E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Hepatitis B |
Chronic Hepatitis B |
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E.1.1.1 | Medical condition in easily understood language |
Long term infection with hepatitis B virus |
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 | 20.1 |
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 |
Cohort 1 (adolescents 12 to <18 years, = 35 kg): -To evaluate the safety, tolerability and antiviral activity (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 TAFmetabolite tenofovir (TFV) and confirm the dose of TAF given once daily in children with CHB Part B: -To evaluate the safety and tolerability of TAF given once daily at Week 48 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 |
Coorte 1 (adolescenti da 12 a < 18 anni, = 35 kg): • Valutare la sicurezza, la tollerabilità e l’attività antivirale (DNA del virus dell’epatite B [HBV] < 20 UI/ml) di tenofovir alafenamide (TAF) 25 mg una volta al giorno rispetto al placebo alla Settimana 24 in soggetti adolescenti con epatite B cronica (CHB) Coorte 2 (bambini da 2 a < 12 anni): Parte A: • Valutare la farmacocinetica (PK) allo stato di equilibrio di TAF e del metabolita di TAF tenofovir (TFV) e confermare la dose di TAF somministrato una volta al giorno in bambini con CHB Parte B: • Valutare la sicurezza e la tollerabilità di TAF somministrato una volta al giorno alla Settimana 48 in bambini con CHB • Valutare l’attività antivirale (DNA dell’HBV < 20 UI/ml) di TAF somministrato una volta al giorno rispetto al placebo alla Settimana 24 in bambini con CHB |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the safety and tolerability of TAF versus placebo at Week 24 in children with CHB -To evaluate the open-label safety of TAF given once daily at Week 48 in adolescents with CHB, and at Weeks 96 and 240 in adolescents and children with CHB -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 -To evaluate the serologic response (loss of HBeAg and seroconversion to anti-HBe, and loss of 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 -To evaluate the biochemical response (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 -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 |
please see protocol synposis |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Other types of substudies Specify title, date and version of each substudy with relative objectives: Cohort 1 - Intensive PK Substudy (Optional): All enrolled subjects may take part in an optional Intensive PK substudy to be performed at either the Week 4 visit or the Week 8 visit. For those subjects who consent to participate in the PK substudy, blood, samples will be collected at 0 (pre-dose, = 30 minutes prior to dosing), 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours post-dose.
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Altre tipologie di sottostudi specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sottostudio facoltativo di PK intensiva (Coorte 1): Tutti i soggetti adolescenti arruolati nella Coorte 1 sono eleggibili a partecipare a un sottostudio facoltativo di PK intensiva alla visita della Settimana 4 o della Settimana 8. I campioni per PK saranno raccolti a 0 (pre-dose, = 30 minuti prima della somministrazione), 15 e 30 minuti, 1, 1,5, 2, 3, 4, 5 e 8 ore post-dose.
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E.3 | Principal inclusion criteria |
1) Males and non-pregnant, non-lactating females 2) Age at Screening: 2 to < 18 years old 3) Weight at Screening as follows: -Cohort 1: 12 years to < 18 years and = 35 kg (=77 lbs) -Cohort 2 (Group 1): 6 years to < 12 years and = 25 kg (=55 lbs) -Cohort 2 (Group 2): 6 years to < 12 years and =17 kg to < 25 kg (=37 lbs to <55 lbs) -Cohort 2 (Group 3^): 2 years to < 6 years and <17 kg^^ (<37 lbs)^^ ^Subjects unable to swallow a tablet ^^Body weight cutoff at Screening to be determined 4) Willing and able to provide written informed consent/assent (child and parent/legal guardian) 5) Documented evidence of CHB (e.g. HBsAg-positive for = 6 months) 6) 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) 7) Treatment-naïve (defined as < 12 weeks of oral antiviral (OAV) treatment with any oral nucleos(t)ide analogue) OR treatmentexperienced 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. 8) Any previous treatment with interferon (pegylated or non-pegylated) must have ended at least 24 weeks prior to the Baseline visit 9) 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)] 10) Normal ECG (or if abnormal, determined by the Investigator not to be clinically significant) 11) Must be willing and able to comply with all study requirements |
see protocol section 4 |
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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 (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 (e.g., ascites, encephalopathy or variceal hemorrhage) 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 (e.g. 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. Subjects under evaluation for possible malignancy are not eligible. 12) Known hypersensitivity to study drugs, metabolites, or formulation excipients. 13) Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance 14) Subjects on prohibited concomitant medications. Subjects on prohibited medications, otherwise eligible, will need a wash out period of at least 28 days prior to the Baseline visit. 15) 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 |
see protocol section 4 |
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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 in subjects treated with TAF or placebo at Week 24 (Cohort 1). -Incidence of treatment-emergent serious adverse events (SAEs) and treatment-emergent adverse events in subjects treated with TAF or placebo at Week 48 for 24 weeks followed by 24 weeks of open-label TAF (Cohort 2). The primary efficacy endpoint for all Cohorts is: -The percentage of subjects with plasma HBV DNA < 20 IU/mL at Week 24. |
The primary safety endpoints are: -Incidence of treatment-emergent serious adverse events (SAEs) and treatment-emergent adverse events in subjects treated with TAF or placebo at Week 24 (Cohort 1). -Incidence of treatment-emergent serious adverse events (SAEs) and treatment-emergent adverse events in subjects treated with TAF or placebo at Week 48 for 24 weeks followed by 24 weeks of open-label TAF (Cohort 2). The primary efficacy endpoint for all Cohorts 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 |
Weeks 24, 48 |
Weeks 24, 48 |
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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 from Baseline in bone mineral density (BMD) of whole body minus head and lumbar spine performed by dual imaging x-ray absorptiometry (DXA) scan, and change in serum creatinine, and eGFR by the Schwartz formula method to evaluate the safety and tolerability of the treatment regimen at Weeks 24, 48, 96, and 240. -Incidence of treatment-emergent SAEs and treatment-emergent adverse events in subjects treated with TAF or placebo at Week 24 (Cohort 2). -Incidence of treatment-emergent SAEs and treatment-emergent adverse events in subjects treated with TAF or placebo for 24 weeks followed by open-label TAF at Week 48 (Cohort 1) and Weeks 96 and 240 (Cohorts 1 and 2) -Evaluation of glucose, phosphate, retinol-binding protein and beta-2- microglobulin at Weeks 4, 8, 12, 24 and 48 (Cohorts 1 and 2) 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 percentage of subjects achieving the composite endpoint of both 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 and seroconversion to anti- HBe at Weeks 24, 48, 96, and 240 (HBeAg-positive subjects only) -The percentage of subjects achieving the composite endpoint of both 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 -Assessment of acceptability/palatability of study drug at Baseline, and Weeks 4, 24, and 36 The primary PK endpoint for Cohort 2 is: -The PK parameter AUCtau for TAF The secondary PK endpoints for Cohorts 1 and 2 are: -PK parameters of AUClast, Cmax, Clast, Tmax, Tlast, ¿z, CL/F, Vz/F, and T1/2 for TAF and TFV, and AUCtau, and Ctau for TFV |
The secondary safety endpoints are: -Graded laboratory abnormalities, Tanner stage assessment, selected bone and renal safety parameters, including percentage change from Baseline in bone mineral density (BMD) of whole body minus head and lumbar spine performed by dual imaging x-ray absorptiometry (DXA) scan, and change in serum creatinine, and eGFR by the Schwartz formula method to evaluate the safety and tolerability of the treatment regimen at Weeks 24, 48, 96, and 240. -Incidence of treatment-emergent SAEs and treatment-emergent adverse events in subjects treated with TAF or placebo at Week 24 (Cohort 2). -Incidence of treatment-emergent SAEs and treatment-emergent adverse events in subjects treated with TAF or placebo for 24 weeks followed by open-label TAF at Week 48 (Cohort 1) and Weeks 96 and 240 (Cohorts 1 and 2) -Evaluation of glucose, phosphate, retinol-binding protein and beta-2- microglobulin at Weeks 4, 8, 12, 24 and 48 (Cohorts 1 and 2) 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 percentage of subjects achieving the composite endpoint of both 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 and seroconversion to anti- HBe at Weeks 24, 48, 96, and 240 (HBeAg-positive subjects only) -The percentage of subjects achieving the composite endpoint of both 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 -Assessment of acceptability/palatability of study drug at Baseline, and Weeks 4, 24, and 36 The primary PK endpoint for Cohort 2 is: -The PK parameter AUCtau for TAF The secondary PK endpoints for Cohorts 1 and 2 are: -PK parameters of AUClast, Cmax, Clast, Tmax, Tlast, ¿z, CL/F, Vz/F, and T1/2 for TAF and TFV, and AUCtau, and Ctau for TFV |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 24, 48, 96, and 240 |
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 | 5 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Hong Kong |
India |
Korea, Republic of |
New Zealand |
Russian Federation |
Taiwan |
United States |
Belgium |
Italy |
Romania |
United Kingdom |
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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) |
last patient last visit (LPLV) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |