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Safety and Efficacy of Switching to Tenofovir Alafenamide (TAF) From Tenofovir Disoproxil Fumarate (TDF) and/or Other Oral Antiviral Treatment (OAV)

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ClinicalTrials.gov Identifier: NCT03180619
Recruitment Status : Active, not recruiting
First Posted : June 8, 2017
Last Update Posted : April 10, 2019
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Brief Summary:

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

This study consists of 2 Parts. Approximately 90 renally impaired participants will be enrolled in Part A and approximately 30 hepatically impaired participants will be enrolled in Part B.


Condition or disease Intervention/treatment Phase
Chronic Hepatitis B Drug: TAF Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 124 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 29, 2017
Actual Primary Completion Date : March 27, 2019
Estimated Study Completion Date : February 2021


Arm Intervention/treatment
Experimental: Part A: Renal Impairment, Part B: Hepatic Impairment
Participants will receive TAF for 96 weeks.
Drug: TAF
25 mg tablet administered orally once daily with food
Other Name: Vemlidy®




Primary Outcome Measures :
  1. Proportion of Participants Experiencing Graded Adverse Events [ Time Frame: Week 24 ]
  2. Proportion of Participants Experiencing Graded Laboratory Abnormalities [ Time Frame: Week 24 ]
  3. Proportion of Participants Achieving Virologic Response (Plasma HBV DNA < 20 IU/mL) [ Time Frame: Week 24 ]

Secondary Outcome Measures :
  1. Proportion of Participants Experiencing Graded Adverse Events at Week 48 [ Time Frame: Week 48 ]
  2. Proportion of Participants Experiencing Graded Adverse Events at Week 96 [ Time Frame: Week 96 ]
  3. Proportion of Participants Experiencing Graded Laboratory Abnormalities at Week 48 [ Time Frame: Week 48 ]
  4. Proportion of Participants Experiencing Graded Laboratory Abnormalities at Week 96 [ Time Frame: Week 96 ]
  5. 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 [ Time Frame: 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) * (body weight in kg) * (0.85 if female) divided by 72 * serum creatinine in mg/dL

  6. Change from Baseline in eGFRcg in Participants with Moderate or Severe Renal Impairment and Hepatically Impaired Participants at Week 48 [ Time Frame: Week 48 ]
  7. Change from Baseline in eGFRcg in Participants with Moderate or Severe Renal Impairment and Hepatically Impaired Participants at Week 96 [ Time Frame: Week 96 ]
  8. Percent Change from Baseline in Hip Bone Mineral Density (BMD) at Week 24 [ Time Frame: Week 24 ]
  9. Percent Change from Baseline in Hip BMD at Week 48 [ Time Frame: Week 48 ]
  10. Percent Change from Baseline in Hip BMD at Week 96 [ Time Frame: Week 96 ]
  11. Percent Change from Baseline in Spine BMD at Week 24 [ Time Frame: Week 24 ]
  12. Percent Change from Baseline in Spine BMD at Week 48 [ Time Frame: Week 48 ]
  13. Percent Change from Baseline in Spine BMD at Week 96 [ Time Frame: Week 96 ]
  14. Proportion of Participants Achieving Virologic Response (Plasma HBV DNA < 20 IU/mL) at Week 48 [ Time Frame: Weeks 48 ]
  15. Proportion of Participants Achieving Virologic Response (Plasma HBV DNA < 20 IU/mL) at Week 96 [ Time Frame: Weeks 96 ]
  16. Proportion of Participants with Plasma HBV DNA < 20 IU/mL and Target Detected (i.e. < Lower Limit of Detection (LLOD)) at Week 24 [ Time Frame: Week 24 ]
  17. Proportion of Participants with Plasma HBV DNA < 20 IU/mL and Target Detected (i.e. < LLOD) at Week 48 [ Time Frame: Week 48 ]
  18. Proportion of Participants with Plasma HBV DNA < 20 IU/mL and Target Detected (i.e. < LLOD) at Week 96 [ Time Frame: Week 96 ]
  19. Proportion of Participants with Plasma HBV DNA < 20 IU/mL and Target Not Detected (i.e. < LLOD) at Week 24 [ Time Frame: Week 24 ]
  20. Proportion of Participants with Plasma HBV DNA < 20 IU/mL and Target Not Detected (i.e. < LLOD) at Week 48 [ Time Frame: Weeks 48 ]
  21. Proportion of Participants with Plasma HBV DNA < 20 IU/mL and Target Not Detected (i.e. < LLOD) at Week 96 [ Time Frame: Weeks 96 ]
  22. Proportion of Participants with Serological Response: Loss of Hepatitis s-Antigen (HBsAg) and Seroconversion to Anti-HBs in Hepatitis B e-Antigen (HBeAg)-Positive Participants at Week 24 [ Time Frame: Week 24 ]
  23. Proportion of Participants with Serological Response: Loss of HBsAg and Seroconversion to Anti-HBs in HBeAg-Positive Participants at Week 48 [ Time Frame: Week 48 ]
  24. Proportion of Participants with Serological Response: Loss of HBsAg and Seroconversion to Anti-HBs in HBeAg-Positive Participants at Week 96 [ Time Frame: Week 96 ]
  25. Proportion of Participants with Serological Response: Loss of HBeAg and Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 24 [ Time Frame: Week 24 ]
  26. Proportion of Participants with Serological Response: Loss of HBeAg and Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 48 [ Time Frame: Week 48 ]
  27. Proportion of Participants with Serological Response: Loss of HBeAg and Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 96 [ Time Frame: Week 96 ]
  28. Proportion of Participants with Normal Alanine Aminotransferase (ALT) at Week 24 [ Time Frame: Week 24 ]
  29. Proportion of Participants with Normal ALT at Week 48 [ Time Frame: Week 48 ]
  30. Proportion of Participants with Normal ALT at Week 96 [ Time Frame: Week 96 ]
  31. Proportion of Participants with Normalized ALT at Week 24 [ Time Frame: Week 24 ]
  32. Proportion of Participants with Normalized ALT at Week 48 [ Time Frame: Week 48 ]
  33. Proportion of Participants with Normalized ALT at Week 96 [ Time Frame: Week 96 ]
  34. Change in Fibrosis as Assessed by FibroTest® at Week 24 [ Time Frame: Week 24 ]
  35. Change in Fibrosis as Assessed by FibroTest® at Week 48 [ Time Frame: Week 48 ]
  36. Change in Fibrosis as Assessed by FibroTest® at Week 96 [ Time Frame: Week 96 ]
  37. Change from Baseline in Child-Pugh-Turcotte (CPT) Score in Hepatically Impaired Participants at Week 24 [ Time Frame: Week 24 ]
    CPT scores grade the severity of cirrhosis and are used to determine the need for liver transplantation.

  38. Change from Baseline in CPT Score in Hepatically Impaired Participants at Week 48 [ Time Frame: Week 48 ]
  39. Change from Baseline in CPT Score in Hepatically Impaired Participants at Week 96 [ Time Frame: Week 96 ]
  40. Change from Baseline in Model for End-Stage Liver Disease (MELD) Score in Hepatically Impaired Participants at Week 24 [ Time Frame: Week 24 ]
    MELD scores are used to assess prognosis and suitability for liver transplantation.

  41. Change from Baseline in MELD Score in Hepatically Impaired Participants at Week 48 [ Time Frame: Week 48 ]
  42. Change from Baseline in MELD Score in Hepatically Impaired Participants at Week 96 [ Time Frame: Week 96 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

All Participants (Parts A and B):

  • Ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures
  • Adult male or non-pregnant female individuals
  • Documented evidence of chronic HBV infection
  • ALT ≤ 10 × upper limit of normal (ULN)

Part A Only (renal impairment):

  • Maintained on TDF and/or other OAV treatment(s) for chronic hepatitis B (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
  • Moderate renal impairment (30 mL/min ≤ 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
  • 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 HCV, HIV, or 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 g/dL
    • Absolute neutrophil count < 750/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
  • 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03180619


Locations
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United States, California
Coalition of Inclusive Medicine
Los Angeles, California, United States, 90020
Silicon Valley Research Institute, Inc
San Jose, California, United States, 95116
United States, Michigan
Henry Ford Health System
Detroit, Michigan, United States, 48202
United States, Washington
Harborview Medical Center
Seattle, Washington, United States, 98104
Canada
University of Calgary Liver Unit
Calgary, Canada, T2N4Z6
Centre de Recherche du Centre Hospitalier de l'Universite de Montreal
Montreal, Canada, H2X 3J4
University Health Network,Toronto general Hospital,Toronto centre for liver disease
Toronto, Canada, M5G 2C4
Toronto Liver Centre
Toronto, Canada, M6H 3M1
(G.I.R.I.) GI Research Institute
Vancouver, Canada, V6Z 2K5
Hong Kong
Prince of Wales Hospital
Shatin, NT, Hong Kong
Princess Margaret Hospital
Kowloon, Hong Kong
Alice Ho Miu Ling Nethersole Hospital
Tai Po, Hong Kong
Italy
U.O. Medicina Generale Epatologia IRCCS Humanitas Centro di Ricerca Traslazionale in Epatologia
Rozzano, Milan, Italy
Dipartimento di Scienze Mediche e Chirurgiche (DIMEC) AOU Policlinico S.Orsola-Malpighi di Bologna
Bologna, Italy, 40138
UOC Gastroenterol-Epatol.-Fondazione IRCCS Ca Granda
Milan, Italy, 20122
Korea, Republic of
Dong-A University Hospital
Busan, Korea, Republic of, 49201
Pusan National University Hospital
Busan, Korea, Republic of, 49241
Asan Medical Center
Seoul, Korea, Republic of, 05505
Yonsei University Health System, Severance Hospital
Seoul, Korea, Republic of, 120-752
New Zealand
Auckland Clinical Studies
Grafton, Auckland, New Zealand, 1010
Taiwan
Changhua Christian Hospital
Changhua, Taiwan, 500
Ditmanson Medical Foundation Chia-Yi Christian Hospital
Chiayi City, Taiwan, 60002
Kaohsiung Chang Gung Memorial Hospital
Kaohsiung City, Taiwan, 83301
Kaohsiung Medical University Chung-Ho Memorial Hospital
Kaohsiung, Taiwan, 807
Taichung Veterans Genl Hosp
Taichung, Taiwan, 40705
National Taiwan University Hospital
Taipei, Taiwan, 10001
Veterans General Hospital-Taipei
Taipei, Taiwan, 11217
Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital
Taoyuan City, Taiwan, 333
United Kingdom
King's College Hospital NHS Foundation Trust
London, United Kingdom
Nottingham University Hospital
Nottingham, United Kingdom, NG7 2UH
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences

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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT03180619     History of Changes
Other Study ID Numbers: GS-US-320-4035
2016-004625-16 ( EudraCT Number )
First Posted: June 8, 2017    Key Record Dates
Last Update Posted: April 10, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Hepatitis
Hepatitis, Chronic
Hepatitis B
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepadnaviridae Infections
DNA Virus Infections
Virus Diseases
Hepatitis, Viral, Human
Tenofovir
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents