Clinical trial NCT01277601: Efficacy & Safety of Tenofovir Disoproxil Fumarate (TDF) Plus Peginterferon α-2a (Peg-IFN) Versus TDF or Peg-IFN Monotherapy in Chronic Hepatitis B
Official title: A Phase 4, Randomized, Open-label, Active-Controlled, Superiority Study to Evaluate the Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) in Combination With Peginterferon α-2a (Pegasys®) Versus Standard of Care Tenofovir Disoproxil Fumarate Monotherapy or Peginterferon α-2a Monotherapy for 48 Weeks in Non-Cirrhotic Subjects With HBeAg-Positive or HBeAg-Negative Chronic Hepatitis B (CHB)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Hepatitis B
Keywords: Chronic Hepatitis B
Hep B
Non cirrhotic
Tenofovir disoproxil fumarate (TDF)
Peginterferon α-2a (Peg-IFN)
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2011-01-17
Enrollment: 751
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to evaluate the efficacy of tenofovir disoproxil fumarate (TDF) plus peginterferon α-2a (Peg-IFN) combination therapy for 48 weeks versus standard of care TDF monotherapy or Peg-IFN monotherapy for 48 weeks in non-cirrhotic adults with chronic hepatitis B virus (HBV) as determined by loss of hepatitis B surface antigen (HBsAg).

The study will consist of 2 phases for participants in the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups. Following an initial 48 weeks of treatment, participants in these groups will be monitored for 24 weeks for signs of worsening HBV, and those meeting TDF retreatment and flare management criteria will be eligible to receive TDF monotherapy during a retreatment phase, up to Week 120.


Eligibility criteria: Inclusion Criteria:

* Adults (age 18-75) with chronic HBV (positive for serum hepatitis B surface antigen (HBsAg) or HBV DNA for at least 6 months) prior to baseline
* Anti-HBV treatment-naive adults; adults who have taken oral anti-HBV nucleoside therapy with the last dose ≥ 24 weeks prior to screening are also eligible.
* Positive or negative for hepatitis B e antigen (HBeAg)
* HBV DNA ≥ 20,000 IU/ml (HBeAg-positive participants) and ≥ 2,000 IU/ml (HBeAg-negative participants)
* Alanine aminotransferase (ALT) \> 54 U/L and ≤ 400 U/L for men and \> 36 U/L and ≤ 300 U/L for women
* Creatinine clearance ≥ 70 mL/min
* Negative serum pregnancy test for females of childbearing potential
* Sexually active females of childbearing potential must agree to use a protocol-recommended method of contraception throughout the study and for 30 days following the last dose of study medication
* Lactating females must agree to discontinue nursing before initiation of study investigational medicinal product

Exclusion Criteria:

* Known bridging fibrosis or cirrhosis and/or decompensated liver disease
* Evidence of hepatocellular carcinoma
* Significant kidney, heart, lung, neurological, autoimmune disease, or bone disease (eg, osteomalacia,chronic osteomyelitis, osteogenesis imperfecta, osteochondrosis, multiple bone fractures)
* Absolute neutrophil count \< 1,500/mm\^3, platelet \< 100,000/mm\^3, hemoglobin \< 10 g/dL (female) or \< 11 g/dL (male)
* History of severe depression or severe psychiatric disease
* Thyroid dysfunction
* Coinfection with HIV, hepatitis C virus (HCV) or hepatitis D virus (HDV)
* Pregnant

Primary outcomes:
measure: Percentage of Participants With HBsAg Loss at Week 72 Following Treatment With 48 Weeks of TDF Plus Peg-IFN Combination Versus Peg-IFN Alone for 48 Weeks or TDF Alone
timeFrame: Baseline; Week 72
Secondary outcomes:
measure: Percentage of Participants With HBsAg Loss at Week 72 Following Treatment With TDF (48 Weeks) Plus Peg-IFN (16 Weeks) Combination Versus Peg-IFN Alone for 48 Weeks or TDF Alone
timeFrame: Baseline; Week 72
measure: Percentage of Participants With HBsAg Loss at Weeks 96 and 120
timeFrame: Baseline; Weeks 96 and 120
measure: Percentage of Participants With HBsAg Seroconversion at Weeks 72, 96, and 120
timeFrame: Baseline; Weeks 72, 96, and 120
measure: Percentage of Participants With HBeAg Loss and Seroconversion at Week 72
timeFrame: Baseline; Week 72
measure: Percentage of Participants With HBeAg Loss and Seroconversion at Week 96
timeFrame: Baseline; Week 96
measure: Percentage of Participants With HBeAg Loss and Seroconversion at Week 120
timeFrame: Baseline; Week 120
measure: Percentage of Participants With Virological Response (HBV DNA < 117 IU/mL) at Week 72
timeFrame: Week 72
measure: Percentage of Participants With Virological Response (HBV DNA < 117 IU/mL) at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Virological Response (HBV DNA < 117 IU/mL) at Week 120
timeFrame: Week 120
measure: Percentage of Participants With Normal ALT at Week 72
timeFrame: Week 72
measure: Percentage of Participants With Normal ALT at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Normal ALT at Week 120
timeFrame: Week 120
measure: Percentage of Participants Who Required Retreatment
timeFrame: Up to 120 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Asian Pacific Liver Center
state: California
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: San Diego
country: United States
facility: Research and Education Inc
state: California
city: San Jose
country: United States
facility: San Jose Gastroenterology
state: California
city: Deland
country: United States
facility: Avail Clinical Research, LLC
state: Florida
city: Maitland
country: United States
facility: Centre for Advanced Gastroenterology
state: Florida
city: Miami
country: United States
facility: University of Miami / Jackson Memorial Medical Center
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: New Orleans
country: United States
facility: LSU Gastroenterology/Center for Digestive Diseases
state: Louisiana
city: New Orleans
country: United States
facility: Tulane University Hospital and Clinic
state: Louisiana
city: Baltimore
country: United States
facility: Digestive Disease Associates
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Hillsborough
country: United States
facility: ID Care, Inc.
state: New Jersey
city: Flushing
country: United States
facility: Medical Procare, PLLC
state: New York
city: Great Neck
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: New York Univ. Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College of Cornell University
state: New York
city: Philadelphia
country: United States
facility: Private Practice
state: Pennsylvania
city: Houston
country: United States
facility: Advanced Liver Therapies at St. Luke's Episcopal Hospital
state: Texas
city: Houston
country: United States
facility: Kelsey Research Foundation
state: Texas
city: Houston
country: United States
facility: Liver Associates of Texas,
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: Liver Institute of Virginia, Bon Secours Health System
state: Virginia
city: Richmond
country: United States
facility: McGuire Research Institute
state: Virginia
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: Saint George's Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital,Gastroenterology Department
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide SA
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Adelaide
country: Australia
facility: Flinders Medical Center
state: South Australia
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Fitzroy
country: Australia
facility: Saint Vincents Hospital
state: Victoria
city: Footscray
country: Australia
facility: Western Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Fremantle
country: Australia
facility: Fremantle Hospital
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
city: Perth
country: Australia
facility: Royal Perth Hospital
city: Calgary
country: Canada
facility: Heritage Med Research Clinic, Univ of Calgary
state: Alberta
city: Zeidler Ledcore Centre
country: Canada
facility: University of Alberta, Zeidler Ledcore Centre
state: Alberta
city: Vancouver
country: Canada
facility: Gastrointestional Research Institute
state: British Columbia
city: Vancouver
country: Canada
facility: Gordon & Leslie Diamond Health Care Centre
state: British Columbia
city: Vancouver
country: Canada
facility: Liver and Intestinal Research Centre
state: British Columbia
city: Ottawa
country: Canada
facility: The Ottawa Hospital,Division of Infectious Diseases
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Liver Centre
state: Ontario
city: Clichy
country: France
facility: Hôpital Beaujon, Service Hepatologie- Centre Pierre Abrami
state: Cedex
city: Lyon
country: France
facility: Hôpital de la Croix Rousse
state: Cedex
city: Paris
country: France
facility: Hopital Tenon
city: Rennes Cedex 9
country: France
facility: Centre Hospitalier Universitaire de Rennes
city: Rouen
country: France
facility: Hopital Charles Nicolle
city: Strasbourg
country: France
facility: Centre Hospitalier Regional et Universitaire de Strasbourg, Hopital Civil
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire Purpan
city: Villejuif Cedex
country: France
facility: Hopital Paul Brousse
city: Mainz
country: Germany
facility: Johannes Gutenberg-Universitat Mainz,
state: Rheinland-pfalz
city: Berlin
country: Germany
facility: Charite Berlin
city: Essen
country: Germany
facility: Universitätsklinikum Essen - klinikum für Gastroenterolgie und Hepatologie,
city: Frankfurt
country: Germany
facility: Johann-Wolfgang-Goethe Universitat,
city: Hamburg
country: Germany
facility: Asklepios Westklinikum
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover,Hastroenterologie und Hepatologie
city: Köln
country: Germany
facility: Universitatsklinik Koln
city: Leipzig
country: Germany
facility: Universitatsklinikum Leipzig
city: Thessaloniki
country: Greece
facility: Ippokratio Hospital Salonica
state: Attica
city: Attica
country: Greece
facility: Ippokratio Hospital Athens
city: Patra
country: Greece
facility: General University Hospital of Patras
city: Thessaloniki
country: Greece
facility: Hippokration General Hospital of Thessaloniki
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Kowloon
country: Hong Kong
facility: Princess Margaret Hospital
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
city: Tai Po
country: Hong Kong
facility: Alice Ho Miu Ling Nethersole Hospital
city: Hyderabad
country: India
facility: Global Hospital, Lakdi Ka Pul
state: Andhra Pradesh
city: Guwahati
country: India
facility: Institute of digestive and liver disease, Dispur Hospital Ganeshguri
state: Assam
city: Ahmedabad
country: India
facility: Vedanta Institute of Medical Sciences
state: Gujarat
city: Surat
country: India
facility: Liver Clinic
state: Gujarat
city: Bangalore
country: India
facility: Manipal Hospitals
state: Karnataka
city: Mumbai
country: India
facility: Department of Hepatology, Institute of Liver Diseases, HPB Surgery and Transplant, Global Hospital
state: Maharashtra
city: Mumbai
country: India
facility: Seth GS Medical College and KEM Hospital, Acharya Donde Marg,Parel
state: Maharashtra
city: Nagpur
country: India
facility: Midas Institute of Gastroenterology
state: Maharashtra
city: Sangli
country: India
facility: Dharamasi Hospital,Chandni Chowk, South Shivajinagar,
state: Maharashtra
city: Delhi
country: India
facility: All India Institute of Medical Sciences, Ansari Nagar
state: New Delhi
city: Coimbatore
country: India
facility: VGM Hospital
state: Tamil Nadu
city: Kolkata
country: India
facility: Institute of Post Graduate Medical Education And Research
state: West Bengal
city: New Delhi
country: India
facility: Institute of Liver and Biliary Sciences
city: Monserrato
country: Italy
facility: Azienda Ospedaliero-Universitaria di Cagliari
state: Cagliari
city: Milano
country: Italy
facility: Fondazione IRCCS Ca Granda - Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Napoli
country: Italy
facility: Seconda Universita degli Studi di Napoli
city: Parma
country: Italy
facility: Azienda Ospedaliera di Parma,Department of Infectious Diseases and hepatology
city: Roma
country: Italy
facility: Fondazione PTV - Policlinico Tor Vergata
city: Rome
country: Italy
facility: Policlinico Umberto I
city: Torino
country: Italy
facility: University of Milan,Azienda Ospedaliera San Giovanni, Battista di Torino,Dipartimento di Gastroenterologia
city: Cheonan
country: Korea, Republic of
facility: SoonChunHyang University Hospital Cheonan
state: Chungcheon
city: Wonju
country: Korea, Republic of
facility: Yonsei Unversity Wonju College of Medicine Wonju Christian Hospital
state: Gangwon-do
city: Ansan-si
country: Korea, Republic of
facility: Korea University Ansan Hospital
state: Gyeonggi-d
city: Bucheon
country: Korea, Republic of
facility: Bucheon St. Mary's Hospital
state: Gyeonggi-d
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
state: Gyeonggi-d
city: Sungnam
country: Korea, Republic of
facility: CHA Bundang Medical Center, CHA University
state: Gyeonggi-d
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
state: Gyeongsang
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
state: Gyeongsang
city: Yangsan
country: Korea, Republic of
facility: Pusan National University Yangsan Hospital
state: Gyeongsang
city: Busan
country: Korea, Republic of
facility: Inje University Busan Paik Hospital
city: Goyang, Gyeonggi-Do
country: Korea, Republic of
facility: Inje University Ilsan Paik Hospital
city: Kwangjin-gu, Seoul
country: Korea, Republic of
facility: Digestive Disease Cntr, Konkuk Univ Hosp
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul Saint Mary's Hospital
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: Lodz
country: Poland
facility: Wojewódzki Specjalistyczny Szpital im. Dr Wladyslawa Bieganskiego w Lodzi
state: Lodzkie
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny 1,Klinika Chorób Zakaznych,ulica Staszica 16
state: Lubelskie
city: Chorzów
country: Poland
facility: Szpital Specjalistyczny w Chorzowie
state: Slaskie
city: Bialystok
country: Poland
facility: Wojewodzki Szpital Specjalistyczny Kazimierza Dluskeigo w Bialymstoku
city: Bydgoszcz
country: Poland
facility: Wojewódzki Szpital Obserwacyjno Zakazny im. Tadeusza Browicza
city: Krakow
country: Poland
facility: Szpital Uniwersytecki w Krakowie
city: Lodz
country: Poland
facility: Wojewódzki Specjalistyczny Szpital im. Dr Wladyslawa Bieganskiego w Lodzi
city: Warszawa
country: Poland
facility: SP ZOZ Wojewodzki Szpital Zakazny
city: Lisboa
country: Portugal
facility: Hospital de Egas Moniz
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria
city: Porto
country: Portugal
facility: Centro Hospitalar do Porto
city: Porto
country: Portugal
facility: Hospital São João
city: Brasov
country: Romania
facility: Neomed Research
city: Bucharest
country: Romania
facility: Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"
city: Bucharest
country: Romania
facility: Institutul National de Boli Infectioase Prof.Dr. Matei Bals
city: Bucharest
country: Romania
facility: Spitalul Clinic de Boli Infectioase si Tropicale "Dr. Victor Babes"
city: Bucuresti
country: Romania
facility: Spitalul Clinic Colentina
city: Sibiu
country: Romania
facility: Spitalul Clinic Judetean de Urgenta Sibiu
city: Timisoara
country: Romania
facility: Cabinet Particular Policlinic Algomed SRL-Gastroenterologie
city: Singapore
country: Singapore
facility: Changi General Hospital
city: Singapore
country: Singapore
facility: National University Hospital Singapore
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Barcelona
country: Spain
facility: Hospital General Universitari Vall d' Hebron
city: Madrid
country: Spain
facility: Hospital Carlos III
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Malaga
country: Spain
facility: Hospital Virgen de la Victoria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Vigo, Pontevedra
country: Spain
facility: Hospital Meixoeiro
city: New Taipei City
country: Taiwan
facility: Far-Eastern Memorial Hosp
state: Banciao Dist
city: Tao-Yuan
country: Taiwan
facility: Chang Gung Medical Foundation.LinKou Branch
state: Taoyuan
city: Changhua
country: Taiwan
facility: Changhua Christain Hospital
city: Chia-Yi
country: Taiwan
facility: Chiayi Christian Hosp
city: Hualien
country: Taiwan
facility: Buddhist Tzu Chi General Hospital
city: Kaohsiung
country: Taiwan
facility: Chang Gung Memorial Hospital
city: Kaosiung
country: Taiwan
facility: Kaohsiung Medical University Hospital
city: Keelung Town/KEELUNG CITY
country: Taiwan
facility: Chang Gung Medical Foundation-Keelung
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taichung
country: Taiwan
facility: Chung Shan Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans Genl Hosp
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: Cathay General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Ankara
country: Turkey
facility: Ankara Üniversitesi Tip Fakültesi
city: Ankara
country: Turkey
facility: Hacettepe Üniversitesi Tip Fakültesi
city: Gaziantep
country: Turkey
facility: Gaziantep Üniversitesi Tip Fakültesi, Sahinbey Arastirma ve Uygulama Hastanesi
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Istanbul Tip Fakultesi
city: Mersin
country: Turkey
facility: Mersin Üniversitesi Tip Fakültesi, Saglik Arastirma ve Uygulama Hastanesi
city: Birmingham, WSTMID
country: United Kingdom
facility: The Queen Elizabeth Hospital
city: Hampstead,London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: Barts and The London NHS Trust
city: London
country: United Kingdom
facility: King's College Hospital
Study officials:
affiliation: Gilead Sciences
name: Belinda Jump
role: STUDY_DIRECTOR
References:
citation: Marcellin P, Ahn SH, Ma X, Caruntu FA, Tak WY, Elkashab M, Chuang WL, Lim SG, Tabak F, Mehta R, Petersen J, Foster GR, Lou L, Martins EB, Dinh P, Lin L, Corsa A, Charuworn P, Subramanian GM, Reiser H, Reesink HW, Fung S, Strasser SI, Trinh H, Buti M, Gaeta GB, Hui AJ, Papatheodoridis G, Flisiak R, Chan HL; Study 149 Investigators. Combination of Tenofovir Disoproxil Fumarate and Peginterferon alpha-2a Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B. Gastroenterology. 2016 Jan;150(1):134-144.e10. doi: 10.1053/j.gastro.2015.09.043. Epub 2015 Oct 8.
citation: Chan HL, Elkhashab M, Trinh H, Tak WY, Ma X, Chuang WL, Kim YJ, Martins EB, Lin L, Dinh P, Charuworn P, Foster GR, Marcellin P. Association of baseline vitamin D levels with clinical parameters and treatment outcomes in chronic hepatitis B. J Hepatol. 2015 Nov;63(5):1086-92. doi: 10.1016/j.jhep.2015.06.025. Epub 2015 Jul 2.