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Study of Tenofovir Alafenamide (TAF) in Children and Teen Participants With Chronic Hepatitis B Virus Infection

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02932150
Recruitment Status : Recruiting
First Posted : October 13, 2016
Last Update Posted : March 22, 2023
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Study Description
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Brief Summary:
The goals of this clinical study are to compare the effectiveness, safety and tolerability of study drug, tenofovir alafenamide (TAF), versus placebo in teens and children with CHB and to learn more about the dosing levels in children.

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

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind Evaluation of the Pharmacokinetics, Safety, and Antiviral Efficacy of Tenofovir Alafenamide (TAF) in Children and Adolescent Subjects With Chronic Hepatitis B Virus Infection
Actual Study Start Date : November 2016
Estimated Primary Completion Date : August 2025
Estimated Study Completion Date : October 2029

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: TAF (Cohort 1)
Participants (12 to < 18 years) weighing ≥ 35 kg will receive TAF 25 mg tablet for 24 weeks
 Drug: TAF
Administered orally once daily
Placebo Comparator: Placebo (Cohort 1)
Participants (12 to < 18 years) weighing ≥ 35 kg will receive placebo tablet for 24 weeks
 Drug: Placebo
Administered orally once daily
Experimental: TAF (Cohort 2 Group 1)
Participants (6 to < 12 years) weighing ≥ 25 kg will receive TAF 25 mg tablet for 24 weeks
 Drug: TAF
Administered orally once daily
Experimental: TAF (Cohort 2 Group 2)
Participants (6 to < 12 years) weighing ≥ 14 kg to < 25 kg will receive TAF 15 mg oral granules for 24 weeks
 Drug: TAF
Administered orally once daily
Experimental: TAF (Cohort 2 Group 3)

Participants (2 to < 6 years) will receive TAF for 24 weeks as follows:

  • weight ≥ 10 kg to < 14 kg (7.5 mg oral granules)
  • weight ≥ 14 kg to < 25 kg (15 mg oral granules)
 Drug: TAF
Administered orally once daily
Placebo Comparator: Cohort 2 Placebo
Participants will receive matching placebo of TAF (tablet or oral granules) for 24 weeks.
 Drug: Placebo
Administered orally once daily
Experimental: Open-Label TAF
Following 24 weeks of blinded randomized treatment, participants will be eligible to participate in an open-label extension phase to receive TAF for an additional 216 weeks.
 Drug: TAF
Administered orally once daily


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Serious Adverse Events (SAEs) at Week 24 [ Time Frame: Week 24 ]
  2. Incidence of Treatment-Emergent Adverse Events (AEs) at Week 24 [ Time Frame: Week 24 ]
  3. Percentage of participants with plasma HBV DNA < 20 IU/mL at Week 24 [ Time Frame: Week 24 ]
  4. PK Parameter: AUCtau of TAF for participants from Cohort 2 Part A [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 or 12 ]
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).


Secondary Outcome Measures :
  1. Percentage of participants experiencing graded laboratory abnormalities [ Time Frame: Weeks 24, 48, 96, and 240 ]
  2. Development as measured by Tanner Stage Assessment [ Time Frame: Weeks 24, 48, 96, and 240 ]
  3. Percentage change from baseline in bone mineral density (BMD) of whole body (minus head) by dual imaging x-ray absorptiometry (DXA) [ Time Frame: Baseline; Weeks 24, 48, 96, and 240 ]
  4. Percentage change from baseline in BMD of lumbar spine by DXA [ Time Frame: Baseline; Weeks 24, 48, 96, and 240 ]
  5. Change from baseline in serum creatinine [ Time Frame: Baseline; Weeks 4, 8, 12, 24, 48, 96, and 240 ]
  6. Change from baseline in estimated glomerular filtration rate (eGFR) by the Schwartz formula [ Time Frame: Baseline; Weeks 24, 48, 96, and 240 ]
  7. Incidence of treatment-emergent SAEs in participants treated with TAF or placebo for 24 weeks followed by open-label TAF at Weeks 48, 96 and 240 [ Time Frame: Weeks 48, 96, and 240 ]
  8. Incidence of treatment-emergentAEs in participants treated with TAF or placebo for 24 weeks followed by open-label TAF at Weeks 48, 96 and 240 [ Time Frame: Weeks 48, 96, and 240 ]
  9. Change from baseline in retinol-binding protein to creatine ratio at Weeks 4, 8, 12, 24, and 48 [ Time Frame: Baseline; Weeks 4, 8, 12, 24, and 48 ]
  10. Change from baseline in beta-2-microglobulin to creatine ratio at Weeks 4, 8, 12, 24, and 48 [ Time Frame: Baseline; Weeks 4, 8, 12, 24, and 48 ]
  11. Change from baseline in glucose at Weeks 4, 8, 12, 24, and 48 [ Time Frame: Baseline; Weeks 4, 8, 12, 24, and 48 ]
  12. Change from baseline in phosphate at Weeks 4, 8, 12, 24, and 48 [ Time Frame: Baseline; Weeks 4, 8, 12, 24, and 48 ]
  13. Percentage of participants with plasma HBV DNA < 20 IU/mL at Weeks 48, 96, and 240 [ Time Frame: Weeks 48, 96, and 240 ]
  14. Proportion of participants with plasma HBV DNA < 20 IU/mL (target not detected) at Weeks 24, 48, 96, and 240 [ Time Frame: Weeks 24, 48, 96, and 240 ]
  15. Percentage of participants with alanine aminotransferase (ALT) normalization at Weeks 24, 48, 96, and 240 [ Time Frame: Weeks 24, 48, 96, and 240 ]
  16. Composite endpoint of percentage of participants with ALT normalization and HBV DNA < 20 IU/mL at Weeks 24, 48, 96 and 240 [ Time Frame: Weeks 24, 48, 96 and 240 ]
  17. Change from baseline in fibrosis as assessed by FibroTest at Weeks 24, 48, 96, and 240 [ Time Frame: Baseline; Weeks 24, 48, 96, and 240 ]
  18. Percentage of participants with hepatitis B e antigen (HBeAg) loss and seroconversion to anti-HBe (HBeAG-positive participants only) at Weeks 24, 48, 96, and 240 [ Time Frame: Weeks 24, 48, 96, and 240 ]
  19. Percentage of participants with composite endpoint of HBeAg seroconversion and HBV DNA < 20 IU/mL at Weeks 24, 48, 96, and 240 (in HBeAg-positive participants only) [ Time Frame: Weeks 24, 48, 96, and 240 ]
  20. Percentage of participants with composite endpoint of ALT normalization, HBeAg seroconversion and HBV DNA < 20 IU/mL at Weeks 24, 48, 96, and 240 (in HBeAg-positive participants only) [ Time Frame: Weeks 24, 48, 96, and 240 ]
  21. Percentage of participants with hepatitis B surface antigen (HBsAg) loss and seroconversion to anti-HBs at Weeks 24, 48, 96, and 240 [ Time Frame: Weeks 24, 48, 96, and 240 ]
  22. Percentage of participants with qHBsAg log10 IU/mL at Weeks 24, 48, 96, and 240 [ Time Frame: Weeks 24, 48, 96, and 240 ]
  23. Incidence of resistance mutations at Weeks 24, 48, 96, and 240 [ Time Frame: Weeks 24, 48, 96, and 240 ]
  24. Acceptability of study drug [ Time Frame: Baseline; Weeks 4, 24, and 36 ]
    To assess acceptability of study drug, the investigator will ask participants if they were able to taste the medication on a scale of 1-5, how much they like the taste of the medication (1 = dislike very much to 5 = like very much).

  25. Palatability of study drug [ Time Frame: Baseline; Weeks 4, 24, and 36 ]
    To assess palatability of study drug, the investigator will ask participants on a scale of 0-3 how easy it was to swallow the pill (0 = poor to 3 = excellent).

  26. PK Parameter: AUCtau of tenofovir (TFV) [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2) ]
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

  27. PK Parameter: AUClast of TAF and TFV [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2) ]
    AUClast is defined as the concentration of drug from time zero to the last observable concentration.

  28. PK Parameter: Ctau of TFV [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2) ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.

  29. PK Parameter: Cmax of TAF and TFV [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2) ]
    Cmax is defined as the maximum observed concentration of drug.

  30. PK Parameter: Clast of TAF and TFV [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2) ]
    Clast is defined as the last observable concentration of drug.

  31. PK Parameter: Tmax of TAF and TFV [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2) ]
    Tmax is defined as the time of Cmax (the maximum concentration of drug).

  32. PK Parameter: Tlast of TAF and TFV [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2) ]
    Tlast is defined as the time (observed time point) of Clast.

  33. PK Parameter: λz of TAF and TFV [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2) ]
    λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug.

  34. PK Parameter: CL/F of TAF and TFV [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2) ]
    CL/F is defined as the apparent oral clearance following administration of the drug.

  35. PK Parameter: Vz/F of TAF and TFV [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2) ]
    Vz/F is defined as the apparent volume of distribution of the drug.

  36. PK Parameter: t1/2 of TAF and TFV [ Time Frame: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2) ]
    t1/2 is defined as the estimate of the terminal elimination half-life of the drug.


Eligibility Criteria
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Ages Eligible for Study:   2 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion criteria:

  • Males and non-pregnant, non-lactating females

  • Weight at screening as follows:

    • Cohort 1 = ≥ 35 kg (≥ 77 lbs)
    • Cohort 2 Group 1 = ≥ 25 kg (≥ 55 lbs)
    • Cohort 2 Group 2 = ≥ 14 kg to < 25 kg (≥ 30 lbs to <55 lbs)

    • Cohort 2 Group 3 = ≥ 10 kg to < 14 kg (≥ 22 lbs to < 30 lbs) or

      • 14 kg to < 25 kg (≥ 30 lbs to < 55 lbs)
  • Willing and able to provide written informed consent/assent (child and parent/legal guardian)
  • Documented evidence of CHB (eg, HBsAg-positive for ≥ 6 months)

  • HBeAg-positive, or HBeAg-negative, chronic HBV infection with all of the following:

    • Screening HBV DNA ≥ 2 × 10^4 IU/mL
    • Screening serum ALT > 45 U/L (> 1.5 × ULN: 30 U/L) and ≤ 10 × ULN (by central laboratory range)
  • Treatment-naive or treatment-experienced will be eligible for enrollment.
  • Estimated creatinine clearance (CLCr) ≥ 80 mL/min/1.73m^2 (using the Schwartz formula)
  • Normal ECG

Key Exclusion criteria:

  • Females who are pregnant or breastfeeding
  • Males and females of reproductive potential who are unwilling to use an "effective", protocol-specified method(s) of contraception during the study.
  • Coinfection with hepatitis C virus (HCV), HIV, or hepatitis D virus (HDV)
  • Evidence of hepatocellular carcinoma (Note: if screening alpha-fetoprotein (AFP) is < 50 ng/mL no imaging study is needed; however, if the screening AFP is > 50 ng/mL an imaging study is required)
  • Any history of, or current evidence of, clinical hepatic decompensation
  • Abnormal hematological and biochemical parameters
  • Chronic liver disease of non-HBV etiology (e.g., hemochromatosis, alpha-1 antitrypsin deficiency, cholangitis)
  • Received solid organ or bone marrow transplant
  • Currently receiving therapy with immunomodulators (eg, corticosteroids), or immunosuppressants
  • Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the Investigator
  • Malignancy within the 5 years prior to screening. Individuals under evaluation for possible malignancy are not eligible.
  • Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance.

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

Contacts and Locations
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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): NCT02932150


Contacts
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Contact: Gilead Study Team GS-US-320-1092@gilead.com

Locations
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Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
More Information
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Additional Information:

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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02932150    
Other Study ID Numbers: GS-US-320-1092
2016-000785-37 ( EudraCT Number )
First Posted: October 13, 2016    Key Record Dates
Last Update Posted: March 22, 2023
Last Verified: March 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gilead Sciences:
CHB
HBV
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis B
Hepatitis B, Chronic
Virus Diseases
Herpesviridae Infections
Hepatitis
Hepatitis, Chronic
Infections
Liver Diseases
 Digestive System Diseases
Hepatitis, Viral, Human
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Blood-Borne Infections
Communicable Diseases
Hepadnaviridae Infections
DNA Virus Infections