E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
CHRONIC HAPATITIS B VIRUS INFECTIONS |
Infezione virale Epatite B cronica |
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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 | 14.1 |
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 |
To assess rates of the following clinical outcomes: 1) malignant neoplasms (overall and non-HCC, in each case including carcinoma in situ [CIS] but excluding non-melanoma skin cancer, and HCC); 2) liver-related events of HBV disease progression; 3) mortality (all cause, liver-related). |
Valutare i tassi dei seguenti esiti clinici: 1) neoplasie maligne (totali e carcinomi non epatocellulari, il carcinoma in situ [CIS] sempre compreso, mentre tumore della pelle non melanocitico e il carcinoma epatocellulare esclusi); 2) eventi di progressione della malattia da HBV fegato correlati; 3) mortalita` (tutte le cause, fegato correlate). |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
>• Sex and Reproductive Status 1) Women who are pregnant or breastfeeding 2) Women with a positive pregnancy test on enrollment or prior to randomization • Target Disease Exceptions 3) Patients who, in the opinion of the investigator, are expected to have a liver transplant-free survival of less than one year 15) Patients who, in the opinion of the investigator, are virologically controlled on their current HBV treatment regimen and clinically responding to treatment, unless the regimen needs to be modified for medication intolerance. • Medical History and Concurrent Diseases 4) Coinfection with HIV, as confirmed by investigator 5) History of malignant neoplasm(s), including HCC and CIS, but excluding nonmelanoma skin cancers. The presence of current malignancy, including HCC, is to be excluded by screening and evaluation practices standard in the country of enrollment. 6) History of dysplastic liver nodules 16) Patients with chronic renal insufficiency, defined as a creatinine clearance < 50 ml/min who do not have either of the following means of dose reducing ETV: a.) an approved country-specific ETV label which includes the extended interval ETVdose modification method and/or b.) an approved country specific label for the ETV oral solution AND access to the oral solution. • Allergies and Adverse Drug Reactions 7) Known history of allergy to nucleoside/tide analogues • Prohibited Therapies and/or Medications 8) Prior or current treatment with ETV 9) An investigator proposed study regimen which will include only IFN-alfa 10) An investigator proposed study regimen of combination (two or more) HBV nucleoside/tide analogue therapy 11) An investigator proposed study regimen which will include TDF, unless TDF is an approved therapy for HBV in the patient`s country 12) An investigator proposed study regimen which will include LdT, unless LdT is an approved therapy for HBV in the patient`s country 13) An investigator proposed study regimen which will include one or more investigational agents for the treatment of HBV • Other Exclusion Criteria 14) Prisoners or patients who are compulsorily detained. |
1) Consenso Informato scritto; 2) Infezione da HBV cronica, confermata dall`Investigatore; 3) Pazienti naive o con precedente terapia HBV nucleosidica/nucleotidica; 4) un candidato che, secondo l`opinione dello sperimentatore, possa essere adeguato per una monoterapia nucleosidica/nucleotidica con ETV o un altro analogo nucleosidico/nucleotidico ad attivita` anti-HBV come trattamento standard; 5) almeno 18 anni di eta`; 6) maschio o femmina. |
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E.4 | Principal exclusion criteria |
• Sex and Reproductive Status 1) Women who are pregnant or breastfeeding 2) Women with a positive pregnancy test on enrollment or prior to randomization • Target Disease Exceptions 3) Patients who, in the opinion of the investigator, are expected to have a liver transplant-free survival of less than one year 15) Patients who, in the opinion of the investigator, are virologically controlled on their current HBV treatment regimen and clinically responding to treatment, unless the regimen needs to be modified for medication intolerance. • Medical History and Concurrent Diseases 4) Coinfection with HIV, as confirmed by investigator 5) History of malignant neoplasm(s), including HCC and CIS, but excluding nonmelanoma skin cancers. The presence of current malignancy, including HCC, is to be excluded by screening and evaluation practices standard in the country of enrollment. 6) History of dysplastic liver nodules 16) Patients with chronic renal insufficiency, defined as a creatinine clearance < 50 ml/min who do not have either of the following means of dose reducing ETV: a.) an approved country-specific ETV label which includes the extended interval ETVdose modification method and/or b.) an approved country specific label for the ETV oral solution AND access to the oral solution. • Allergies and Adverse Drug Reactions 7) Known history of allergy to nucleoside/tide analogues • Prohibited Therapies and/or Medications 8) Prior or current treatment with ETV 9) An investigator proposed study regimen which will include only IFN-alfa 10) An investigator proposed study regimen of combination (two or more) HBV nucleoside/tide analogue therapy 11) An investigator proposed study regimen which will include TDF, unless TDF is an approved therapy for HBV in the patient`s country 12) An investigator proposed study regimen which will include LdT, unless LdT is an approved therapy for HBV in the patient`s country 13) An investigator proposed study regimen which will include one or more investigational agents for the treatment of HBV • Other Exclusion Criteria 14) Prisoners or patients who are compulsorily detained. |
1) Donne in gravidanza o in allattamento; 2)Donne con un test di gravidanza positivo all`arruolamento o prima della randomizzazione; 3) Pazienti che, ad opinione dello sperimentatore, senza trapianto di fegato si prevede abbiano una sopravvivenza inferiore a un anno; 15) Pazienti che, ad opinione dell`Investigatore, sono controllati virologicamente e rispondono clinicamente al loro attuale regime di trattamento HBV, a meno che il regime debba essere modificato per intolleranza al farmaco; 4) Coinfezione con HIV, confermata dall`Investigatore; 5) Storie di neoplasie maligne, incluso HCC e CIS ma escluso tumore della pelle non melanocitico; 6)Storia di noduli epatici displasici; 16) Pazienti con insufficienza renale cronica, definita come clearance della creatinina < 50 ml/min che non abbiano nessuna delle seguenti riduzioni di dosaggio ETV: a) un`etichetta ETV approvata specifica per la Nazione che includa un esteso intervallo di metodo di modifica dose ETV e/o b) un`etichetta approvata specifica per la Nazione per la soluzione orale di ETV E per l`accesso alla soluzione orale; 7) Storia di allergia conosciuta ad analoghi nucleosidici/nucleotidici; 8) Precedente o attuale terapia con Entecavir (ETV); 9) Un regime di studio proposto che includa alfa-interferone; 10) Un regime di studio proposto con una terapia di combinazione che includa terapia per HBV con due o piu` analoghi nucleosidici/nucleotidici; 11) Un regime di studio proposto che includa TDF, a meno che TDF sia una terapia approvata per HBV in quella determinata Nazione; 12) Un regime di studio proposto che includa LdT, a meno che LdT sia una terapia approvata per HBV in quella determinata Nazione; 13) Un regime di studio proposto che includa uno o piu` agenti investigativi per il trattamento dell`HBV; 14) Prigionieri o pazienti che siano detenuti in modo coatto. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Clinical Outcome Measures: • Non-HCC malignant neoplasm rates (including CIS, but excluding non-melanoma skin cancer) • HCC rates • Overall malignant neoplasm rates (including CIS, but excluding non-melanoma skin cancer) • Mortality (all cause, liver-related) • Rates of liver-related manifestations of HBV disease progression rates, defined as: `' progression from non-cirrhotic liver status to cirrhosis `' progression from compensated to decompensated cirrhosis (e.g. gastroesophageal variceal bleeding, ascites, hepatic encephalopathy, hepatorenal syndrome) `' progression from decompensated cirrhosis (e.g. history or presence at enrollment of one/more manifestations of decompensated cirrhosis) to worsening of decompensated cirrhosis (e.g. new, recurrent or ongoing event of decompensated cirrhosis following enrollment) `' development of HCC `' liver-related death `' decision to list for liver transplantation. |
1) Neoplasie maligne (totali e carcinomi non epatocellulari, il carcinoma in situ [CIS] sempre compreso, mentre tumore della pelle non melanocitico e il carcinoma epatocellulare esclusi); 2) eventi di progressione della malattia da HBV fegato correlati; 3) mortalita` (tutte le cause, fegato correlate). |
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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 | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Yes |
E.8.2.2 | Placebo | No |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 72 |
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 | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
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 | 10 |
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 |