Clinical trial NCT01940471: Study to Compare Tenofovir Alafenamide (TAF) Versus Tenofovir Disoproxil Fumarate (TDF) in Participants With Chronic Hepatitis B Infection Who Are Positive for Hepatitis B e Antigen
Official title: A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Tenofovir Alafenamide (TAF) 25 mg QD Versus Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the Treatment of HBeAg-Positive, Chronic Hepatitis B
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HBeAg-positive Chronic Hepatitis B
Keywords: Hepatitis
Tenofovir
Viread
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2013-09-12
Enrollment: 875
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: The primary objective of this study is to compare the efficacy, safety, and tolerability of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF) in treatment-naive and treatment-experienced adults with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (HBV) infection.

Detailed description: This study GS-US-320-0110 is a multi-center clinical trial planned to enroll participants in multiple countries, including China. However, due to the review timeline difference in China, full enrollment was reached in the main study before China was able to participate. Therefore, details for the China cohort are registered separately (NCT02836249) on ClinicalTrials.gov as this cohort will not be part of the main study analysis.

Eligibility criteria: Key Inclusion Criteria:

* Ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
* Adult males and non-pregnant, non-lactating females.
* Documented evidence of chronic HBV infection.
* HBeAg-positive, chronic hepatitis B with all of the following:

  * HBeAg-positive at screening.
  * Screening HBV DNA ≥ 2 x 10\^4 IU/mL
  * Screening serum alanine aminotransferase (ALT) level \> 60 U/L (males) or \> 38 U/L (females) and ≤ 10 x the upper limit of the normal range (ULN).
* Treatment-naive participants (defined as \< 12 weeks of oral antiviral treatment with any nucleoside or nucleotide analogue) OR treatment-experienced participants (defined as participants meeting all entry criteria \[including HBV DNA and serum ALT criteria\] and with ≥ 12 weeks of previous treatment with any nucleoside or nucleotide analogue).
* Previous treatment with interferon (pegylated or non-pegylated) must have ended at least 6 months prior to the baseline visit.
* Adequate renal function.
* Normal electrocardiogram (ECG).

Key Exclusion Criteria:

* Females who are breastfeeding.
* Males and females of reproductive potential who are unwilling to use an "effective", protocol specified method(s) of contraception during the study.
* Co-infection with hepatitis C virus, human immunodeficiency virus (HIV), or hepatitis D virus.
* Evidence of hepatocellular carcinoma .
* Any history of, or current evidence of, clinical hepatic decompensation.
* Abnormal hematological and biochemical parameters, including aspartate aminotransferase (AST) \> 10 x ULN.
* Received solid organ or bone marrow transplant.
* History of malignancy within the past 5 years, with the exception of specific cancers that are cured by surgical resection; individuals under evaluation for possible malignancy are not eligible.
* Currently receiving therapy with immunomodulators (eg, corticosteroids), investigational agents, nephrotoxic agents, or agents capable of modifying renal excretion.
* Individuals receiving ongoing therapy with drugs not to be used with tenofovir alafenamide or tenofovir disoproxil fumarate or individuals with a known hypersensitivity to study drugs, metabolites, or formulation excipients.
* Current alcohol or substance abuse judged by the investigator to potentially interfere with participant compliance.
* Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for the study or unable to comply with dosing requirements.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Percentage of Participants With Hepatitis B Virus (HBV) DNA < 29 IU/mL at Week 48
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion to Antibody Against Hepatitis B e Antigen (Anti-HBe) at Week 48
timeFrame: Week 48
measure: Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48
timeFrame: Baseline, Week 48
measure: Percent Change From Baseline in Spine BMD at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline at Week 48 in Serum Creatinine
timeFrame: Baseline, Week 48
Other outcomes:
measure: Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48
timeFrame: Up to 48 weeks
Locations:
city: Los Angeles
country: United States
facility: Coalition of Inclusive Medicine
state: California
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Pasadena
country: United States
facility: Huntington Medical Research Institutes
state: California
city: San Diego
country: United States
facility: Research and Education, Inc.
state: California
city: San Jose
country: United States
facility: Silicon Valley Research Institute
state: California
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Catonsville
country: United States
facility: Digestive Disease Associates, PA
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center, Inc
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Flushing
country: United States
facility: Sing Chan Private Practice
state: New York
city: Flushing
country: United States
facility: New Discovery, LLC
state: New York
city: Philadelphia
country: United States
facility: Jefferson Medical College
state: Pennsylvania
city: Philadelphia
country: United States
facility: Xiaoli Ma, PC
state: Pennsylvania
city: Arlington
country: United States
facility: Texas Clinical Research Institute, LLC
state: Texas
city: Houston
country: United States
facility: Kelsey Research Foundation
state: Texas
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: Westmead
country: Australia
facility: Westmead Hospital Westmead
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Fitzroy
country: Australia
facility: St. Vincent's Hospital
state: Victoria
city: Footscray
country: Australia
facility: Footscray Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Sofia
country: Bulgaria
facility: Tokuda Hospital - Sofia
city: Sofia
country: Bulgaria
facility: MHAT Alexandrovska Medical University, Sofia
city: Sofia
country: Bulgaria
facility: MMA Hospital of Active Treatment
city: Sofia
country: Bulgaria
facility: MHAT Sofia Med
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: Zeidler Ledcor Centre Division of Gastroenterology / Department of Medicine
state: Alberta
city: Vancouver
country: Canada
facility: Liver and Intestinal Research Centre
state: British Columbia
city: Vancouver
country: Canada
facility: Gordon and Leslie Diamond Health Care Centre
state: British Columbia
city: Vancouver
country: Canada
facility: Dr. John Farley, Inc.
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver Infectious Disease Research and Care Centre
state: British Columbia
city: Vancouver
country: Canada
facility: Gastrointestinal Research Institute (GIRI)
state: British Columbia
city: Winnipeg
country: Canada
facility: University of Manitoba, Health Sciences Center
state: Manitoba
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network / Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Inspiration Research Limited
state: Ontario
city: Toronto
country: Canada
facility: Toronto Liver Centre
state: Ontario
city: Clichy
country: France
facility: Hopital Beaujon
city: Paris
country: France
facility: Hopital Pitie Salpetriere
city: Strasbourg
country: France
facility: Hopital Civil de Strasbourg
city: Villejuif
country: France
facility: Hopital Paul Brousse
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Lai Chi Kok
country: Hong Kong
facility: Princess Margaret Hospital
city: Sha Tin
country: Hong Kong
facility: Prince of Wales Hospital
city: Tai Po
country: Hong Kong
facility: Alice Ho Miu Ling Nethersole Hospital
city: Tuen Mun
country: Hong Kong
facility: Tuen Mun Hospital
city: Mumbai
country: India
facility: BYL Nair Hospital & T N Medical College
state: Maharashtra
city: Nagpur
country: India
facility: Government Medical College and Superspecialty Hospital
state: Maharashtra
city: Nagpur
country: India
facility: Midas Multispecialty Hospital
state: Maharashtra
city: Jaipur
country: India
facility: SMS Medical College & Hospital
state: Rajasthan
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education & Research
city: Chennai
country: India
facility: YR Gaitonde Centre for AIDS Research and Education
city: Coimbatore
country: India
facility: VGM Hospital
city: Hyderabad
country: India
facility: Gleneagles Global Hospital
city: Hyderabad
country: India
facility: Centre for Liver Research & Diagnostic, Deccan College of Medical Sciences and Allied Hospitals
city: Jaipur
country: India
facility: S. R Kalla Memorial Gastro & General Hospital
city: Kolkata
country: India
facility: Peerless Hospital & B.K.Roy Research Center
city: Kolkata
country: India
facility: Postgraduate Institute of Medical Education & Research
city: Mumbai
country: India
facility: Seth GS Medical College and KEM Hospital
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
city: New Delhi
country: India
facility: Sir Ganga Ram Hospital
city: New Delhi
country: India
facility: Institute of Liver and Biliary Sciences
city: Parel
country: India
facility: Global Hospital Super Specialty & Transplant Centre
city: Surat
country: India
facility: Nirmal Hospital
city: Bologna
country: Italy
facility: Azienda Ospedaliera di Bologna - Policlinico S. Orsola Malpighi
city: Bologna
country: Italy
facility: Istituto Europeo di Oncologia
city: Foggia
country: Italy
facility: Azienda Ospedaliero Universitaria Ospedali Riuniti di
city: Messina
country: Italy
facility: Policlinico Universitario G. Martino via Consolare
city: Milano
country: Italy
facility: Azienda Ospedale San Paolo
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
state: Fukuoka-shi
city: Fukuoka
country: Japan
facility: Shin-Kokura Hospital
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Medical Center
city: Kagawa
country: Japan
facility: Kagawa Prefectural Central Hospital
city: Kobe
country: Japan
facility: Kobe City Medical Center General Hospital
city: Kofu
country: Japan
facility: Yamanashi Prefectural Central Hospital
city: Kurume
country: Japan
facility: Kurume University Hospital
city: Kyoto
country: Japan
facility: Kyoto Prefectural University of Medicine
city: Musashino
country: Japan
facility: Japan Red Cross Musashino Hospital
city: Nishinomiya
country: Japan
facility: Hyogo College of Medicine
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Omura
country: Japan
facility: National Hospital Organization Nagasaki Medical Center
city: Osaka
country: Japan
facility: Osaka Red Cross Hospital
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
city: Tokyo
country: Japan
facility: Medical Hospital of Tokyo Medical and Dental University
city: Busan
country: Korea, Republic of
facility: Kosin University College of Medicine
state: Seo-gu
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Cheonan
country: Korea, Republic of
facility: SoonChunHyang University Hospital Cheonan
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Medical Center
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Daejeon
country: Korea, Republic of
facility: Konyang University Hospital
city: Gyeonggi-do
country: Korea, Republic of
facility: Inje University Ilsan Paik Hospital
city: Gyeonggi-do
country: Korea, Republic of
facility: Ajou University Hospital
city: Gyeonggi-Do
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul Saint Mary Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: SMG-SNU Boramae Medical Center
city: Seoul
country: Korea, Republic of
facility: Chung-Ang University Hospital
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
city: Wŏnju
country: Korea, Republic of
facility: Yonsei Unversity Wonju
city: Yangsan
country: Korea, Republic of
facility: Pusan National University Yangsan Hospital
city: Auckland
country: New Zealand
facility: Auckland Clinical Studies Limited
city: Hamilton
country: New Zealand
facility: Waikato Hospital (District Health Board)
city: Bialystok
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Bialymstoku Klinika
city: Chorzow
country: Poland
facility: Szpital Specjalistyczny
city: Lodz
country: Poland
facility: SPZOZ, Wojewódzki Specjalistyczny Szpital
city: Warszawa
country: Poland
facility: SP ZOZ Wojewódzki Szpital Zakazny
city: Wroclaw
country: Poland
facility: Centrum Badan Klinicznych
city: Bucharest
country: Romania
facility: Centrul Medical de Diagnostic si Tratament "Dr. Victor Babes"
city: Bucuresti
country: Romania
facility: Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"
city: Constanţa
country: Romania
facility: Spitatul Clinic de Boli Infectioase Constanta
city: Iasi
country: Romania
facility: Gastromedica SRL
city: Timişoara
country: Romania
facility: Spitalul Clinic Judetean de Urgenta Timisoara
city: Lipetsk
country: Russian Federation
facility: Lipetsk Regional Center for Prevention and Control of AIDS and Infectious Diseases
city: Moscow
country: Russian Federation
facility: Scientific Research Institute of Nutrition
city: Moscow
country: Russian Federation
facility: People's Friendship University of Russia
city: Moscow
country: Russian Federation
facility: 1st Moscow State Medical University University Clinical Hospital #3
city: Moscow
country: Russian Federation
facility: Limited Liability Company "Modern Medicine Clinic"
city: Novosibirsk
country: Russian Federation
facility: Institute of Clinical Immunology RAMS, Clinic of Immunopathology
city: Novosibirsk
country: Russian Federation
facility: Scientific Research Institute of Clinical Immunology
city: Saint-Petersburg
country: Russian Federation
facility: Municipal Clinical Hospital n.a. S.P. Botkin
city: Saint-Petersburg
country: Russian Federation
facility: Research Institute of Influenza
city: Samara
country: Russian Federation
facility: Medical Company Hepatology
city: Yekaterinburg
country: Russian Federation
facility: Sverdlovsk Regional Clinical Hospital #1
city: Singapore
country: Singapore
facility: National University Hospital Singapore
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Singapore
country: Singapore
facility: Changi General Hospital Pte Ltd.
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Chiayi
country: Taiwan
facility: Chiayi Christian Hospital
city: Hualien
country: Taiwan
facility: Hualien Tzu Chi Medical Center
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Med. College Hosp. Dept. of Internal Medicine
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Cathay General Hospital
city: Taipei
country: Taiwan
facility: Far-Eastern Memorial Hospital
city: Ankara
country: Turkey
facility: Ankara Üniversitesi Gastroenteroloji Bilim Dalı Cebeci
city: Bursa
country: Turkey
facility: University of Uludag
city: Diyarbakir
country: Turkey
facility: Dicle University Medical Faculty Department of Infectious Diseases
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Cerrahpassa Tip Fakultesi Enfeksiyon
city: Izmir
country: Turkey
facility: Ege Universitesi Tip Fakultesi Hastanesi
city: London
country: United Kingdom
facility: Barts & The London NHS Trust
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: Cathcart AL, Chan HL, Bhardwaj N, Liu Y, Marcellin P, Pan CQ, Shalimar, Buti M, Cox S, Parhy B, Zhou E, Martin R, Chang S, Lin L, Flaherty JF, Kitrinos KM, Gaggar A, Izumi N, Lim YS. No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B Infection. Antimicrob Agents Chemother. 2018 Sep 24;62(10):e01064-18. doi: 10.1128/AAC.01064-18. Print 2018 Oct.
citation: Seto WK, Asahina Y, Brown TT, Peng CY, Stanciu C, Abdurakhmanov D, Tabak F, Nguyen TT, Chuang WL, Inokuma T, Ikeda F, Santantonio TA, Habersetzer F, Ramji A, Lau AH, Suri V, Flaherty JF, Wang H, Gaggar A, Subramanian GM, Mukewar S, Brunetto MR, Fung S, Chan HL. Improved Bone Safety of Tenofovir Alafenamide Compared to Tenofovir Disoproxil Fumarate Over 2 Years in Patients With Chronic HBV Infection. Clin Gastroenterol Hepatol. 2018 Jun 20:S1542-3565(18)30633-5. doi: 10.1016/j.cgh.2018.06.023. Online ahead of print.
citation: Agarwal K, Brunetto M, Seto WK, Lim YS, Fung S, Marcellin P, Ahn SH, Izumi N, Chuang WL, Bae H, Sharma M, Janssen HLA, Pan CQ, Celen MK, Furusyo N, Shalimar D, Yoon KT, Trinh H, Flaherty JF, Gaggar A, Lau AH, Cathcart AL, Lin L, Bhardwaj N, Suri V, Mani Subramanian G, Gane EJ, Buti M, Chan HLY; GS-US-320-0110; GS-US-320-0108 Investigators. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol. 2018 Apr;68(4):672-681. doi: 10.1016/j.jhep.2017.11.039. Epub 2018 Jan 17.
citation: Chan HL, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, Hui AJ, Janssen HL, Chowdhury A, Tsang TY, Mehta R, Gane E, Flaherty JF, Massetto B, Gaggar A, Kitrinos KM, Lin L, Subramanian GM, McHutchison JG, Lim YS, Acharya SK, Agarwal K; GS-US-320-0110 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):185-195. doi: 10.1016/S2468-1253(16)30024-3. Epub 2016 Sep 22.