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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: TAF
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAF (Cohort 1)<br>Participants (12 to < 18 years) weighing ≥ 35 kg will receive TAF 25 mg tablet for 24 weeks | Drug: TAF<br>* Administered orally once daily<br>|
| Placebo Comparator: Placebo (Cohort 1)<br>Participants (12 to < 18 years) weighing ≥ 35 kg will receive placebo tablet for 24 weeks | Drug: Placebo<br>* Administered orally once daily<br>|
| Experimental: TAF (Cohort 2 Group 1)<br>Participants (6 to < 12 years) weighing ≥ 25 kg will receive TAF 25 mg tablet for 24 weeks | Drug: TAF<br>* Administered orally once daily<br>|
| Experimental: TAF (Cohort 2 Group 2)<br>Participants (6 to < 12 years) weighing ≥ 14 kg to < 25 kg will receive TAF 15 mg oral granules for 24 weeks | Drug: TAF<br>* Administered orally once daily<br>|
| Experimental: TAF (Cohort 2 Group 3)<br>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<br>* Administered orally once daily<br>|
| Placebo Comparator: Cohort 2 Placebo<br>Participants will receive matching placebo of TAF (tablet or oral granules) for 24 weeks. | Drug: Placebo<br>* Administered orally once daily<br>|
| Experimental: Open-Label TAF<br>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<br>* Administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | Weeks 48, 96, and 240 | 
| 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 |  | Weeks 48, 96, and 240 | 
| Change from baseline in retinol-binding protein to creatine ratio at Weeks 4, 8, 12, 24, and 48 |  | Baseline; Weeks 4, 8, 12, 24, and 48 | 
| Change from baseline in beta-2-microglobulin to creatine ratio at Weeks 4, 8, 12, 24, and 48 |  | Baseline; Weeks 4, 8, 12, 24, and 48 | 
| Change from baseline in glucose at Weeks 4, 8, 12, 24, and 48 |  | Baseline; Weeks 4, 8, 12, 24, and 48 | 
| Change from baseline in phosphate at Weeks 4, 8, 12, 24, and 48 |  | Baseline; Weeks 4, 8, 12, 24, and 48 | 
| Percentage of participants with plasma HBV DNA < 20 IU/mL at Weeks 48, 96, and 240 |  | Weeks 48, 96, and 240 | 
| Proportion of participants with plasma HBV DNA < 20 IU/mL (target not detected) at Weeks 24, 48, 96, and 240 |  | Weeks 24, 48, 96, and 240 | 
| Percentage of participants with alanine aminotransferase (ALT) normalization at Weeks 24, 48, 96, and 240 |  | Weeks 24, 48, 96, and 240 | 
| Composite endpoint of percentage of participants with ALT normalization and HBV DNA < 20 IU/mL at Weeks 24, 48, 96 and 240 |  | Weeks 24, 48, 96 and 240 | 
| Change from baseline in fibrosis as assessed by FibroTest at Weeks 24, 48, 96, and 240 |  | Baseline; Weeks 24, 48, 96, and 240 | 
| 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 |  | Weeks 24, 48, 96, and 240 | 
| 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) |  | Weeks 24, 48, 96, and 240 | 
| 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) |  | Weeks 24, 48, 96, and 240 | 
| Percentage of participants with hepatitis B surface antigen (HBsAg) loss and seroconversion to anti-HBs at Weeks 24, 48, 96, and 240 |  | Weeks 24, 48, 96, and 240 | 
| Percentage of participants with qHBsAg log10 IU/mL at Weeks 24, 48, 96, and 240 |  | Weeks 24, 48, 96, and 240 | 
| Incidence of resistance mutations at Weeks 24, 48, 96, and 240 |  | Weeks 24, 48, 96, and 240 | 
| Acceptability of study drug | 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). | Baseline; Weeks 4, 24, and 36 | 
| Palatability of study drug | 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). | Baseline; Weeks 4, 24, and 36 | 
| PK Parameter: AUCtau of tenofovir (TFV) | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | 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) | 
| PK Parameter: AUClast of TAF and TFV | AUClast is defined as the concentration of drug from time zero to the last observable concentration. | 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) | 
| PK Parameter: Ctau of TFV | Ctau is defined as the observed drug concentration at the end of the dosing interval. | 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) | 
| PK Parameter: Cmax of TAF and TFV | Cmax is defined as the maximum observed concentration of drug. | 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) | 
| PK Parameter: Clast of TAF and TFV | Clast is defined as the last observable concentration of drug. | 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) | 
| PK Parameter: Tmax of TAF and TFV | Tmax is defined as the time of Cmax (the maximum concentration of drug). | 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) | 
| PK Parameter: Tlast of TAF and TFV | Tlast is defined as the time (observed time point) of Clast. | 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) | 
| PK Parameter: λz of TAF and TFV | 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. | 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) | 
| PK Parameter: CL/F of TAF and TFV | CL/F is defined as the apparent oral clearance following administration of the drug. | 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) | 
| PK Parameter: Vz/F of TAF and TFV | Vz/F is defined as the apparent volume of distribution of the drug. | 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) | 
| PK Parameter: t1/2 of TAF and TFV | t1/2 is defined as the estimate of the terminal elimination half-life of the drug. | 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) | 
| Percentage of participants experiencing graded laboratory abnormalities |  | Weeks 24, 48, 96, and 240 | 
| Development as measured by Tanner Stage Assessment |  | Weeks 24, 48, 96, and 240 | 
| Percentage change from baseline in bone mineral density (BMD) of whole body (minus head) by dual imaging x-ray absorptiometry (DXA) |  | Baseline; Weeks 24, 48, 96, and 240 | 
| Percentage change from baseline in BMD of lumbar spine by DXA |  | Baseline; Weeks 24, 48, 96, and 240 | 
| Change from baseline in serum creatinine |  | Baseline; Weeks 4, 8, 12, 24, 48, 96, and 240 | 
| Change from baseline in estimated glomerular filtration rate (eGFR) by the Schwartz formula |  | Baseline; Weeks 24, 48, 96, and 240 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CHB, HBV