Clinical trial NCT03719313: Study of the Efficacy and Safety of Lonafarnib / Ritonavir With and Without Pegylated Interferon -Alfa-2a
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis Delta Virus
Lead sponsor: Eiger BioPharmaceuticals
Sponsor class: INDUSTRY
First posted: 2018-10-25
Enrollment: 407
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: 48 weeks
measure: 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.
timeFrame: 48 weeks
Secondary outcomes:
measure: To compare the histologic response rate at EOT in patients who receive LNF 50 mg/RTV 100 mg BID vs patients who receive placebo.
timeFrame: 48 weeks
measure: 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.
timeFrame: 48 weeks
measure: 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.
timeFrame: 48 weeks
measure: 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.
timeFrame: 48 weeks
measure: 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.
timeFrame: 48 weeks
measure: 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.
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Fresno
country: United States
facility: UCSF Fresno
state: California
city: Los Angeles
country: United States
facility: Ruane Clinical Research Group Inc.
state: California
city: Los Angeles
country: United States
facility: Asia Pacific Liver Center
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Sacramento
country: United States
facility: University of California Davis Health System
state: California
city: Sacramento
country: United States
facility: Kaiser Permanente Medical Center Sacramento
state: California
city: New Haven
country: United States
facility: Yale University Medical Center
state: Connecticut
city: Miami
country: United States
facility: University of Miami Schiff Center for Liver Disease
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Bethesda
country: United States
facility: National Institutes of Health
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: New York
country: United States
facility: Mt. Sinai Hospital
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Norman
country: United States
facility: Central Sooner Research
state: Oklahoma
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor St. Luke's Medical Center
state: Texas
city: Antwerpen
country: Belgium
facility: ZNA Stuivenberg
city: Bruxelles
country: Belgium
facility: C.H.U. Brugmann
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires de Bruxelles Hopital Erasme
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Liège
country: Belgium
facility: CHU Sart Tilman
city: Sofia
country: Bulgaria
facility: Acibadem City Clinic Tokuda Hospital Ead
city: Sofia
country: Bulgaria
facility: UMHAT "Alexandrovska" EAD
city: Sofia
country: Bulgaria
facility: UMHAT "Sv. Ivan Rilski", EAD
city: Stara Zagora
country: Bulgaria
facility: Medical Center "Nov Rehabilitatsionen Tsentar", EOOD
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Toronto
country: Canada
facility: Toronto Liver Centre
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre/Glen Site / Royal Victoria Hospital
state: Quebec
city: Nice Cedex 3
country: France
facility: CHU Nice - Hôpital de l'Archet 2
state: Alpes Maritimes
city: Strasbourg Cedex
country: France
facility: CHU Strasbourg - Hôpital Hautepierre
state: Bas Rhin
city: Pessac
country: France
facility: CHU Bordeaux - Hôpital Haut-Lévêque
state: Gironde
city: Clichy cedex
country: France
facility: Hôpital Beaujon
state: Hauts De Seine
city: La Tronche
country: France
facility: CHU de Grenoble - Hôpital Nord
state: Isere
city: Lyon
country: France
facility: Centre Hospitalier de la Croix Rousse
state: Rhone
city: Bondy
country: France
facility: Hôpital Jean Verdier
state: Seine Saint Denis
city: Villejuif
country: France
facility: Hôpital Paul Brousse
state: Val De Marne
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
state: Baden Wuerttemberg
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
state: Baden Wuerttemberg
city: Frankfurt
country: Germany
facility: Goethe Universität Frankfurt Am Main
state: Hessen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachsen
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
state: Nordrhein Westfalen
city: Berlin
country: Germany
facility: Zentrum für Infektiologie Berlin Prenzlauer Berg GmbH
city: Berlin
country: Germany
facility: Charite - Campus Virchow-Klinikum
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf
city: Athens
country: Greece
facility: General Hospital of Athens Laiko
city: Afula
country: Israel
facility: HaEmek Medical Center
city: Beer-Sheva
country: Israel
facility: Soroka University Medical Center
city: Haifa
country: Israel
facility: Rambam Health Care Center
city: Haifa
country: Israel
facility: The Lady Davis Carmel Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Jerusalem
country: Israel
facility: Hadassah University Hospital - Ein Kerem
city: Nahariya
country: Israel
facility: Galilee Medical Center
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: San Giovanni Rotondo
country: Italy
facility: IRCCS Ospedale Casa Sollievo della Sofferenza
state: Foggia
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Milano
city: Brescia
country: Italy
facility: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (Presidio Spedali Civili)
city: Foggia
country: Italy
facility: Azienda Ospedaliero Universitaria Ospedali Riuniti di Foggia
city: Messina
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico G. Martino
city: Milano
country: Italy
facility: Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: Azienda Socio Sanitaria Territoriale Niguarda (Grande Ospedale Metropolitano Niguarda)
city: Modena
country: Italy
facility: Universita di Modena e Reggio Emilia. Nuovo Ospedale civil
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria "Federico II"
city: Parma
country: Italy
facility: Azienda Ospedaliero Universitaria di Parma
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Roma
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Tor Vergata
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino
city: Chisinau
country: Moldova, Republic of
facility: ISMP Spitalul Clinic Republican "Timofei Mosneaga"
city: Chisinau
country: Moldova, Republic of
facility: Rtl Sm Srl
city: Ulaanbaatar
country: Mongolia
facility: The Liver Center
city: Grafton
country: New Zealand
facility: Auckland City Hospital
city: Karachi
country: Pakistan
facility: The Aga Khan University
city: Bucuresti
country: Romania
facility: S.C MedLife S.A
city: Bucuresti
country: Romania
facility: Spitalul Universitar de Urgenta Militar Central "Dr. Carol Davila"
city: Bucuresti
country: Romania
facility: Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"
city: Bucuresti
country: Romania
facility: Institutul Clinic Fundeni
city: Bucuresti
country: Romania
facility: Fundatia "Dr. Victor Babes"
city: Cluj-Napoca
country: Romania
facility: Spitalul Clinic Judetean de Urgenta Cluj Napoca
city: Chelyabinsk
country: Russian Federation
facility: Clinic of the Ministry of health of the South Ural state medical UNIVERSITY Russia, 2 infectious diseases Department.
city: Krasnodar
country: Russian Federation
facility: Krasnodar specialized clinical infectious diseases hospital
city: Moscow
country: Russian Federation
facility: Modern Medicine Clinic, LLC
city: Moscow
country: Russian Federation
facility: H-Clinic, LLC
city: Moscow
country: Russian Federation
facility: National medical research center Phthisiopulmonology and infectious diseases of the Ministry of health of the Russian Federation
city: Novosibirsk
country: Russian Federation
facility: Healthy Family, LLC
city: Pyatigorsk
country: Russian Federation
facility: Clinica UZI 4D, LLC
city: Samara
country: Russian Federation
facility: Medical University "Reaviz"
city: Samara
country: Russian Federation
facility: Hepatolog, LLC
city: Stavropol
country: Russian Federation
facility: State Budgetary Educational Institution of Higher Profesional Education "Stavropol State Medical University" of MoH
city: Yakutsk
country: Russian Federation
facility: Office for treatment of patients with viral hepatitis GBU Sakha (Yakutia) "Yakut Republican clinical hospital"
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Falun
country: Sweden
facility: Falu Lasarett
city: Huddinge
country: Sweden
facility: Karolinska Universitetssjukhuset Huddinge
city: Malmö
country: Sweden
facility: Skånes Universitetssjukhus
city: Bern
country: Switzerland
facility: Inselspital Bern, Hepatologie, Bauchzentrum, INO- A, Ms. Kathrin Husi
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Chia-Yi City
country: Taiwan
facility: Chia-Yi Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan County
country: Taiwan
facility: Chang Gung Memorial Hospital, Linkou
city: Diyarbakir
country: Turkey
facility: Dicle University, Medical Faculty
city: Istanbul
country: Turkey
facility: Koc University Hospital
city: Izmir
country: Turkey
facility: Ege University Medical Faculty
city: Kharkiv
country: Ukraine
facility: Hospital of the state institution "National Institute of Therapy named after L.T. Maloi of the National Academy of Medical Sciences of Ukraine"
city: Kyiv
country: Ukraine
facility: Medical Center "Harmony of Beauty", LLC
city: Kyiv
country: Ukraine
facility: Medical Center 'Ok!Clinic+' of International Institute of Clinical Research LLC
city: Kyiv
country: Ukraine
facility: Medical Center "Preventclinic", LLC
city: Poltava
country: Ukraine
facility: Municipal Enterprise "Poltava Regional Clinical Infectious Hospital of Poltava Regional Council"
city: Sumy
country: Ukraine
facility: University Hospital of Sumy State University
city: Vinnytsia
country: Ukraine
facility: Municipal non-profit enterprise " Vinnytsia city clinical hospital No. 1"
city: London
country: United Kingdom
facility: Royal London Hospital
state: Greater London
city: Glasgow
country: United Kingdom
facility: Gartnavel General Hospital
state: Strathclyde
Study officials:
References: