| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| CHRONIC HEPATITIS B VIRUS,PEDIATRIC |
|
| E.1.1.1 | Medical condition in easily understood language |
| CHRONIC HEPATITIS B VIRUS,PEDIATRIC |
|
| 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 | 15.1 |
| 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 |
To compare the proportion of subjects in each treatment group who achieve a
combination of HBV DNA suppression and HBeAg seroconversion (undetectable
HBeAg AND detectable anti-HBe antibodies) at Week 48. |
|
| E.2.2 | Secondary objectives of the trial |
• Assess the serologic response rates (defined as HBsAg loss and/
and HBeAg loss and/or seroconversion) including durability
treatment;
• Assess the virological response rates;
• Assess the biochemical response rates;
• Assess ETV resistance rates;
• Evaluate the long-term safety of ETV use in pediatric patients. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
a) Freely given informed consent must be obtained prior to clinical trial
participation, including informed consent for any screening procedures conducted
to establish subject eligibility for the trial. Minor’s parents or legally acceptable
representatives must give fully informed written consent. Assent should be
obtained when the minor is judged to be of an age of reason (see Appendix 1);
2) Target Population
a) History of CHB infection defined as HBsAg-positive at the Screening visit and on
at least one other occasion ≥ 24 weeks prior to screening;
b) Detectable HBeAg AND no detectable anti-HBe antibodies at screening and at
least once ≥ 4 weeks prior to screening;
c) Serum ALT 1.5 to < 10 x ULN at screening and at least on one other occasion
within 8 to 24 weeks prior to screening;
d) HBV DNA by PCR ≥ 100 000 copies/mL at screening and evidence of the presence of
HBV DNA at least once ≥ 4 weeks prior to screening;
3) Age and Sex
a) Male and females, 2 to <18 years of age.
Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 6 weeks after
the last dose of investigational product in such a manner that the risk of pregnancy
is minimized.
WOCBP include any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation,
or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined
as:
• Amenorrhea ≥ 12 consecutive months without another cause or
• For women with irregular menstrual periods and on hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level
> 35 mIU/mL
Women who are using oral contraceptives, other hormonal contraceptives
(vaginal products, skin patches, or implanted or injectable products), or
mechanical products such as an intrauterine device or barrier methods
(diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing
abstinence or where their partner is sterile (eg, vasectomy) should be considered
to be of childbearing potential.
WOCBP must have a negative serum or urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of HCG) at screening AND within
72 hours prior to the start of investigational product.
|
|
| E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period and for up to 6 weeks after the last dose of
investigational product;
b) WOCBP using a prohibited contraceptive method. At this time there are no
known contraindicated contraceptives to entecavir;
c) Women who are pregnant or breastfeeding;
d) Women with a positive pregnancy test on enrollment or prior to investigational
product administration;
e) Sexually active fertile men not using effective birth control if their partners are
WOCBP;
2) Target Disease Exceptions
a) Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV)
or hepatitis D virus (HDV);
b) Other forms of acute and chronic conditions which may cause increased ALT as
determined by the investigators (eg, acute viral illness, Wilson Disease, other
metabolic disorders, autoimmune hepatitis, alcoholic liver disease);
c) Liver transplant recipients;
3) Medical History and Concurrent Diseases
a) Current evidence of, or history of variceal bleeding, hepatic encephalopathy, or
ascites requiring diuretics or paracentesis or evidence of these on physical
examination performed for this study;
b) Current evidence of, or history of pancreatitis;
c) Received bone marrow or organ transplant or therapy with an
immunomodulatory, cytotoxic, or systemic corticosteroid therapies within
2 months of enrollment;
d) Evidence of current pre-malignant lesions and malignancies including HCC; (to
be excluded by screening and evaluation practices standard in the country of
enrollment);
e) Other serious medical conditions that might preclude completion of this study;
4) Physical and Laboratory Test Findings
a) Hemoglobin < 10.0 g/dL;
b) Platelet count < 70,000/mm³
c) Inadequate renal function with estimated glomerular filtration rate of
< 50 mL/min/1.73m² (using the Schwartz formula; [k * Ht]/Cr)
d) Total serum bilirubin > 2.5 mg/dL (> 42.75 μmol/L);
e) INR > 1.5;
f) Serum albumin < 3.0 g/dL (< 30 g/L);
g) Alpha Fetoprotein ≥ 50 ng/mL;
Allergies and Adverse Drug Reactions
a) Known allergy to nucleoside analogues;
Prohibited Treatments and/or Therapies
a) ≥ 12 weeks of prior therapy with any nucleoside or nucleotide antiviral agent with
activity against hepatitis B virus (including but not limited to adefovir, tenofovir,
famciclovir, clevudine, lamivudine, telbivudine, or emtricitabine);
b) Therapy with interferon alpha, thymosin alpha or any nucleos[t]ide antiviral agent
with activity against hepatitis B virus within 24 weeks of screening;
c) Any prior therapy with ETV;
d) Any use of illegal drugs OR use of alcoholic beverages which in the investigator’s
opinion is sufficient to prevent adequate compliance with study procedures or
increase the risk pancreatitis or hepatotoxicty;
e) Concomitant medications which may cause immunosuppression, nephrotoxicity
or hepatotoxicity or affect renal excretion or hepatic metabolism are not
permitted;
Concomitant use of Traditional Chinese Medicines or other herbal products
purported to have antiviral activity or intended for use in improving/protecting
liver function;
During the treatment phase of the study, a subject may not be coenrolled in
another clinical trial where an investigational drug is administered;
Other Exclusion Criteria
Unable to tolerate oral medication;
Children that are currently breastfeeding, or those who were breastfed while their
mother received LVD; maternal LVD treatment during pregnancy;
Prisoners or subjects who are involuntarily incarcerated;
Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness.
liver biopsy prior to the start of study medication is optional. If a biopsy has been
performed prior to randomization, then histological results will be collected; likewise,
results from any subsequent on-study biopsies will be collected.
Subjects may be rescreened twice (for a total of three screens) if it can be reasonably
expected that study criteria will be met. However, beyond this, subjects should be
reevaluated only after consultation with the study team.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The proportion of subjects who achieve: 1) HBV DNA < 50 IU/mL (approximately
300 copies/mL) using the Roche COBAS® TaqMan HBV Test for use with the High
Pure System (HPS) assay; and 2) HBeAg seroconversion (undetectable HBeAg AND
detectable anti-HBe antibodies) at Week 48 of study treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) The proportion of subjects with serum ALT < = 1 times the upper limit of normal
2) The number and percent of subjects with adverse events, serious adverse events, discontinuations due to adverse events, and HBV disease progression |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) At Week 48
2) Day 1 through Week 48 |
|
| 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) | 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 | 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 |
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 | 14 |
| 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 |
| Belgium |
| Brazil |
| Canada |
| Germany |
| Greece |
| India |
| Israel |
| Poland |
| Romania |
| Russian Federation |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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