Clinical trial NCT01940341: Study to Compare Tenofovir Alafenamide (TAF) Versus Tenofovir Disoproxil Fumarate (TDF) in Participants With Chronic Hepatitis B Infection Who Are Negative 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-Negative, Chronic Hepatitis B
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HBeAg-negative Chronic Hepatitis B
Keywords: Hepatitis
Tenofovir
Viread
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2013-09-12
Enrollment: 426
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)-negative chronic hepatitis B virus (HBV) infection.

Detailed description: Study GS-US-320-0108 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 was registered separately (NCT02836236) on ClinicalTrials.gov as the China 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.
* Hepatitis e antigen (HBeAg)-negative, chronic hepatitis B with all of the following:

  * HBeAg-negative and hepatitis B e antibody (HBeAb) 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 Baseline.
* 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
timeFrame: Week 48
Secondary outcomes:
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 in Serum Creatinine at Week 48
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: Asian Pacific Liver Center
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 Francisco
country: United States
facility: University California San Francisco (UCSF)
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: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Hillsborough
country: United States
facility: ID Care
state: New Jersey
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: Xiaoli Ma, PC
state: Pennsylvania
city: Richmond
country: United States
facility: Hunter Holmes McGuire VA DVMC
state: Virginia
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Fitzroy
country: Australia
facility: St. Vincent's Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: Zeidler Ledcor Centre Division of Gastroenterology
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
state: Manitoba
city: Toronto
country: Canada
facility: 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: Lyon cedex 04
country: France
facility: Hôpital de la Croix Rousse
city: Strasbourg
country: France
facility: Hopital Civil de Strasbourg- CHU Service
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
state: Hong Kong SAR
city: Kwai Chung
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 Hospitals
state: Andhra Pradesh
city: Hyderabad
country: India
facility: Centre for Liver Research & Diagnostic, Deccan College of Medical Sciences and Allied Hospitals
state: Andhra Pradesh
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
state: Delhi
city: Surat
country: India
facility: Nirmal Hospital
state: Gujarat
city: Mumbai
country: India
facility: Seth GS Medical College and KEM Hospital
state: Maharastra
city: Parel
country: India
facility: Global Hospital Super Specialty & Transplant Centre
state: Mumbai
city: Jaipur
country: India
facility: S. R Kalla Memorial Gastro & General Hospital
state: Rajasthan
city: Kolkata
country: India
facility: Institute of Post Graduate Medical Education And Research
state: West Bengal
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education and Research
city: New Delhi
country: India
facility: Institute of Liver and Biliary Sciences
city: San Giovanni Rotondo
country: Italy
facility: IRCCS Ospedale Casa Sollievo della Sofferenza
state: Foggia
city: Bologna
country: Italy
facility: Azienda Ospedaliera S. Orsola - Malpighi
city: Foggia
country: Italy
facility: Azienda Ospedaliero Universitaria Ospedali
city: Pisa
country: Italy
facility: Azienda Ospedaliero- Universitaria Pisana
city: Kurume-shi
country: Japan
facility: Kurume University Hospital
state: Fukuoka-ken
city: Fukuoka
country: Japan
facility: Kyushu University Hospital Fukuoka
state: Fukuoka-shi
city: Omura-shi
country: Japan
facility: National Hospital Organization Nagasaki Medical Center
state: Nagasaki
city: Suita
country: Japan
facility: Osaka University Hospital
state: Osaka
city: Kitakyushu
country: Japan
facility: Shin-Kokura Hospital
city: Kobe
country: Japan
facility: Kobe City Medical Center General Hospital
city: Musashino
country: Japan
facility: Japan Red Cross Musashino Hospital
city: Nishinomiya
country: Japan
facility: The Hospital of Hyogo College of Medicine
city: Osaka
country: Japan
facility: Osaka Red Cross Hospital
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
city: Tokyo
country: Japan
facility: Medical Hospital of Tokyo Medical and Dental University
city: Yangsan
country: Korea, Republic of
facility: Pusan National University Yangsan Hospital
state: Gyeongsangnam-do
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Medical Center
city: Seoul
country: Korea, Republic of
facility: Yonsei University, Severance Hospital
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: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul Saint Mary Hospital
city: Seoul
country: Korea, Republic of
facility: Chung-Ang University Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Auckland
country: New Zealand
facility: Auckland Clinical Studies Limited
city: Bialystok
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Bialymstoku Klinika
city: Chorzow
country: Poland
facility: Szpital Specjalistyczny w Chorzowie Oddział
city: Lodz
country: Poland
facility: SPZOZ, Wojewódzki Specjalistyczny Szpital
city: Wroclaw
country: Poland
facility: Centrum Badan Klinicznych - Przychodnia Badan
city: Bucharest
country: Romania
facility: Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"
state: Bucuresti
city: Bucuresti
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: Constanta
country: Romania
facility: Spitatul Clinic de Boli Infectioase Constanta
city: Iasi
country: Romania
facility: Gastromedica SRL
city: Koltsovo
country: Russian Federation
facility: Infection Center LLC Building 20, MSH #163 Territory Koltsovo
state: Novosibirsk
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: Moscow
country: Russian Federation
facility: Infectious Clinical Hospital #1 of Moscow Healthcare Department
city: Novosibirsk
country: Russian Federation
facility: Novosibirsk State Medical University
city: Novosibirsk
country: Russian Federation
facility: State Novosibirsk Regional Clinical Hospital
city: Novosibirsk
country: Russian Federation
facility: Scientific Research Institute of Clinical Immunology
city: Saint-Petersburg
country: Russian Federation
facility: Clinical Infectious Hospital named after S.P.Botkin
city: Saint-Petersburg
country: Russian Federation
facility: Kirov Medical Military Academy
city: Saint-Petersburg
country: Russian Federation
facility: Research Institute of Influenza
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Hualien City
country: Taiwan
facility: Hualien Tzu Chi Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Diyarbakir
country: Turkey
facility: Dicle University Medical Faculty Department of Infectious Diseases
state: Diyarbakri
city: Ankara
country: Turkey
facility: Ankara Üniversitesi Gastroenteroloji Bilim Dalı Cebeci
city: Bursa
country: Turkey
facility: Uludag Üniversitesi Tıp Fakültesi Gastroenteroloji
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Cerrahpassa Tip Fakultesi Hastanesi
city: Izmir
country: Turkey
facility: Ege Universitesi Tip Fakultesi Hastanesi
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
state: Nottinghamshire
city: London
country: United Kingdom
facility: Barts and The London NHS Trust Royal London Hospital
city: London
country: United Kingdom
facility: King's College Hospital
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: Buti M, Gane E, Seto WK, Chan HL, Chuang WL, Stepanova T, Hui AJ, Lim YS, Mehta R, Janssen HL, Acharya SK, Flaherty JF, Massetto B, Cathcart AL, Kim K, Gaggar A, Subramanian GM, McHutchison JG, Pan CQ, Brunetto M, Izumi N, Marcellin P; GS-US-320-0108 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):196-206. doi: 10.1016/S2468-1253(16)30107-8. Epub 2016 Sep 22.