Clinical trial NCT03180619: Study to Evaluate the Safety and Efficacy of Switching to Tenofovir Alafenamide (TAF) From Tenofovir Disoproxil Fumarate (TDF) and/or Other Oral Antiviral Treatment (OAV)
Official title: A Phase 2, Open-label Study to Evaluate the Safety and Efficacy of Switching to Tenofovir Alafenamide (TAF) From Tenofovir Disoproxil Fumarate (TDF) and/or Other Oral Antiviral Treatment (OAV) in Virologically Suppressed Chronic Hepatitis B Subjects With Renal and/or Hepatic Impairment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Hepatitis B
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2017-06-08
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to evaluate the safety and tolerability and virologic response of tenofovir alafenamide (TAF) in virologically suppressed chronic hepatitis B participants with renal and/or hepatic impairment.


Eligibility criteria: Key Inclusion Criteria:

All Participants (Parts A and B):

* Adult male or non-pregnant female individuals
* Documented evidence of chronic HBV infection
* Alanine aminotransferase (ALT) ≤ 10 × upper limit of normal (ULN)

Part A Only (renal impairment):

* Maintained on TDF and/or other OAV treatment(s) for CHB for at least 48 weeks and with viral suppression (HBV deoxyribonucleic acid \[DNA\] \< lower limit of quantitation \[LLOQ\]) for ≥ 6 months prior to screening

  * All individuals must have HBV DNA \< 20 International units per milliliter (IU/mL) at screening by central laboratory
  * Both Hepatitis B e-Antigen (HBeAg) positive and negative individuals are eligible to participate
* Moderate renal impairment (30 milliliters per minute \[mL/min\] ≤ estimated glomerular filtration rate by the cockcroft-gault formula \[eGFRcg\] ≤ 59 mL/min), severe renal impairment (15 mL/min ≤ eGFRcg \< 30 mL/min) or end stage renal disease (ESRD) (eGFR \< 15 mL/min) maintained on hemodialysis (HD)
* Stable renal function (for participants with moderate or severe impairment): serum creatinine measured at least once within three months prior to screening. The measurement difference between the value measured within three months prior to screening versus the screening value must be ≤ 25% of the screening value

Part B Only (hepatic impairment):

* Maintained on TDF and/or other OAV(s) for CHB for at least 48 weeks and with viral suppression (HBV DNA \< LLOQ) for ≥ 6 months prior to screening

  * All individuals must have HBV DNA \< 20 IU/mL at screening by central laboratory
  * Both HBeAg positive and negative individuals are eligible to participate
* Child-pugh-turcotte (CPT) score of 7-12 (inclusive) OR a past history of CPT score ≥ 7 and any CPT score ≤ 12 at screening
* eGFRCG ≥ 30 mL/min using the Cockcroft-Gault equation

Key Exclusion Criteria:

All Individuals (Parts A \& B):

* Women who are breastfeeding or who believe they may wish to become pregnant during the course of the study
* 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 (HCV), human immunodeficiency virus (HIV), or hepatitis D virus (HDV)
* Prior Interferon (IFN) use within 6 months of screening
* Evidence of hepatocellular carcinoma
* Received solid organ or bone marrow transplant
* Significant cardiovascular, pulmonary, or neurological disease
* Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc.). Individuals under evaluation for possible malignancy are not eligible
* Currently receiving therapy with immunomodulators (e.g. corticosteroids), nephrotoxic agents, or agents capable of modifying renal excretion
* Known hypersensitivity to study drugs, metabolites, or formulation excipients
* Current alcohol or substance abuse judged by the investigator to potentially interfere with individual's compliance
* Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the individual unsuitable for the study or unable to comply with dosing requirements.

Part A Only (Renal Impairment):

* Current or historical evidence of clinical hepatic decompensation (e.g., ascites, encephalopathy or variceal hemorrhage)
* Abnormal hematological and biochemical parameters, including:

  * Hemoglobin \< 9 grams per deciliter (g/dL)
  * Absolute neutrophil count \< 750/cubic millimeter (mm\^3)
  * Platelets ≤ 50,000/mm\^3
  * Aspartate aminotransferase (AST) \> 10 × ULN
  * Albumin \< 3.0 g/dL
  * Total bilirubin \> 2.5 × ULN
  * International normalized ratio of prothrombin time (INR) \> 1.5 × ULN (unless stable on anticoagulant regimen)
* Individuals with ESRD (i.e. eGFRcg \< 15 mL/min) not on HD, or those on other forms of renal replacement therapy (i.e. peritoneal dialysis)

Part B Only (Hepatic Impairment):

* Active variceal bleeding within 6 months or prior placement of a portosystemic shunt (such as transjugular intrahepatic portosystemic shunt \[TIPS\])
* History of hepatorenal syndrome, hepatopulmonary syndrome, Grade 3 or Grade 4 hepatic encephalopathy, or spontaneous bacterial peritonitis within 6 months of screening
* Grade 2 hepatic encephalopathy at screening
* Model for end-stage liver disease (MELD) score ≥ 30
* Abnormal hematological and biochemical parameters, including

  * Absolute neutrophil count \< 750/mm\^3
  * Platelets \< 30,000/mm\^3
  * Hemoglobin \< 8.0 g/dL

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

Primary outcomes:
measure: Percentage of Participants Achieving Virologic Response (Plasma Hepatitis B Virus [HBV] Deoxyribonucleic Acid [DNA] < 20 IU/mL) at Week 24
timeFrame: Week 24
measure: Percentage of Participants Who Experienced Graded Treatment-Emergent Adverse Events (AEs) at Week 24
timeFrame: Week 24
measure: Percentage of Participants Who Experienced Graded Treatment-Emergent Laboratory Abnormalities at Week 24
timeFrame: Week 24
Secondary outcomes:
measure: Percentage of Participants Who Experienced Graded Treatment-Emergent AEs at Week 48
timeFrame: Week 48
measure: Percentage of Participants Who Experienced Graded Treatment-Emergent AEs at Week 96
timeFrame: Week 96
measure: Percentage of Participants Who Experienced Graded Treatment-Emergent Laboratory Abnormalities at Week 48
timeFrame: Week 48
measure: Percentage of Participants Who Experienced Graded Treatment-Emergent Laboratory Abnormalities at Week 96
timeFrame: Week 96
measure: Change From Baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFRcg) in Participants With Moderate or Severe Renal Impairment and Hepatically Impaired Participants at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in eGFRcg in Participants With Moderate or Severe Renal Impairment and Hepatically Impaired Participants at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in eGFRcg in Participants With Moderate or Severe Renal Impairment and Hepatically Impaired Participants at Week 96
timeFrame: Baseline, Week 96
measure: Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 24
timeFrame: Baseline, Week 24
measure: Percent Change From Baseline in Hip BMD at Week 48
timeFrame: Baseline, Week 48
measure: Percent Change From Baseline in Hip BMD at Week 96
timeFrame: Baseline, Week 96
measure: Percent Change From Baseline in Spine BMD at Week 24
timeFrame: Baseline, Week 24
measure: Percent Change From Baseline in Spine BMD at Week 48
timeFrame: Baseline, Week 48
measure: Percent Change From Baseline in Spine BMD at Week 96
timeFrame: Baseline, Week 96
measure: Percentage of Participants Achieving Virologic Response (Plasma HBV DNA < 20 IU/mL) at Week 48
timeFrame: Weeks 48
measure: Percentage of Participants Achieving Virologic Response (Plasma HBV DNA < 20 IU/mL) at Week 96
timeFrame: Weeks 96
measure: Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (≥ Lower Limit of Detection [LLOD]) at Week 24
timeFrame: Week 24
measure: Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (≥ LLOD) at Week 48
timeFrame: Week 48
measure: Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (≥ LLOD) at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 24
timeFrame: Week 24
measure: Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 48
timeFrame: Weeks 48
measure: Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 96
timeFrame: Weeks 96
measure: Percentage of Participants With Serological Response: Loss of Hepatitis B s-Antigen (HBsAg) at Week 24
timeFrame: Week 24
measure: Percentage of Participants With Serological Response: Loss of HBsAg at Week 48
timeFrame: Week 48
measure: Percentage of Participants With Serological Response: Loss of HBsAg at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Serological Response: Seroconversion to Anti-HBs at Week 24
timeFrame: Week 24
measure: Percentage of Participants With Serological Response: Seroconversion to Anti-HBs at Week 48
timeFrame: Week 48
measure: Percentage of Participants With Serological Response: Seroconversion to Anti-HBs at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 24
timeFrame: Week 24
measure: Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 48
timeFrame: Week 48
measure: Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 24
timeFrame: Week 24
measure: Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 48
timeFrame: Week 48
measure: Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Week 24 by Central Laboratory and the American Association for the Study of Liver Diseases (AASLD) Criteria
timeFrame: Week 24
measure: Percentage of Participants With Normal ALT at Week 48 by Central Laboratory and the AASLD Criteria
timeFrame: Week 48
measure: Percentage of Participants With Normal ALT at Week 96 by Central Laboratory and the AASLD Criteria
timeFrame: Week 96
measure: Percentage of Participants With Normalized ALT at Week 24 by Central Laboratory and the AASLD Criteria
timeFrame: Week 24
measure: Percentage of Participants With Normalized ALT at Week 48 by Central Laboratory and the AASLD Criteria
timeFrame: Week 48
measure: Percentage of Participants With Normalized ALT at Week 96 by Central Laboratory and the AASLD Criteria
timeFrame: Week 96
measure: Change From Baseline in FibroTest® Score at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in FibroTest® Score at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in FibroTest® Score at Week 96
timeFrame: Week 96
measure: Change From Baseline in Child-Pugh-Turcotte (CPT) Score in Hepatically Impaired Participants at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in CPT Score in Hepatically Impaired Participants at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in CPT Score in Hepatically Impaired Participants at Week 96
timeFrame: Baseline, Week 96
measure: Change From Baseline in Model for End-Stage Liver Disease (MELD) Score in Hepatically Impaired Participants at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in MELD Score in Hepatically Impaired Participants at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in MELD Score in Hepatically Impaired Participants at Week 96
timeFrame: Baseline, Week 96
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Coalition of Inclusive Medicine
state: California
city: San Jose
country: United States
facility: Silicon Valley Research Institute, Inc
state: California
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Calgary
country: Canada
facility: University of Calgary Liver Unit
city: Montreal
country: Canada
facility: Centre de Recherche du Centre Hospitalier de l'Universite de Montreal
city: Toronto
country: Canada
facility: University Health Network,Toronto general Hospital,Toronto centre for liver disease
city: Toronto
country: Canada
facility: Toronto Liver Centre
city: Vancouver
country: Canada
facility: (G.I.R.I.) GI Research Institute
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
state: NT
city: Kowloon
country: Hong Kong
facility: Princess Margaret Hospital
city: Tai Po
country: Hong Kong
facility: Alice Ho Miu Ling Nethersole Hospital
city: Rozzano
country: Italy
facility: U.O. Medicina Generale Epatologia IRCCS Humanitas Centro di Ricerca Traslazionale in Epatologia
state: Milan
city: Bologna
country: Italy
facility: Dipartimento di Scienze Mediche e Chirurgiche (DIMEC) AOU Policlinico S.Orsola-Malpighi di Bologna
city: Milan
country: Italy
facility: UOC Gastroenterol-Epatol.-Fondazione IRCCS Ca Granda
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System, Severance Hospital
city: Grafton
country: New Zealand
facility: Auckland Clinical Studies
state: Auckland
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Chiayi City
country: Taiwan
facility: Ditmanson Medical Foundation Chia-Yi Christian Hospital
city: Kaohsiung City
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans Genl Hosp
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Veterans General Hospital-Taipei
city: Taoyuan City
country: Taiwan
facility: Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital
city: London
country: United Kingdom
facility: Nottingham University Hospital
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: Lim YS, Lin CY, Heo J, Bae H, Chuang WL, Hui AJ, et al. Safety and Efficacy of Switching to Tenofovir Alafenamide in Virally Suppressed Chronic Hepatitis B Patients With Hepatic Impairment: Week-48 Results From a Phase 2 Open-label Study [Poster SAT442]. The Digital International Liver Congress (ILC); 2020 27-29 August.
citation: Janssen HLA, Lampertico P, Chen CY, Heo J, Fournier C, Ahn SH, et al. Safety and Efficacy of Switching to Tenofovir Alafenamide in Virally Suppressed Chronic Hepatitis B Patients With Renal Impairment: Week-48 Results From a Phase 2 Open-label Study [Poster SAT429]. The Digital International Liver Congress (ILC); 2020 27-29 August.
citation: Lim YS, Lampertico P, Bae H, Chuang WL, Heo J, Huang YH, et al. Switching From Tenofovir Disoproxil Fumarate or Other Oral Antiviral Therapy to Tenofovir Alafenamide in Virally Suppressed Chronic Hepatitis B Patients With Hepatic Impairment: Week 24 Efficacy and Safety Results From a Phase 2 Open-label Study [Poster 501]. AASLD: The Liver Meeting; 2019 08-12 November; Boston, MA.
citation: Janssen HLA, Lim YS, Gane EJ, Fournier C, Ahn SH, Tsang O, et al. Efficacy and Safety of Switching to Tenofovir Alafenamide in Virally Suppressed Chronic Hepatitis B Patients With Renal Impairment: Week 24 Results From a Phase 2 Open-label Study [Poster 483]. AASLD: The Liver Meeting; 2019 08-12 November; Boston, MA.