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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Gilead Sciences Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

16 May 2018 → ongoing

Decision date (initial)

2023-08-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Gilead Sciences Inc.

External identifiers

EU CT number

2023-506143-42-00

EudraCT number

2016-000785-37

ClinicalTrials.gov

NCT02932150

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

Cohort 1 (adolescents 12 to < 18 years, ≥ 35 kg):
-To evaluate the safety, tolerability, and antiviral activity (hepatitis B virus [HBV] DNA < 20 IU/mL) of tenofovir alafenamide (TAF) 25 mg once daily versus placebo at Week 24 in adolescent subjects with chronic hepatitis B (CHB)

Cohort 2 (children 2 to < 12 years of age):
Part A:
- To evaluate the steady-state pharmacokinetics (PK) of TAF and TAF-metabolite, tenofovir (TFV), and confirm the dose of TAF given once daily in children with CHB
Part B:
- To evaluate the safety, efficacy, and tolerability of TAF given once daily at Week 24 in children with CHB
- To evaluate the antiviral activity (HBV DNA < 20 IU/mL) of TAF given once daily versus placebo at Week 24 in children with CHB

Secondary objectives 8

1. To evaluate the open-label safety and tolerability of TAF given once daily at Weeks 48, 96, and 240 in adolescents and children with CHB
2. To evaluate the antiviral activity (HBV DNA < 20 IU/mL) of open-label TAF at Weeks 48, 96, and 240 in adolescents and children with CHB
3. To evaluate the serologic response (loss of hepatitis B e antigen [HBeAg] and seroconversion to anti-HBe, and loss of hepatitis B surface antigen [HBsAg] and seroconversion to anti-HBs) of TAF versus placebo at Week 24, and of open-label TAF at Weeks 48, 96, and 240 in adolescents and children with CHB
4. To evaluate the biochemical response (alanine aminotransferase [ALT] normalization) of TAF versus placebo at Week 24, and of open-label TAF at Weeks 48, 96, and 240 in adolescents and children with CHB
5. To evaluate the change in fibrosis as assessed by FibroTest® of TAF versus placebo at Week 24, and of open-label TAF at Weeks 48, 96, and 240 in adolescents and children with CHB
6. To evaluate the palatability and acceptability of TAF formulation at baseline and at Weeks 4, 24, and 36 in adolescents and children with CHB
7. To evaluate the incidence of drug resistance mutations associated with TAF at Weeks 24, 48, 96, and 240 in adolescents and children with CHB
8. To evaluate the steady-state PK of TAF and TFV following administration of TAF 25 mg once daily in adolescents with CHB

Conditions and MedDRA coding

Chronic Hepatitis B

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-001584-PIP01-13

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Ages Eligible for Study: 2 Years to 17 Years (Child)
2. Males and non-pregnant, non-lactating females
3. 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)
4. Willing and able to provide written informed consent/assent (child and parent/legal guardian)
5. Documented evidence of CHB (eg, HBsAg-positive for ≥ 6 months)
6. 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)
7. Treatment-naive or treatment-experienced will be eligible for enrollment.
8. Estimated creatinine clearance (CLCr) ≥ 80 mL/min/1.73m^2 (using the Schwartz formula)
9. Normal ECG
10. Note: Other protocol defined Inclusion criteria may apply.

Exclusion criteria 13

1. Females who are pregnant or breastfeeding
2. Males and females of reproductive potential who are unwilling to use an "effective", protocol-specified method(s) of contraception during the study.
3. Coinfection with hepatitis C virus (HCV), HIV, or hepatitis D virus (HDV)
4. 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)
5. Any history of, or current evidence of, clinical hepatic decompensation
6. Abnormal hematological and biochemical parameters
7. Chronic liver disease of non-HBV etiology (e.g., hemochromatosis, alpha-1 antitrypsin deficiency, cholangitis)
8. Received solid organ or bone marrow transplant
9. Currently receiving therapy with immunomodulators (eg, corticosteroids), or immunosuppressants
10. Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the Investigator
11. Malignancy within the 5 years prior to screening. Individuals under evaluation for possible malignancy are not eligible
12. Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance.
13. Note: Other protocol defined Exclusion criteria may apply.'

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

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 endpoints 36

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) ] AUClast 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Gilead Sciences Inc.

Sponsor organisation

Gilead Sciences Inc.

Address

333 Lakeside Drive

City

Foster City

Postcode

94404-1147

Country

United States

Scientific contact point

Organisation

Gilead Sciences Inc.

Contact name

EU CT Support

Public contact point

Organisation

Gilead Sciences Inc.

Contact name

EU CT Support

Third parties 6

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications