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)

Chronic Hepatitis B Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03180619
• Other study ID #: GS-US-320-4035
• Secondary ID: 2016-004625-16
• Status: Completed
• Phase: Phase 2
• Start date: June 29, 2017
• Est. completion date: September 4, 2020

Study information

• Verified date: August 2021
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 124
• Est. completion date: September 4, 2020
• Est. primary completion date: March 27, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• TAF
Tablet administered orally once daily

Locations

Country	Name	City	State
Canada	University of Calgary Liver Unit	Calgary
Canada	Centre de Recherche du Centre Hospitalier de l'Universite de Montreal	Montreal
Canada	Toronto Liver Centre	Toronto
Canada	University Health Network,Toronto general Hospital,Toronto centre for liver disease	Toronto
Canada	(G.I.R.I.) GI Research Institute	Vancouver
Hong Kong	Princess Margaret Hospital	Kowloon
Hong Kong	Prince of Wales Hospital	Shatin	NT
Hong Kong	Alice Ho Miu Ling Nethersole Hospital	Tai Po
Italy	Dipartimento di Scienze Mediche e Chirurgiche (DIMEC) AOU Policlinico S.Orsola-Malpighi di Bologna	Bologna
Italy	UOC Gastroenterol-Epatol.-Fondazione IRCCS Ca Granda	Milan
Italy	U.O. Medicina Generale Epatologia IRCCS Humanitas Centro di Ricerca Traslazionale in Epatologia	Rozzano	Milan
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Yonsei University Health System, Severance Hospital	Seoul
New Zealand	Auckland Clinical Studies	Grafton	Auckland
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Ditmanson Medical Foundation Chia-Yi Christian Hospital	Chiayi City
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung City
Taiwan	Taichung Veterans Genl Hosp	Taichung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Veterans General Hospital-Taipei	Taipei
Taiwan	Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital	Taoyuan City
United Kingdom	King's College Hospital NHS Foundation Trust	London
United Kingdom	Nottingham University Hospital	London
United States	Henry Ford Health System	Detroit	Michigan
United States	Coalition of Inclusive Medicine	Los Angeles	California
United States	Silicon Valley Research Institute, Inc	San Jose	California
United States	Harborview Medical Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Canada,  Hong Kong,  Italy,  Korea, Republic of,  New Zealand,  Taiwan,  United Kingdom, 

References & Publications (4)

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 [Post

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 4

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 Effic

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].

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Achieving Virologic Response (Plasma Hepatitis B Virus [HBV] Deoxyribonucleic Acid [DNA] < 20 IU/mL) at Week 24	The percentage of participants with HBV DNA < 20 IU/mL at Week 24 was determined by the Missing = Failure (M = F) approach.	Week 24
Primary	Percentage of Participants Who Experienced Graded Treatment-Emergent Adverse Events (AEs) at Week 24	Treatment-emergent AEs were defined as: Any AEs with an onset date on or after the study drug start date and no later than the study drug stop date + 3 days after permanent discontinuation of study drug; Any AEs with onset date on or after the study drug start date for those who have not permanently discontinued study drug; Any AEs leading to premature discontinuation of study drug.; The most severe graded AE from all tests was counted for each participant.	Week 24
Primary	Percentage of Participants Who Experienced Graded Treatment-Emergent Laboratory Abnormalities at Week 24	Graded treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any postbaseline visit, up to and including the date of last dose of study drug + 3 days for participants who permanently discontinued study drug or the last available date in the database snapshot for participants who were on treatment at the time of the analysis.; The most severe graded abnormality from all tests was counted for each participant.	Week 24
Secondary	Percentage of Participants Who Experienced Graded Treatment-Emergent AEs at Week 48	Treatment-emergent AEs were defined as: Any AEs with an onset date on or after the study drug start date and no later than the study drug stop date + 3 days after permanent discontinuation of study drug; Any AEs with onset date on or after the study drug start date for those who have not permanently discontinued study drug; Any AEs leading to premature discontinuation of study drug. The most severe graded AE from all tests was counted for each participant.	Week 48
Secondary	Percentage of Participants Who Experienced Graded Treatment-Emergent AEs at Week 96	Treatment-emergent AEs were defined as: Any AEs with an onset date on or after the study drug start date and no later than the study drug stop date + 3 days after permanent discontinuation of study drug; Any AEs with onset date on or after the study drug start date for those who have not permanently discontinued study drug; Any AEs leading to premature discontinuation of study drug. The most severe graded AE from all tests was counted for each participant.	Week 96
Secondary	Percentage of Participants Who Experienced Graded Treatment-Emergent Laboratory Abnormalities at Week 48	Graded treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any postbaseline visit, up to and including the date of last dose of study drug + 3 days for participants who permanently discontinued study drug or the last available date in the database snapshot for participants who were on treatment at the time of the analysis.; The most severe graded abnormality from all tests was counted for each participant.	Week 48
Secondary	Percentage of Participants Who Experienced Graded Treatment-Emergent Laboratory Abnormalities at Week 96	Graded treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any post-baseline visit, up to and including the date of last dose of study drug + 3 days for participants who permanently discontinued study drug or the last available date in the database snapshot for participants who were on treatment at the time of the analysis. The most severe graded abnormality from all tests was counted for each participant.	Week 96
Secondary	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	GFR is a measure of the rate at which blood is filtered by the kidney. Cockcroft-Gault is an equation (calculation) used to estimate GFR based on serum creatinine, weight, and gender. eGFRcg = (140 - age in years) x (body weight in kg) x (0.85 if female) divided by 72 x serum creatinine in mg/dL.; Moderate renal impairment= 30 mL/min = eGFRCG = 59 mL/min Severe renal impairment= 15 mL/min = eGFRCG < 30 mL/min Change from baseline was calculated as the value at Week 24 minus the value at Baseline.	Baseline, Week 24
Secondary	Change From Baseline in eGFRcg in Participants With Moderate or Severe Renal Impairment and Hepatically Impaired Participants at Week 48	GFR is a measure of the rate at which blood is filtered by the kidney. Cockcroft-Gault is an equation (calculation) used to estimate GFR based on serum creatinine, weight, and gender. eGFRcg = (140 - age in years) x (body weight in kg) x (0.85 if female) divided by 72 x serum creatinine in mg/dL.; Moderate renal impairment= 30 mL/min = eGFRCG = 59 mL/min Severe renal impairment= 15 mL/min = eGFRCG < 30 mL/min Change from baseline was calculated as the value at Week 48 minus the value at Baseline.	Baseline, Week 48
Secondary	Change From Baseline in eGFRcg in Participants With Moderate or Severe Renal Impairment and Hepatically Impaired Participants at Week 96	GFR is a measure of the rate at which blood is filtered by the kidney. Cockcroft-Gault is an equation (calculation) used to estimate GFR based on serum creatinine, weight, and gender. eGFRcg = (140 - age in years) x (body weight in kg) x (0.85 if female) divided by 72 x serum creatinine in mg/dL.; Moderate renal impairment= 30 mL/min = eGFRCG = 59 mL/min Severe renal impairment= 15 mL/min = eGFRCG < 30 mL/min Change from baseline was calculated as the value at Week 96 minus the value at Baseline.	Baseline, Week 96
Secondary	Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 24	Percent change = Change from baseline at a postbaseline visit/baseline * 100%.	Baseline, Week 24
Secondary	Percent Change From Baseline in Hip BMD at Week 48	Percent change = Change from baseline at a postbaseline visit/baseline * 100%.	Baseline, Week 48
Secondary	Percent Change From Baseline in Hip BMD at Week 96	Percent change = Change from baseline at a postbaseline visit/baseline * 100%.	Baseline, Week 96
Secondary	Percent Change From Baseline in Spine BMD at Week 24	Percent change = Change from baseline at a postbaseline visit/baseline * 100%.	Baseline, Week 24
Secondary	Percent Change From Baseline in Spine BMD at Week 48	Percent change = Change from baseline at a postbaseline visit/baseline * 100%.	Baseline, Week 48
Secondary	Percent Change From Baseline in Spine BMD at Week 96	Percent change = Change from baseline at a postbaseline visit/baseline * 100%.	Baseline, Week 96
Secondary	Percentage of Participants Achieving Virologic Response (Plasma HBV DNA < 20 IU/mL) at Week 48	The percentage of participants with HBV DNA < 20 IU/mL at Week 48 was determined by the Missing = Failure (M = F) approach.	Weeks 48
Secondary	Percentage of Participants Achieving Virologic Response (Plasma HBV DNA < 20 IU/mL) at Week 96	The percentage of participants with HBV DNA < 20 IU/mL at Week 48 was determined by the Missing = Failure (M = F) approach.	Weeks 96
Secondary	Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (= Lower Limit of Detection [LLOD]) at Week 24	The percentage of participants with HBV DNA < 20 IU/mL and target detected (= LLOD; i.e. 10 IU/mL) at Week 24 was determined by the M = F approach.	Week 24
Secondary	Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (= LLOD) at Week 48	The percentage of participants with HBV DNA < 20 IU/mL and target detected (= LLOD; i.e. 10 IU/mL) at Week 48 was determined by the M = F approach.	Week 48
Secondary	Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (= LLOD) at Week 96	The percentage of participants with HBV DNA < 20 IU/mL and target detected (= LLOD; i.e. 10 IU/mL) at Week 96 was determined by the M = F approach.	Week 96
Secondary	Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 24	The percentage of participants with HBV DNA < 20 IU/mL and target not detected (< LLOD; i.e. 10 IU/mL) at Week 24 was determined by the M = F approach.	Week 24
Secondary	Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 48	The percentage of participants with HBV DNA < 20 IU/mL and target not detected (< LLOD; i.e. 10 IU/mL) at Week 48 was determined by the M = F approach.	Weeks 48
Secondary	Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 96	The percentage of participants with HBV DNA < 20 IU/mL and target not detected (< LLOD; i.e. 10 IU/mL) at Week 96 was determined by the M = F approach.	Weeks 96
Secondary	Percentage of Participants With Serological Response: Loss of Hepatitis B s-Antigen (HBsAg) at Week 24	HBsAg loss was defined as HBsAg changing from positive at baseline to negative at a postbaseline. The M = F approach was used for this analysis.	Week 24
Secondary	Percentage of Participants With Serological Response: Loss of HBsAg at Week 48	HBsAg loss was defined as HBsAg changing from positive at baseline to negative at a postbaseline. The M = F approach was used for this analysis.	Week 48
Secondary	Percentage of Participants With Serological Response: Loss of HBsAg at Week 96	HBsAg loss was defined as HBsAg changing from positive at baseline to negative at a postbaseline. The M = F approach was used for this analysis.	Week 96
Secondary	Percentage of Participants With Serological Response: Seroconversion to Anti-HBs at Week 24	HBsAg seroconversion was defined as HBsAg loss and HBsAb test changing from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis.	Week 24
Secondary	Percentage of Participants With Serological Response: Seroconversion to Anti-HBs at Week 48	HBsAg seroconversion was defined as HBsAg loss and HBsAb test changing from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis.	Week 48
Secondary	Percentage of Participants With Serological Response: Seroconversion to Anti-HBs at Week 96	HBsAg seroconversion was defined as HBsAg loss and HBsAb test changing from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis.	Week 96
Secondary	Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 24	HBeAg loss was defined as HBeAg changing from positive at baseline to negative at a postbaseline. The M = F approach was used for this analysis.	Week 24
Secondary	Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 48	HBeAg loss was defined as HBeAg changing from positive at baseline to negative at a postbaseline. The M = F approach was used for this analysis.	Week 48
Secondary	Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 96	HBeAg loss was defined as HBeAg changing from positive at baseline to negative at a postbaseline. The M = F approach was used for this analysis.	Week 96
Secondary	Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 24	HBeAg seroconversion was defined as HBeAg loss and HBeAb test changing from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis.	Week 24
Secondary	Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 48	HBeAg seroconversion was defined as HBeAg loss and HBeAb test changing from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis.	Week 48
Secondary	Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 96	HBeAg seroconversion was defined as HBeAg loss and HBeAb test changing from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis.	Week 96
Secondary	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	Central laboratory ULN for ALT were as follows: = 43 U/L for males aged 18 to < 69 years and = 35 U/L for males aged = 69 years; = 34 U/L for females aged 18 to < 69 years and = 32 U/L for females aged = 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. The M = F approach was used for this analysis.	Week 24
Secondary	Percentage of Participants With Normal ALT at Week 48 by Central Laboratory and the AASLD Criteria	Central laboratory ULN for ALT were as follows: = 43 U/L for males aged 18 to < 69 years and = 35 U/L for males aged = 69 years; = 34 U/L for females aged 18 to < 69 years and = 32 U/L for females aged = 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. The M = F approach was used for this analysis.	Week 48
Secondary	Percentage of Participants With Normal ALT at Week 96 by Central Laboratory and the AASLD Criteria	Central laboratory ULN for ALT were as follows: = 43 U/L for males aged 18 to < 69 years and = 35 U/L for males aged = 69 years; = 34 U/L for females aged 18 to < 69 years and = 32 U/L for females aged = 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. The M = F approach was used for this analysis.	Week 96
Secondary	Percentage of Participants With Normalized ALT at Week 24 by Central Laboratory and the AASLD Criteria	ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Central laboratory ULN for ALT were as follows: = 43 U/L for males aged 18 to < 69 years and = 35 U/L for males aged = 69 years; = 34 U/L for females aged 18 to < 69 years and = 32 U/L for females aged = 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. The M = F approach was used for this analysis.	Week 24
Secondary	Percentage of Participants With Normalized ALT at Week 48 by Central Laboratory and the AASLD Criteria	ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Central laboratory ULN for ALT were as follows: = 43 U/L for males aged 18 to < 69 years and = 35 U/L for males aged = 69 years; = 34 U/L for females aged 18 to < 69 years and = 32 U/L for females aged = 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. The M = F approach was used for this analysis.	Week 48
Secondary	Percentage of Participants With Normalized ALT at Week 96 by Central Laboratory and the AASLD Criteria	ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Central laboratory ULN for ALT were as follows: = 43 U/L for males aged 18 to < 69 years and = 35 U/L for males aged = 69 years; = 34 U/L for females aged 18 to < 69 years and = 32 U/L for females aged = 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. The M = F approach was used for this analysis.	Week 96
Secondary	Change From Baseline in FibroTest® Score at Week 24	The FibroTest® score is used to assess liver fibrosis. Scores range from 0.00 to 1.00, with higher scores indicating a greater degree of fibrosis. Change from baseline was calculated as the value at Week 24 minus the value at Baseline.	Baseline, Week 24
Secondary	Change From Baseline in FibroTest® Score at Week 48	The FibroTest® score is used to assess liver fibrosis. Scores range from 0.00 to 1.00, with higher scores indicating a greater degree of fibrosis. Change from baseline was calculated as the value at Week 48 minus the value at Baseline.	Baseline, Week 48
Secondary	Change From Baseline in FibroTest® Score at Week 96	The FibroTest® score is used to assess liver fibrosis. Scores range from 0.00 to 1.00, with higher scores indicating a greater degree of fibrosis. Change from baseline was calculated as the value at Week 96 minus the value at Baseline.	Week 96
Secondary	Change From Baseline in Child-Pugh-Turcotte (CPT) Score in Hepatically Impaired Participants at Week 24	CPT scores grade the severity of cirrhosis and are used to determine the need for liver transplantation. Scores can range from 5 to 15, with higher scores indicating a greater severity of disease.	Baseline, Week 24
Secondary	Change From Baseline in CPT Score in Hepatically Impaired Participants at Week 48	CPT scores grade the severity of cirrhosis and are used to determine the need for liver transplantation. Scores can range from 5 to 15, with higher scores indicating a greater severity of disease.	Baseline, Week 48
Secondary	Change From Baseline in CPT Score in Hepatically Impaired Participants at Week 96	CPT scores grade the severity of cirrhosis and are used to determine the need for liver transplantation. Scores can range from 5 to 15, with higher scores indicating a greater severity of disease.	Baseline, Week 96
Secondary	Change From Baseline in Model for End-Stage Liver Disease (MELD) Score in Hepatically Impaired Participants at Week 24	MELD scores are used to assess prognosis and suitability for liver transplantation. Scores can range from 6 to 40, with higher scores indicating greater disease severity.	Baseline, Week 24
Secondary	Change From Baseline in MELD Score in Hepatically Impaired Participants at Week 48	MELD scores are used to assess prognosis and suitability for liver transplantation. Scores can range from 6 to 40, with higher scores indicating greater disease severity.	Baseline, Week 48
Secondary	Change From Baseline in MELD Score in Hepatically Impaired Participants at Week 96	MELD scores are used to assess prognosis and suitability for liver transplantation. Scores can range from 6 to 40, with higher scores indicating greater disease severity.	Baseline, Week 96