| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis B Virus Infection |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008910 |
| E.1.2 | Term | Chronic hepatitis B |
|
| 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 describe the efficacy of the combination therapy of ETV plus TDF at 48 weeks of treatment, in control of viral load (HBV DNA < 50 IU/mL) in chronic HBV infected subjects who have failed previous treatment |
|
| E.2.2 | Secondary objectives of the trial |
•Proportion of subjects with undetectable HBV DNA (< 50 IU/mL) at Weeks 24 and 96;
•Proportion of subjects who achieve HBV DNA < the lower limit of detection (LLD) as defined by the COBAS® TaqMan assay in use at the central lab at Weeks 24, 48 and 96;
•To evaluate changes in HBeAg and HBsAg status at Weeks 24, 48 and 96;
•To evaluate the emergence of resistant mutations during treatment with ETV plus TDF;
•To evaluate mean change of viral load from baseline;
•To assess the long-term safety of the combination therapy of ETV plus TDF.
|
|
| 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 from subjects prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the study.
2)Target Population
a)Subjects with previously diagnosed and currently treated chronic HBV infection (positive HBsAg at screening), either HBeAg-negative or HBeAg-positive;
b)Subjects must have a treatment failure (HBV DNA > 50 IU/mL) to their current nucleoside/nucleotide treatment regimen, defined as either
i)A primary non-response: <1log10 decrease in HBV-DNA level (IU/mL) after 3 months of therapy OR
ii)A virological breakthrough defined as a confirmed increase in HBV-DNA level (IU/mL) of >1log10 compared to the nadir (i.e.: lowest value) HBV DNA level on initiating treatment OR
iii)A partial virological response defined as a decrease in HBV DNA of >1 log10 IU/ml but detectable HBV DNA levels (HBV DNA ≥ 50 IU/mL)
(1)For patients receiving lamivudine, adefovir or telbivudine, failure to reduce HBV DNA to below the limit of detectability within 24 weeks of commencing study drug treatment;
(2)For patients receiving entecavir or tenofovir, failure to reduce HBV DNA to below the limit of detectability within 48 weeks of commencing study drug treatment.
c)Prior entecavir and/or tenofovir monotherapy is allowed;
d)Subjects must have compensated liver function and must meet ALL of the following criteria
i) International Normalization Ratio (INR) ≤ 1.5;
ii) Serum albumin ≥ 3 g/dL (≥ 30 g/L);
iii) Serum total bilirubin ≤ 2.5 mg/dL (≤ 42.75 µmol/L).
3) Age and Sex
a) Men and women, ages 18 or older.
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) 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) Women who are pregnant or breastfeeding;
c) Women with a positive pregnancy test on enrollment or prior to investigational product administration;
d) Sexually active fertile men not using effective birth control if their partners are WOCBP.
2) Target Disease Exceptions
a) Evidence of decompensated cirrhosis including but not limited to: variceal bleeding, hepatic encephalopathy, or ascites requiring management with diuretics or paracentesis;
b) Co-infection with HIV, hepatitis C virus (HCV) [co-infection is defined as HCV Ab-positive with detectable HCV ribonucleic acid (RNA) by PCR], or hepatitis D virus (HDV).
3) Medical History and Concurrent Diseases
a) Moderate or severe renal impairment, i.e. creatinine clearance <50mL/min;
b) Recent history of pancreatitis (within 24 weeks prior to the first dose of study medication);
c) Currently abusing illegal drugs or alcohol sufficient in the Investigator’s opinion, to prevent adequate compliance with study therapy or to increase the risk of hepatotoxicity or pancreatitis;
d) Other serious medical conditions that might preclude completion of this study or that require chronic administration of prohibited medications (see Exclusion Criteria under number 6).
4) Physical and Laboratory Test Findings
a) Phosphatemia, i.e. blood levels of phosphate <1.5 mg/mL;
b) Hemoglobin < 10.0 g/dL;
c) Platelet count < 70,000/mm3;
d) Absolute neutrophil count < 1500 cells/mm3;
e) ALT>10xULN;
f) Serum alpha fetoprotein (AFP) level > 50 ng/mL.
5) Allergies and Adverse Drug Reactions
a) Known history of allergy to nucleoside or nucleotide analogues.
6) Prohibited Treatments and/or Therapies
a) Therapy with interferon, thymosin alpha or other immuno-stimulators within 24 weeks of being assigned to study drug;
b) Required chronic administration of medications which cause immunosuppression or which are associated with a high risk of nephrotoxicity, hepatotoxicity or which affect renal excretion;
c) Prior entecavir/tenofovir combination therapy.
7) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated ;
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness;
c) Unable to tolerate oral medication;
d) Poor peripheral venous access;
e) Off HBV therapy for greater than 7 days before initiation of study treatment.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects who achieve a virological response defined as HBV DNA < 50 IU/mL at 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The end of the study will be reached when the last subject performs the last follow-up visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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