center Phthisiopulmonology and infectious diseases of the Ministry of health of the Russian Federation	Moscow
Russian Federation	Healthy Family, LLC	Novosibirsk
Russian Federation	Clinica UZI 4D, LLC	Pyatigorsk
Russian Federation	Hepatolog, LLC	Samara
Russian Federation	Medical University "Reaviz"	Samara
Russian Federation	State Budgetary Educational Institution of Higher Profesional Education "Stavropol State Medical University" of MoH	Stavropol
Russian Federation	Office for treatment of patients with viral hepatitis GBU Sakha (Yakutia) "Yakut Republican clinical hospital"	Yakutsk
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Sweden	Falu Lasarett	Falun
Sweden	Karolinska Universitetssjukhuset Huddinge	Huddinge
Sweden	Skånes Universitetssjukhus	Malmö
Switzerland	Inselspital Bern, Hepatologie, Bauchzentrum, INO- A, Ms. Kathrin Husi	Bern
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Chia-Yi Christian Hospital	Chia-Yi City
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital, Linkou	Taoyuan County
Turkey	Dicle University, Medical Faculty	Diyarbakir
Turkey	Koc University Hospital	Istanbul
Turkey	Ege University Medical Faculty	Izmir
Ukraine	Hospital of the state institution "National Institute of Therapy named after L.T. Maloi of the National Academy of Medical Sciences of Ukraine"	Kharkiv
Ukraine	Medical Center "Harmony of Beauty", LLC	Kyiv
Ukraine	Medical Center "Preventclinic", LLC	Kyiv
Ukraine	Medical Center 'Ok!Clinic+' of International Institute of Clinical Research LLC	Kyiv
Ukraine	Municipal Enterprise "Poltava Regional Clinical Infectious Hospital of Poltava Regional Council"	Poltava
Ukraine	University Hospital of Sumy State University	Sumy
Ukraine	Municipal non-profit enterprise " Vinnytsia city clinical hospital No. 1"	Vinnytsia
United Kingdom	Gartnavel General Hospital	Glasgow	Strathclyde
United Kingdom	Royal London Hospital	London	Greater London
United States	National Institutes of Health	Bethesda	Maryland
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	UCSF Fresno	Fresno	California
United States	Baylor St. Luke's Medical Center	Houston	Texas
United States	University of Iowa Hospitals & Clinics	Iowa City	Iowa
United States	Asia Pacific Liver Center	Los Angeles	California
United States	Ruane Clinical Research Group Inc.	Los Angeles	California
United States	University of Miami Schiff Center for Liver Disease	Miami	Florida
United States	Yale University Medical Center	New Haven	Connecticut
United States	Mt. Sinai Hospital	New York	New York
United States	NYU Langone Medical Center	New York	New York
United States	Central Sooner Research	Norman	Oklahoma
United States	Stanford University	Palo Alto	California
United States	University of Rochester Medical Center	Rochester	New York
United States	Kaiser Permanente Medical Center Sacramento	Sacramento	California
United States	University of California Davis Health System	Sacramento	California

Sponsors (1)

Lead Sponsor	Collaborator
Eiger BioPharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  Bulgaria,  Canada,  France,  Germany,  Greece,  Israel,  Italy,  Moldova, Republic of,  Mongolia,  New Zealand,  Pakistan,  Romania,  Russian Federation,  Spain,  Sweden,  Switzerland,  Taiwan,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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