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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03180619
Recruitment Status : Active, not recruiting
First Posted : June 8, 2017
Results First Posted : April 9, 2020
Last Update Posted : April 9, 2020
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
Allocation: Non-Randomized
Intervention Model: Parallel 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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Part A (Renal Impairment): Moderate or Severe Renal Impairment
Virologically suppressed participants with chronic hepatitis B (CHB) and moderate or severe renal impairment taking TDF, a TDF-containing anti-hepatitis B virus (HBV) regimen, or other OAVs, will switch to TAF.
Drug: TAF
25 mg tablet will be administered orally once daily for 96 weeks with food
Other Name: Vemlidy®

Experimental: Part A (Renal Impairment): End Stage Renal Disease
Virologically suppressed participants with CHB and end stage renal disease taking TDF, a TDF-containing anti-HBV regimen, or OAVs, will switch to TAF.
Drug: TAF
25 mg tablet will be administered orally once daily for 96 weeks with food
Other Name: Vemlidy®

Experimental: Part B: Hepatic Impairment
Virologically suppressed participants with CHB and moderate or severe hepatic impairment taking TDF, a TDF-containing anti-HBV regimen, or OAVs, will switch to TAF.
Drug: TAF
25 mg tablet will be administered orally once daily for 96 weeks with food
Other Name: Vemlidy®




Primary Outcome Measures :
  1. Percentage of Participants Achieving Virologic Response (Plasma Hepatitis B Virus [HBV] Deoxyribonucleic Acid [DNA] < 20 IU/mL) at Week 24 [ Time Frame: Week 24 ]
    The percentage of participants with HBV DNA < 20 IU/mL at Week 24 was determined by the Missing = Failure (M = F) approach.

  2. Percentage of Participants Who Experienced Graded Treatment-Emergent Adverse Events (AEs) at Week 24 [ Time Frame: 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.


  3. Percentage of Participants Who Experienced Graded Treatment-Emergent Laboratory Abnormalities at Week 24 [ Time Frame: 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.



Secondary Outcome Measures :
  1. Percentage of Participants Who Experienced Graded Treatment-Emergent AEs at Week 48 [ Time Frame: Week 48 ]
  2. Percentage of Participants Who Experienced Graded Treatment-Emergent AEs at Week 96 [ Time Frame: Week 96 ]
  3. Percentage of Participants Who Experienced Graded Treatment-Emergent Laboratory Abnormalities at Week 48 [ Time Frame: Week 48 ]
  4. Percentage of Participants Who Experienced Graded Treatment-Emergent 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: Baseline, 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.


  6. Change From Baseline in eGFRcg in Participants With Moderate or Severe Renal Impairment and Hepatically Impaired Participants at Week 48 [ Time Frame: Baseline, 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: Baseline, Week 96 ]
  8. Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 24 [ Time Frame: Baseline, Week 24 ]
    Percent change = Change from baseline at a postbaseline visit/baseline * 100%.

  9. Percent Change From Baseline in Hip BMD at Week 48 [ Time Frame: Baseline, Week 48 ]
  10. Percent Change From Baseline in Hip BMD at Week 96 [ Time Frame: Baseline, Week 96 ]
  11. Percent Change From Baseline in Spine BMD at Week 24 [ Time Frame: Baseline, Week 24 ]
    Percent change = Change from baseline at a postbaseline visit/baseline * 100%.

  12. Percent Change From Baseline in Spine BMD at Week 48 [ Time Frame: Baseline, Week 48 ]
  13. Percent Change From Baseline in Spine BMD at Week 96 [ Time Frame: Baseline, Week 96 ]
  14. Percentage of Participants Achieving Virologic Response (Plasma HBV DNA < 20 IU/mL) at Week 48 [ Time Frame: Weeks 48 ]
  15. Percentage of Participants Achieving Virologic Response (Plasma HBV DNA < 20 IU/mL) at Week 96 [ Time Frame: Weeks 96 ]
  16. Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (≥ Lower Limit of Detection [LLOD]) at Week 24 [ Time Frame: 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.

  17. Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (≥ LLOD) at Week 48 [ Time Frame: Week 48 ]
  18. Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (≥ LLOD) at Week 96 [ Time Frame: Week 96 ]
  19. Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 24 [ Time Frame: 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.

  20. Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 48 [ Time Frame: Weeks 48 ]
  21. Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 96 [ Time Frame: Weeks 96 ]
  22. Percentage of Participants With Serological Response: Loss of Hepatitis s-Antigen (HBsAg) in Hepatitis B e-Antigen (HBeAg)-Positive Participants at Week 24 [ Time Frame: 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.

  23. Percentage of Participants With Serological Response: Loss of HBsAg in HBeAg-Positive Participants at Week 48 [ Time Frame: Week 48 ]
  24. Percentage of Participants With Serological Response: Loss of HBsAg in HBeAg-Positive Participants at Week 96 [ Time Frame: Week 96 ]
  25. Percentage of Participants With Serological Response: Seroconversion to Anti-HBs in HBeAg-Positive Participants at Week 24 [ Time Frame: 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.

  26. Percentage of Participants With Serological Response: Seroconversion to Anti-HBs in HBeAg-Positive Participants at Week 48 [ Time Frame: Week 48 ]
  27. Percentage of Participants With Serological Response: Seroconversion to Anti-HBs in HBeAg-Positive Participants at Week 96 [ Time Frame: Week 96 ]
  28. Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 24 [ Time Frame: 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.

  29. Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 48 [ Time Frame: Week 48 ]
  30. Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 96 [ Time Frame: Week 96 ]
  31. Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 24 [ Time Frame: 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.

  32. Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 48 [ Time Frame: Week 48 ]
  33. Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 96 [ Time Frame: Week 96 ]
  34. 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 [ Time Frame: Week 24 ]
    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.

  35. Percentage of Participants With Normal ALT at Week 48 by Central Laboratory and the AASLD Criteria [ Time Frame: Week 48 ]
  36. Percentage of Participants With Normal ALT at Week 96 by Central Laboratory and the AASLD Criteria [ Time Frame: Week 96 ]
  37. Percentage of Participants With Normalized ALT at Week 24 by Central Laboratory and the AASLD Criteria [ Time Frame: Week 24 ]
    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.

  38. Percentage of Participants With Normalized ALT at Week 48 by Central Laboratory and the AASLD Criteria [ Time Frame: Week 48 ]
  39. Percentage of Participants With Normalized ALT at Week 96 by Central Laboratory and the AASLD Criteria [ Time Frame: Week 96 ]
  40. Change From Baseline in FibroTest® Score at Week 24 [ Time Frame: Baseline, 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.

  41. Change From Baseline in FibroTest® Score at Week 48 [ Time Frame: Baseline, Week 48 ]
  42. Change From Baseline in FibroTest® Score at Week 96 [ Time Frame: Week 96 ]
  43. Change From Baseline in Child-Pugh-Turcotte (CPT) Score in Hepatically Impaired Participants at Week 24 [ Time Frame: Baseline, 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.

  44. Change From Baseline in CPT Score in Hepatically Impaired Participants at Week 48 [ Time Frame: Baseline, Week 48 ]
  45. Change From Baseline in CPT Score in Hepatically Impaired Participants at Week 96 [ Time Frame: Baseline, Week 96 ]
  46. Change From Baseline in Model for End-Stage Liver Disease (MELD) Score in Hepatically Impaired Participants at Week 24 [ Time Frame: Baseline, 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.

  47. Change From Baseline in MELD Score in Hepatically Impaired Participants at Week 48 [ Time Frame: Baseline, Week 48 ]
  48. Change From Baseline in MELD Score in Hepatically Impaired Participants at Week 96 [ Time Frame: Baseline, 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):

  • 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 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 ≤ 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 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
  • 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.


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
Show Show 30 study locations
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
  Study Documents (Full-Text)

Documents provided by Gilead Sciences:
Study Protocol  [PDF] May 23, 2017
Statistical Analysis Plan  [PDF] May 9, 2019

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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT03180619    
Other Study ID Numbers: GS-US-320-4035
2016-004625-16 ( EudraCT Number )
First Posted: June 8, 2017    Key Record Dates
Results First Posted: April 9, 2020
Last Update Posted: April 9, 2020
Last Verified: March 2020

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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 B
Hepatitis B, Chronic
Hepatitis
Hepatitis, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Hepadnaviridae Infections
DNA Virus Infections