Tenofovir Alafenamide (TAF) in Children and Adolescents With Chronic Hepatitis B Virus Infection

Sponsor

Gilead Sciences (Industry)

Overall Status

Recruiting

CT.gov ID

NCT02932150

Collaborator

(none)

150

Enrollment

Locations

Arms

155

Anticipated Duration (Months)

2.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of Cohort 1 (adolescents aged 12 to < 18 years, ≥ 35 kg body weight):

of this study is to evaluate the safety, tolerability, and antiviral activity (HBV DNA < 20 IU/mL) of tenofovir alafenamide (TAF) 25 mg once daily versus placebo through Week 24 in treatment-naive and treatment-experienced adolescents with chronic hepatitis B (CHB).

Cohort 2 (children 2 to < 12 years of age) will consist of 2 parts: Part A and Part B. Intensive pharmacokinetic (PK) data will be collected from all participants in Part A to confirm the dose of TAF in each dose group and the remaining participants will be enrolled into Part B once dose confirmation is achieved. The primary objectives of Part A are to evaluate the steady-state PK of TAF and tenofovir (TFV) and confirm the dose of TAF given once daily in children (with CHB. The primary objective of Part B is to evaluate the safety, efficacy and tolerability of TAF at Week 24 and the antiviral activity (HBV DNA < 20 IU/mL) of TAF at Week 24 in children with CHB.

Condition or Disease	Intervention/Treatment	Phase
Chronic Hepatitis B	Drug: TAF Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Anticipated 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 :

Nov 1, 2016

Anticipated Primary Completion Date :

Aug 1, 2025

Anticipated Study Completion Date :

Oct 1, 2029

Arms and Interventions

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

Primary Outcome Measures

Incidence of Treatment-Emergent Serious Adverse Events (SAEs) at Week 24 [Week 24]
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]
PK Parameter: AUCtau of TAF for participants from Cohort 2 Part A [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

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]
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 [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).
Palatability of study drug [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).
PK Parameter: AUCtau of tenofovir (TFV) [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).
PK Parameter: AUClast of TAF and TFV [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.
PK Parameter: Ctau of TFV [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.
PK Parameter: Cmax of TAF and TFV [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.
PK Parameter: Clast of TAF and TFV [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.
PK Parameter: Tmax of TAF and TFV [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).
PK Parameter: Tlast of TAF and TFV [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.
PK Parameter: λz of TAF and TFV [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.
PK Parameter: CL/F of TAF and TFV [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.
PK Parameter: Vz/F of TAF and TFV [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.
PK Parameter: t1/2 of TAF and TFV [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

Criteria

Ages Eligible for Study:

2 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
2	Rady Childrens Hospital	San Diego	California	United States	92123
3	University of California, San Francisco (UCSF)	San Francisco	California	United States	94158
4	Children's Hospital Colorado	Aurora	Colorado	United States	80045
5	University of Miami/Schiff Center for Liver Diseases	Miami	Florida	United States	33136
6	AdventHealth Medical Group	Orlando	Florida	United States	32803
7	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
8	Indiana University School of Medicine	Indianapolis	Indiana	United States	46202
9	Johns Hopkins University	Baltimore	Maryland	United States	21287
10	University of Minnesota Masonic Children's Hospital	Minneapolis	Minnesota	United States	55455
11	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
12	Children's Hospital & Medical Center	Omaha	Nebraska	United States	68198
13	The Children's Hospital at Montefiore	Bronx	New York	United States	10467
14	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
15	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
16	Monroe Carell Jr. Children's Hospital at Vanderbilt	Nashville	Tennessee	United States	37232
17	Children's Medical Center	Dallas	Texas	United States	75235
18	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
19	Texas Children's Hospital - Main Hospital	Houston	Texas	United States	77030
20	American Research Corporation at Texas Liver Institute	San Antonio	Texas	United States	78215
21	Seattle Children's Hospital	Seattle	Washington	United States	98105
22	West Virginia University Hospitals	Morgantown	West Virginia	United States	26506
23	Cliniques Universitaires Saint-LUC UCL	Brussels		Belgium	1200
24	The Hospital for Sick Children	Toronto		Canada	M5G 1X8
25	BC Children's Hospital	Vancouver		Canada	V6H3V4
26	Prince of Wales Hospital	Shatin		Hong Kong
27	SR Kalla Memorial Gastro And General Hospital	Jaipur		India	302001
28	Pratha Gastro Liver Center	Kanpur		India	208012
29	Institute of Post Graduation Medical Education & Research	Kolkata		India	700020
30	M. V Hospital and Research Center	Lucknow		India	226003
31	Seth GS Medical College and KEM hospital, Parel	Mumbai		India	400022
32	Nandita Hospital and Research Centre	Nagpur		India	440003
33	Midas Multispecility Hospital PVT. LTD.	Nagpur		India	440010
34	All India Institute of Medical Sciences	New Delhi		India	110029
35	Surat Institute of Digestive Sciences	Surat		India	395002
36	Samvedna Hospital	Varanasi		India	221005
37	AOU di Bologna - Policlinico S. Orsola Malpighi - Dipartimento Malattic dell'Apparato Digerente e Medicina Intema	Bologna		Italy	40138
38	Kyungpook National University Hospital	Daegu		Korea, Republic of	41944
39	Seoul National University Hospital	Seoul		Korea, Republic of	03080
40	Asan Medical Center	Seoul		Korea, Republic of	5505
41	Samsung Medical Center	Seoul		Korea, Republic of	6351
42	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of
43	Auckland Clinical Studies Limited	Auckland		New Zealand	1010
44	Spitalul Grigore Alexandrescu-Sectia Pediatrie III	Bucharest		Romania	11743
45	Institutul National de Boli Infectioase "Prof.Dr. Matei Bals"	Bucharest		Romania	21105
46	Krasnoyarsk Regional Clinical Center of Maternal and Child Welfare	Krasnoyarsk		Russian Federation	660022
47	Federal Budgetary Institution of Science "Central Scientific-Research Institute of Epidemiology"	Moscow		Russian Federation	111123
48	Federal Research Centre of Nutrition, Biotechnology and Food Safety	Moscow		Russian Federation	115446
49	Scientific Center of Children's Health of the Ministry of Health of the Russian Federation	Moscow		Russian Federation	119991
50	Federal State-Financed Institution Pediatric Research and Clinical Center for Infectious Diseases	Saint-Petersburg		Russian Federation	197022
51	Federal Budgetary Scientific Institution Pasteur St. Petersburg Scientific Research Institute of Epidemiology and Microbiology	Saint-Petersburg		Russian Federation	197101
52	Republican Clinical Hospital of Infectious Diseases named after A.F. Agafonov	Tatarstan		Russian Federation	420110
53	Limited Medical Company Hepatolog	Tolyatti		Russian Federation	445009
54	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung City		Taiwan	807
55	Chang Gung Medical Foundation, Kaohsiung Chang Gung Memorial Hospital	Kaohsiung		Taiwan	83301
56	National Cheng Kung University Hospital	Tainan		Taiwan	704
57	National Taiwan University Hospital	Taipei		Taiwan	100
58	Taipei Mackay Memorial Hospital	Taipei		Taiwan	104
59	Chang Gung Medical Foundation, Chang Gung Memorial Hospital, Linkou	Taoyuan		Taiwan	33305