Efficacy & Safety of Tenofovir Disoproxil Fumarate (TDF) Plus Peginterferon α-2a (PEG) Versus TDF or PEG Monotherapy in Chronic Hepatitis B

Chronic Hepatitis B Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01277601
• Other study ID #: GS-US-174-0149
• Status: Completed
• Phase: Phase 4
• First received: January 13, 2011
• Last updated: September 9, 2015
• Start date: April 2011
• Est. completion date: July 2015

Study information

• Verified date: September 2015
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the safety and efficacy of tenofovir disoproxil fumarate (TDF) plus peginterferon α-2a (PEG) combination therapy versus standard of care TDF monotherapy or PEG monotherapy in non-cirrhotic adults with chronic hepatitis B virus (HBV).

The study will consist of 2 phases for participants in the TDF+PEG 48 week, TDF 48 week+PEG 16 week, and PEG 48 week 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 with new signs and/or symptoms will be eligible to receive TDF monotherapy during a retreatment phase, up to Week 120.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 751
• Est. completion date: July 2015
• Est. primary completion date: August 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• TDF
TDF 300 mg tablets administered orally once daily
• PEG
PEG 180 µg administered via subcutaneous injection once weekly

Locations

Country	Name	City	State
Australia	Flinders Medical Center	Adelaide	South Australia
Australia	Royal Adelaide Hospital	Adelaide SA	South Australia
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	Saint Vincents Hospital	Fitzroy	Victoria
Australia	Western Hospital	Footscray	Victoria
Australia	Fremantle Hospital	Fremantle
Australia	Austin Health	Heidelberg	Victoria
Australia	Royal Brisbane & Women's Hospital	Herston	Queensland
Australia	Saint George's Hospital	Kogarah	New South Wales
Australia	Liverpool Hospital,Gastroenterology Department	Liverpool	New South Wales
Australia	Alfred Hospital	Melbourne	Victoria
Australia	Box Hill Hospital	Melbourne	Victoria
Australia	Sir Charles Gairdner Hospital	Nedlands
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal Perth Hospital	Perth
Australia	Westmead Hospital	Westmead	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Canada	Heritage Med Research Clinic, Univ of Calgary	Calgary	Alberta
Canada	The Ottawa Hospital,Division of Infectious Diseases	Ottawa	Ontario
Canada	Toronto General Hospital	Toronto	Ontario
Canada	Toronto Liver Centre	Toronto	Ontario
Canada	Gastrointestional Research Institute	Vancouver	British Columbia
Canada	Gordon & Leslie Diamond Health Care Centre	Vancouver	British Columbia
Canada	Liver and Intestinal Research Centre	Vancouver	British Columbia
Canada	University of Alberta, Zeidler Ledcore Centre	Zeidler Ledcore Centre	Alberta
France	Hôpital Beaujon, Service Hepatologie- Centre Pierre Abrami	Clichy	Cedex
France	Hôpital de la Croix Rousse	Lyon	Cedex
France	Hopital Tenon	Paris
France	Centre Hospitalier Universitaire de Rennes	Rennes Cedex 9
France	Hopital Charles Nicolle	Rouen
France	Centre Hospitalier Regional et Universitaire de Strasbourg, Hopital Civil	Strasbourg
France	Centre Hospitalier Universitaire Purpan	Toulouse
France	Hopital Paul Brousse	Villejuif Cedex
Germany	Charite Berlin	Berlin
Germany	Universitätsklinikum Essen - klinikum für Gastroenterolgie und Hepatologie,	Essen
Germany	Johann-Wolfgang-Goethe Universitat,	Frankfurt
Germany	Asklepios Westklinikum	Hamburg
Germany	Medizinische Hochschule Hannover,Hastroenterologie und Hepatologie	Hannover
Germany	Universitatsklinik Koln	Köln
Germany	Universitatsklinikum Leipzig	Leipzig
Germany	Johannes Gutenberg-Universitat Mainz,	Mainz	Rheinland-pfalz
Greece	Ippokratio Hospital Athens	Attica
Greece	General University Hospital of Patras	Patra
Greece	Hippokration General Hospital of Thessaloniki	Thessaloniki
Greece	Ippokratio Hospital Salonica	Thessaloniki	Attica
Hong Kong	Queen Mary Hospital	Hong Kong
Hong Kong	Princess Margaret Hospital	Kowloon
Hong Kong	Prince of Wales Hospital	Shatin
Hong Kong	Alice Ho Miu Ling Nethersole Hospital	Tai Po
India	Vedanta Institute of Medical Sciences	Ahmedabad	Gujarat
India	Manipal Hospitals	Bangalore	Karnataka
India	VGM Hospital	Coimbatore	Tamil Nadu
India	All India Institute of Medical Sciences, Ansari Nagar	Delhi	New Delhi
India	Institute of digestive and liver disease, Dispur Hospital Ganeshguri	Guwahati	Assam
India	Global Hospital, Lakdi Ka Pul	Hyderabad	Andhra Pradesh
India	Institute of Post Graduate Medical Education And Research	Kolkata	West Bengal
India	Department of Hepatology, Institute of Liver Diseases, HPB Surgery and Transplant, Global Hospital	Mumbai	Maharashtra
India	Seth GS Medical College and KEM Hospital, Acharya Donde Marg,Parel	Mumbai	Maharashtra
India	Midas Institute of Gastroenterology	Nagpur	Maharashtra
India	Institute of Liver and Biliary Sciences	New Delhi
India	Dharamasi Hospital,Chandni Chowk, South Shivajinagar,	Sangli	Maharashtra
India	Liver Clinic	Surat	Gujarat
Italy	Fondazione IRCCS Ca Granda - Ospedale Maggiore Policlinico	Milano
Italy	Ospedale San Raffaele	Milano
Italy	Azienda Ospedaliero-Universitaria di Cagliari	Monserrato	Cagliari
Italy	Seconda Universita degli Studi di Napoli	Napoli
Italy	Azienda Ospedaliera di Parma,Department of Infectious Diseases and hepatology	Parma
Italy	Fondazione PTV - Policlinico Tor Vergata	Roma
Italy	Policlinico Umberto I	Rome
Italy	University of Milan,Azienda Ospedaliera San Giovanni, Battista di Torino,Dipartimento di Gastroenterologia	Torino
Korea, Republic of	Korea University Ansan Hospital	Ansan-si	Gyeonggi-d
Korea, Republic of	Bucheon St. Mary's Hospital	Bucheon	Gyeonggi-d
Korea, Republic of	Inje University Busan Paik Hospital	Busan
Korea, Republic of	Pusan National University Hospital	Busan	Gyeongsang
Korea, Republic of	SoonChunHyang University Hospital Cheonan	Cheonan	Chungcheon
Korea, Republic of	Kyungpook National University Hospital	Daegu	Gyeongsang
Korea, Republic of	Inje University Ilsan Paik Hospital	Goyang, Gyeonggi-Do
Korea, Republic of	Digestive Disease Cntr, Konkuk Univ Hosp	Kwangjin-gu, Seoul
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Gangnam Severance Hospital	Seoul
Korea, Republic of	Konkuk University Medical Center	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul	Gyeonggi-d
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Seoul Saint Mary's Hospital	Seoul
Korea, Republic of	CHA Bundang Medical Center, CHA University	Sungnam	Gyeonggi-d
Korea, Republic of	Yonsei Unversity Wonju College of Medicine Wonju Christian Hospital	Wonju	Gangwon-do
Korea, Republic of	Pusan National University Yangsan Hospital	Yangsan	Gyeongsang
Netherlands	Academisch Medisch Centrum	Amsterdam
Netherlands	Vrije Universiteit Medisch Centrum	Amsterdam
Netherlands	Erasmus Medisch Centrum	Rotterdam
Poland	Wojewodzki Szpital Specjalistyczny Kazimierza Dluskeigo w Bialymstoku	Bialystok
Poland	Wojewódzki Szpital Obserwacyjno Zakazny im. Tadeusza Browicza	Bydgoszcz
Poland	Szpital Specjalistyczny w Chorzowie	Chorzów	Slaskie
Poland	Szpital Uniwersytecki w Krakowie	Krakow
Poland	Wojewódzki Specjalistyczny Szpital im. Dr Wladyslawa Bieganskiego w Lodzi	Lodz
Poland	Wojewódzki Specjalistyczny Szpital im. Dr Wladyslawa Bieganskiego w Lodzi	Lodz	Lodzkie
Poland	Samodzielny Publiczny Szpital Kliniczny 1,Klinika Chorób Zakaznych,ulica Staszica 16	Lublin	Lubelskie
Poland	SP ZOZ Wojewodzki Szpital Zakazny	Warszawa
Portugal	Hospital de Egas Moniz	Lisboa
Portugal	Hospital de Santa Maria	Lisboa
Portugal	Centro Hospitalar do Porto	Porto
Portugal	Hospital São João	Porto
Romania	Neomed Research	Brasov
Romania	Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"	Bucharest
Romania	Institutul National de Boli Infectioase Prof.Dr. Matei Bals	Bucharest
Romania	Spitalul Clinic de Boli Infectioase si Tropicale "Dr. Victor Babes"	Bucharest
Romania	Spitalul Clinic Colentina	Bucuresti
Romania	Spitalul Clinic Judetean de Urgenta Sibiu	Sibiu
Romania	Cabinet Particular Policlinic Algomed SRL-Gastroenterologie	Timisoara
Singapore	Changi General Hospital	Singapore
Singapore	National University Hospital Singapore	Singapore
Singapore	Singapore General Hospital	Singapore
Singapore	Tan Tock Seng Hospital	Singapore
Spain	Hospital General Universitari Vall d' Hebron	Barcelona
Spain	Hospital Carlos III	Madrid
Spain	Hospital Universitario de La Princesa	Madrid
Spain	Hospital Virgen de la Victoria	Malaga
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Meixoeiro	Vigo, Pontevedra
Taiwan	Changhua Christain Hospital	Changhua
Taiwan	Chiayi Christian Hosp	Chia-Yi
Taiwan	Buddhist Tzu Chi General Hospital	Hualien
Taiwan	Chang Gung Memorial Hospital	Kaohsiung
Taiwan	Kaohsiung Medical University Hospital	Kaosiung
Taiwan	Chang Gung Medical Foundation-Keelung	Keelung Town/KEELUNG CITY
Taiwan	Far-Eastern Memorial Hosp	New Taipei City	Banciao Dist
Taiwan	China Medical University Hospital	Taichung
Taiwan	Chung Shan Medical University Hospital	Taichung
Taiwan	Taichung Veterans Genl Hosp	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	Cathay General Hospital	Taipei
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Chang Gung Medical Foundation.LinKou Branch	Tao-Yuan	Taoyuan
Turkey	Ankara Üniversitesi Tip Fakültesi	Ankara
Turkey	Hacettepe Üniversitesi Tip Fakültesi	Ankara
Turkey	Gaziantep Üniversitesi Tip Fakültesi, Sahinbey Arastirma ve Uygulama Hastanesi	Gaziantep
Turkey	Istanbul Universitesi Istanbul Tip Fakultesi	Istanbul
Turkey	Mersin Üniversitesi Tip Fakültesi, Saglik Arastirma ve Uygulama Hastanesi	Mersin
United Kingdom	The Queen Elizabeth Hospital	Birmingham, WSTMID
United Kingdom	Royal Free Hospital	Hampstead,London
United Kingdom	Barts and The London NHS Trust	London
United Kingdom	King's College Hospital	London
United States	Digestive Disease Associates	Baltimore	Maryland
United States	Tufts Medical Center	Boston	Massachusetts
United States	University of Chicago	Chicago	Illinois
United States	Avail Clinical Research, LLC	Deland	Florida
United States	Henry Ford Hospital	Detroit	Michigan
United States	Medical Procare, PLLC	Flushing	New York
United States	North Shore University Hospital	Great Neck	New York
United States	ID Care, Inc.	Hillsborough	New Jersey
United States	Advanced Liver Therapies at St. Luke's Episcopal Hospital	Houston	Texas
United States	Kelsey Research Foundation	Houston	Texas
United States	Liver Associates of Texas,	Houston	Texas
United States	Asian Pacific Liver Center	Los Angeles	California
United States	Centre for Advanced Gastroenterology	Maitland	Florida
United States	University of Miami / Jackson Memorial Medical Center	Miami	Florida
United States	LSU Gastroenterology/Center for Digestive Diseases	New Orleans	Louisiana
United States	Tulane University Hospital and Clinic	New Orleans	Louisiana
United States	Beth Israel Medical Center	New York	New York
United States	New York Univ. Medical Center	New York	New York
United States	Weill Cornell Medical College of Cornell University	New York	New York
United States	Stanford University Medical Center	Palo Alto	California
United States	Private Practice	Philadelphia	Pennsylvania
United States	Liver Institute of Virginia, Bon Secours Health System	Richmond	Virginia
United States	McGuire Research Institute	Richmond	Virginia
United States	University of Utah	Salt Lake City	Utah
United States	Research and Education Inc	San Diego	California
United States	San Jose Gastroenterology	San Jose	California

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Greece,  Hong Kong,  India,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Portugal,  Romania,  Singapore,  Spain,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With HBsAg Loss at Week 72 Following Treatment With 48 Weeks of TDF Plus PEG Combination Versus PEG Alone for 48 Weeks or TDF Alone	Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. Proportions are based on a Kaplan-Meier estimate.; The analysis visit window for Week 72 comprised study Days 491 (Week 70) through 546 (Week 78), so results up to Week 78 are included in this analysis.	Baseline; Week 72	No
Secondary	Percentage of Participants With HBsAg Loss at Week 72 Following Treatment With TDF (48 Weeks) Plus PEG (16 Weeks) Combination Versus PEG Alone for 48 Weeks or TDF Alone	Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. Proportions are based on a Kaplan-Meier estimate.; The analysis visit window for Week 72 comprised study Days 491 (Week 70) through 546 (Week 78), so results up to Week 78 are included in this analysis.	Baseline; Week 72	No
Secondary	Percentage of Participants With HBsAg Seroconversion at Week 72	HBsAg seroconversion was defined as change of detectable antibody to HBsAg from negative to positive. Proportions are based on a Kaplan-Meier estimate.; The analysis visit window for Week 72 comprised study Days 491 (Week 70) through 546 (Week 78), so results up to Week 78 are included in this analysis.	Baseline; Week 72	No
Secondary	Percentage of Participants With HBeAg Loss and Seroconversion at Week 72	Loss of HBeAg was defined as change of detectable HBeAg from positive to negative. HBeAg seroconversion was defined as change of detectable antibody to HBeAg from negative to positive. Percentages were based on the number of subjects with non-missing HBeAg results or missing HBeAg results imputed as failures at each visit.; For the TDF+PEG 48 week, TDF 48 week+PEG 16 week, and PEG 48 week groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 72, and in the "Retreated" column for participants who did enter the retreatment phase by Week 72.	Baseline; Week 72	No
Secondary	Percentage of Participants With Virological Response (HBV DNA < 117 IU/mL) at Week 72	For the TDF+PEG 48 week, TDF 48 week+PEG 16 week, and PEG 48 week groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 72, and in the "Retreated" column for participants who did enter the retreatment phase by Week 72.	Week 72	No
Secondary	Percentage of Participants With Normal ALT at Week 72	Normal ALT was = 30 U/L for males and = 19 U/L for females (based on the American Association for the Study of Liver Diseases (AASLD) 2008 guidelines), and = 41 U/L for males and = 31 U/L for females (based on central laboratory upper limit of the normal range (ULN) for ALT).; For the TDF+PEG 48 week, TDF 48 week+PEG 16 week, and PEG 48 week groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 72, and in the "Retreated" column for participants who did enter the retreatment phase by Week 72.	Week 72	No
Secondary	Percentage of Participants Who Required Retreatment	Participants in the TDF 120 week group were not eligible to enter the retreatment phase and are not presented.	Up to 120 weeks	No