| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Long term infection with the hepatitis B virus |
|
| 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 |
|
| 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 |
| The primary objective of this study is to evaluate the antiviral efficacy of tenofovir DF versus placebo in pediatric patients (aged 2 to < 12 years, at the time of enrollment) with chronic hepatitis B infection |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the proportion of subjects with HBeAg seroconversion at Week 48 (in subjects with baseline HBeAg sero-positivity)
- To characterize the safety and tolerability profile of tenofovir DF in pediatric patients (aged 2 to < 12 years, at the time of enrollment) with chronic hepatitis B infection
- To evaluate the biochemical and serological responses to tenofovir DF versus placebo
- To evaluate the incidence of potential resistance mutations to tenofovir DF in the hepatitis B virus polymerase/reverse transcriptase (pol/RT)
- To assess the pharmacokinetics of tenofovir in subjects receiving the tablet formulation and those receiving the oral powder formulation |
|
| 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 |
PK substudy:
To evaluate the PK of different formulations of tenofovir DF in a pediatric population, two intensive PK substudies (oral powder and tablet cohorts) will be performed on a subset of subjects. The intensive PK sampling will be performed over 8 hours during one day between Week 2 and Week 12. A target of 12 randomized subjects at each dosage level (150, 200, 250, 300 mg) will be enrolled in the tablet cohort, and up to a total of 30 randomized subjects will be enrolled in the oral powder cohort.
Subjects are allowed to participate in up to two intensive PK substudies with the second intensive PK substudy occurring after Week 12, but prior to end of the double-blind phase.
Subjects who are eligible to take the oral powder (either tenofovir DF or matching placebo) based on body weight and/or preference for this dosage form, and subjects who qualify for the tablet formulation but are willing to initiate treatment with the oral powder for purposes of accruing additional PK data, will be offered the opportunity to participate in the oral powder cohort. Those subjects who opt to initiate treatement with oral powder and subsequently switch to tablets following completion of the powder intensive PK visit,or those subjects who are required to change dose strengths of the tablet based on the weight-based dosing requirements (see protocol Section 5.3) will also have the option to participate in a second tablet intensive PK visit.
Irrespective of choice of formulation (tablet versus oral powder), if a subject is switching from tablets to powder, the subject must be taking powder for at least 2 weeks prior to the powder intensive PK visit. Similarly, subjects must be taking tablets for at least 2 weeks prior to the tablet intensive PK visit.
Biomarker substudy:
For subjects in whom a separate consent is provided, a blood sample for biomarker (including pharmacogenomic analysis) will be collected for the exploration of appropriate markers that may be predictive of virologic response and/or the tolerability of HBV therapies. |
|
| E.3 | Principal inclusion criteria |
• Male or female
• 2 years to < 12 years of age (consent of parent or legal guardian required)
• Body weight ≥ 10kg
• Documented chronic HBV infection, defined as positive serum HBsAg ≥ 6 months
• HBeAg-positive or HBeAg-negative
• HBV DNA ≥ 105 copies/mL (PCR method)
• ALT ≥ 1.5 × ULN at screening,
• Estimated glomerular filtration rate (creatinine clearance) ≥ 80 mL/min/1.73m2
-Estimated creatinine clearance using Schwartz Formula (mL/min/1.73m2) = k × L/Scr
-[(k is a proportionality constant: pediatric males/females ≥ 2 years to < 12 years
k = 0.55; 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)]
• Adequate hematologic function (absolute neutrophil count ≥ 1,500/mm3; hemoglobin ≥ 10.0 g/dL)
• Negative serum β-HCG pregnancy test (for females of childbearing potential only)
• Male and female subjects of childbearing potential (defined in section 7.7.1) identified as choosing to become sexually active must agree to utilize highly effective contraception methods or agree to abstain from heterosexual intercourse while on study treatment and for 30 days following the last dose of study drugs; (refer to protocol section 7.7.2)
• Parent or legal guardian able to provide written informed consent prior to any screening evaluations and willing to comply with study requirements
• Subject able to provide written assent as determined by IRB/IEC/local requirements and Investigator’s discretion
• No prior tenofovir DF therapy (subjects may have received prior interferon-alfa and/or other oral anti-HBV nucleoside/nucleotide therapy; subjects must have discontinued interferon-alfa therapy ≥ 6 months prior to screening; subjects experienced on other anti-HBV nucleoside/nucleotide therapy must have discontinued therapy ≥ 16 weeks prior to screening to avoid flare if randomized to the placebo arm) |
|
| E.4 | Principal exclusion criteria |
• Pregnant or lactating subjects.
• Sexually-active males or females of childbearing potential who are not willing to use a highly effective method of contraception during the study (see Section 7.7.2 for further details).
• Decompensated liver disease defined as PT > 1.2 × ULN, platelets < 150,000/mm3, serum albumin < 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites,jaundice, encephalopathy, variceal hemorrhage).
• Receipt of interferon (pegylated or not) therapy within 6 months of the Screening Visit
• Receipt of anti-HBV nucleoside/nucleotide therapy within 16 weeks of the Screening Visit
• α-fetoprotein > 50 ng/mL
• Evidence of hepatocellular carcinoma (HCC)
• Co-infection with HIV, acute HAV, HCV, or HDV
• Chronic liver disease of non-HBV etiology (e.g., hemochromatosis, alpha-1 antitrypsin deficiency, cholangitis)
• History of significant renal disease (e.g., nephrotic syndrome, renal dysgenesis, polycystic kidney disease, congenital nephrosis, acute tubular necrosis, other renal disease)
• History of significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochrondroses, multiple bone fractures)
• Significant cardiovascular, pulmonary or neurological disease
• Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of orally administered medications
• History of solid organ or bone marrow transplantation
• Ongoing therapy with any of the following:
• Nephrotoxic agents
• Parenteral aminoglycoside antibiotics (e.g., gentamicin, tobramycin, amikacin)
• Cidofovir
• Cisplatin
• Foscarnet
• IV amphotericin B
• IV pentamidine
• Oral or IV ganciclovir
• Cyclosporine
• Tacrolimus
• IV vancomycin
• Chronic daily non-steroidal anti-inflammatory drug therapy
• Competitors of renal excretion (e.g., probenecid)
• Systemic chemotherapeutic agents
• Systemic corticosteroids (pulmonary administration via MDI/nebulizer and oral steroids administered for less that 5 days are permitted)
• Interleukin-2 (IL-2) and other immunomodulating agents
• Investigational agents (except with the expressed approval of the Sponsor)
• Administration of any of the above medications must be discontinued at least 45 days prior to the Baseline Visit and for the duration of the study period.
• Known hypersensitivity to the study drugs, the metabolites or formulation excipients
• Any other condition (including alcohol or substance abuse) 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of patients with
serum HBV DNA < 400 copies/mL (69 IU/mL) at Week 48 in each arm. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
proportion of subjects with HBeAg seroconversion (in subjects with baseline HBeAg sero-positivity only) at Week 48
|
|
| E.5.2 | Secondary end point(s) |
- proportion of subjects with normal ALT and normalization of ALT
- composite endpoint of proportion of subjects with HBV DNA < 400 copies/mL (69 IU/mL) and normalized ALT
- proportion of subjects with HBV DNA < 169 copies/mL (29 IU/mL)
- proportions of subjects with HBsAg loss and seroconversion
- sequence changes from baseline within the HBV polymerase for subjects who were viremic (HBV DNA ≥ 400 copies/mL, 69 IU/mL) at Weeks 48, 96, 144, 192 or Early Discontinuation; including subjects with confirmed virologic breakthrough
- cumulative incidence of at least a 4% decrease from baseline in bone mineral density of lumbar spine
- percent change from baseline in bone mineral density of lumbar spine
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 48, 96, 144 and / or 192 |
|
| 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 | Yes |
| 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 | Yes |
| 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) | No |
| 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 | No |
| 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 |
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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 | No |
| 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 |
| Taiwan |
| India |
| Korea, Republic of |
| United States |
| Bulgaria |
| Poland |
| Romania |
|
| 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
|
Last patient last visit at the end of the open-label extension phase
(2027) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 14 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 14 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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