E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Long term infection with hepatitis B virus |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008910 |
E.1.2 | Term | Chronic hepatitis B |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Part A:
-To evaluate the steady state pharmacokinetics (PK) of tenofovir alafenamide (TAF) and confirm the dose of TAF 25 mg tablet given once daily in treatment-naïve and treatment-experienced adolescent subjects (aged 12 to < 18 years) with chronic hepatitis B (CHB).
Part B:
To evaluate the safety, tolerability, and antiviral activity (HBV DNA < 20 IU/mL) of TAF 25 mg once daily versus placebo through Week 24 in treatment-naive and treatment-experienced adolescent subjects with CHB |
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E.2.2 | Secondary objectives of the trial |
-To evaluate for TAF 25 mg once daily versus placebo through Week 24 in treatment-naive and treatment-experienced adolescent subjects with CHB
the following:
1) the serologic response (loss of HBeAg and seroconversion to anti-HBe, and loss of HBsAg and seroconversion to anti-HBs)
2)the biochemical (ALT normalisation)
3) the change in fibrosis as assessed by FibroTest
4) incidence of drug resistance mutations
-To evaluate the palatability and acceptability of TAF 25 mg once daily in treatment-naïve and treatment-experienced adolescent subjects with CHB
-To evaluate the open-label efficacy and safety of TAF 25 mg once daily from Week 24 to Week 240 in subjects initially randomized to TAF 25 mg once daily, and in subjects sequentially treated with placebo for 24 weeks and then switched to open-label TAF |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Males and non-pregnant, non-lactating females
2) Age at Baseline: 12 to < 18 years old
3) Weight at Screening: ≥ 35 kg (77 lbs)
4) Able to swallow oral tablets
5) Willing and able to provide written informed consent/assent (child and parent/legal guardian)
6) Documented evidence of CHB (e.g. HBsAg-positive for ≥ 6 months)
7) HBeAg-positive, or HBeAg-negative, chronic HBV infection with all of the following:
a) Screening HBV DNA ≥ 2 × 10000 IU/mL
b) Screening serum ALT > 45 U/L (1.5 × ULN; 30 U/L) and ≤ 10 × ULN (by central laboratory range)
8) Treatment-naïve (defined as < 12 weeks of oral antiviral (OAV) treatment with any oral nucleos(t)ide analogue) OR treatment-experienced subjects (defined as subjects meeting all entry criteria [including HBV DNA and serum ALT criteria] and with ≥ 12 weeks of previous treatment with any nucleos(t)ide analogue) will be eligible for enrollment. All treatment-experienced subjects must have discontinued oral nucleos(t)ide therapy ≥ 16 weeks
prior to screening to avoid ALT flare if randomized to the placebo arm.
9) Any previous treatment with interferon (pegylated or non-pegylated) must have ended at least 24 weeks prior to the Baseline visit
10) Estimated creatinine clearance (CLCr) ≥ 80 mL/min/1.73m^2 (using the Schwartz formula; = k × L/sCr) [(k is a proportionality constant: for adolescent females ≥ 12 years old, k = 0.55, and for adolescent males ≥ 12 years, k = 0.70); L is height in centimeters (cm); and sCr is serum creatinine (mg/dL)]
11) Normal ECG (or if abnormal, determined by the Investigator not to be clinically significant)
12) Must be willing and able to comply with all study requirements |
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E.4 | Principal exclusion criteria |
1) Pregnant females, females who are breastfeeding or who believe they may wish to become pregnant during the course of the study
2) Males and females of reproductive potential who are unwilling to use an “effective”, protocol-specified method(s) of contraception during the study. For a list of protocol-specified contraceptive methods, refer to Appendix 5.
3) Coinfection with HCV, HIV, or HDV
4) Evidence of hepatocellular carcinoma (screening alpha-fetoprotein [AFP] > 50 ng/mL or recent imaging study if AFP < 50 ng/mL)
5) Any history of, or current evidence of, clinical hepatic decompensation (e.g., ascites, encephalopathy or variceal hemorrhage)
6) Abnormal hematological and biochemical parameters
7) Received solid organ or bone marrow transplant
8) Currently receiving therapy with immunomodulators (e.g. corticosteroids), or immunosuppressants
9) Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the Investigator
10) Malignancy within the 5 years prior to screening. Subjects under evaluation for possible malignancy are not eligible.
11) Known hypersensitivity to study drugs, metabolites, or formulation excipients.
12) Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance
13) Subjects on prohibited concomitant medications. Subjects on prohibited medications, otherwise eligible, will need a wash out period of at least 30 days prior to the baseline visit.
14) Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with dosing requirements |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary safety endpoints are:
-Incidence of treatment-emergent serious adverse events (SAEs) and treatment-emergent adverse events at Week 24.
The primary efficacy endpoint is:
-The percentage of subjects with plasma HBV DNA < 20 IU/mL at Week 24 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary safety endpoints are:
-Graded laboratory abnormalities, Tanner stage assessment, selected bone and renal safety parameters, including percentage change in bone mineral density (BMD) of whole body minus head and lumbar spine by dual imaging x-ray absorptiometry (DXA), and change in serum creatinine, and eGFR by the Schwartz method to evaluate the safety and tolerability of the treatment regimen at Weeks 24, 48, 96, and 240.
The secondary efficacy endpoints are:
-The percentage of subjects with plasma HBV DNA < 20 IU/mL at Weeks 48, 96, and 240
-The proportion of subjects with plasma HBV DNA < 20 IU/mL (target not detected) at Weeks 24, 48, 96, and 240
-The percentage of subjects with ALT normalization at Weeks 24, 48, 96, and 240
-The composite endpoint of ALT normalization and HBV DNA < 20 IU/mL at Weeks 24, 48, 96 and 240
-The change from baseline in fibrosis as assessed by FibroTest at Weeks 24, 48, 96, and 240
-The percentage of subjects with HBeAg loss at Weeks 24, 48, 96, and 240, and the percentage of subjects with HBeAg seroconversion to anti-HBe at Weeks 24, 48, 96, and 240 (HBeAg-positive subjects only)
-The composite endpoint of HBeAg seroconversion and HBV DNA < 20 IU/mL at Weeks 24, 48, 96, and 240 (HBeAg-positive subjects only)
-The percentage of subjects with HBsAg loss and seroconversion to anti-HBs at Weeks 24, 48, 96, and 240
- Incidence of resistance mutations at Weeks 24, 48, 96, and 240
- Acceptability/palatability of study drug at Baseline and Week 4, Week 24 , and at Week 36 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 24, 48, 96, and 240 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
Hong Kong |
Korea, Republic of |
Russian Federation |
Taiwan |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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last patient last visit (LPLV) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |