| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic hepatitis B infection |
| Infezione da Epatite B cronica |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic hepatitis B infection |
| Infezione da Epatite B cronica |
|
| 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 | 17.0 |
| 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 investigate whether and to what extent 24 weeks of PEG-IFN therapy can improve HBV-specific T cell responses in HBeAg negative genotype D positive patients with chronic hepatitis B and persistently suppressed viremia induced by NUC therapy |
| Valutare se e in quale misura 24 settimane di terapia con PEG-IFN alfa sono in grado di migliorare le risposte T linfocitarie HBV-specifiche in pazienti con epatite cronica B di genotipo D HBeAg negativi con viremia persistentemente soppressa in terapia di lunga durata con NUC. |
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| E.2.2 | Secondary objectives of the trial |
Secondary efficacy objectives:
• to assess whether during the following 24 weeks of PEG-IFN therapy HBV-specific T cell responses can be further improved;
• to elucidate whether strength and quality of HBV-specific T cell responses are correlated with HBsAg kinetics during PEG-IFN therapy.
Secondary safety objective:
• to assess the safety profile of 48 weeks PEG-IFN a2a therapy with nucleoside analogues.
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Obiettivi secondari di efficacia:
• valutare se durante le successive 24 settimane di terapia con PEG-IFN alfa le risposte T linfocitarie HBV-specifiche possono essere ulteriormente migliorate;
• chiarire se l’entità e la qualità delle risposte T linfocitarie HBV-specifiche sono correlate con la cinetica di HBsAg durante la terapia con PEG-IFN alfa
Obiettivi secondari di sicurezza:
• valutare il profilo di sicurezza della terapia con PEG-IFN alfa-2a per 48 settimane in corso di trattamento con NUC
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. willingness to participate in the study protocol and to provide informed consent
2. male and female, age between 18 and 70 years
3. HBeAg negative/anti-HBe positive chronic hepatitis B (+/- cirrhosis) proven by histology or non invasive techniques (Fibroscan) before entry
4. if cirrhosis is present, absence of portal hypertension, HCC and -FP levels <200 ng has to be documented at screening
5. complete viral suppression on nucleos(t)ide analogues (HBV-DNA undetectable < 20 IU/ml) from 2-3 years
6. serum albumine >3.5 gr/dL, bilirubin < 1.5 mg/dL
7. Absolute neutrophil count >1,500 cells/mm3; PLTs >90,000/ mm3
8. Negative urine or serum pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of the drug. Additionally, all fertile male patients with female partners of childbearing age and females must be using two reliable forms of effective contraception (combined) during the study and for 3 months after treatment completion.
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disponibilità a partecipare al protocollo di studio e a fornire il consenso informato
2. maschi e femmine, di età compresa tra i 18 e i 70 anni
3. epatite cronica B HBeAg negativa/ anti-HBe positiva (in assenza/presenza di cirrosi), comprovata da esame istologico o tecniche non invasive (Fibroscan) prima dell’ingresso nello studio
4. in presenza di cirrosi, allo screening devono essere documentati assenza di ipertensione portale, assenza di HCC e livelli di -FP <200 ng
5. soppressione virale completa da 2-3 anni in terapia con analoghi nucleos(t)idici (HBV-DNA non rilevabile, <20 UI/mL)
6. Albumina sierica > 3.5 g/dL, bilirubina < 1.5 mg/dL
7. Conta assoluta dei neutrofili > 1500 cellule/mm3; piastrine > 90000/mm3
8. Per donne potenzialmente fertili, test di gravidanza sul siero negativo, eseguito nelle 24 ore precedenti alla prima dose di farmaco. Inoltre, tutti i pazienti maschi fertili aventi compagne donne potenzialmente fertili e tutte le femmine fertili devono utilizzare due metodi affidabili di contraccezione efficace in combinazione per l’intera durata dello studio e per i 3 mesi successivi alla fine del trattamento.
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| E.4 | Principal exclusion criteria |
1. Child B or C cirrhosis
2. women who are pregnancy, intent to become pregnant, or who are breast feeding
3. history of severe psychiatric disease, especially depression
4. history of neurological disease, especially epilepsy
5. Addison disease
6. hypertension (PA sis > 170 mmHg; PA dia > 100 mmHg)
7. history or evidence of symptoms of severe cardiac, gastrointestinal and kidney disease
8. ALT ≥ 10xULN
9. positive anti-HDV; positive anti-HCV; positive anti-HIV
10. positive ANA and/or ASMA (> 1/40)
11. antiviral therapy with Interferon in the previous 3 years
12. use of systemic anti-neoplastic or immunomodulatory treatments in the previous 6 months
13. retynopathies
14. tyreopathies
15. history or other evidence of severe illness or any other conditions which would make the patients, in the opinion of investigator, unsuitable for the study.
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1. cirrosi Child B o C
2. donne in gravidanza, che intendono intraprendere una gravidanza o che stanno allattando
3. storia di malattia psichiatrica grave, in particolare depressione
4. storia di malattia neurologica, in particolare epilessia
5. Morbo di Addison
6. ipertensione (PA sis > 170 mmHg; PA dia > 100 mmHg)
7. storia o evidenza di sintomi di gravi malattie cardiache, gastrointestinali e renali
8. ALT ≥ 10xULN
9. Anti-HDV positività; anti-HCV positività; anti-HIV positività
10. ANA e/o ASMA positività (> 1/40)
11. terapia antivirale con Interferone nei 3 anni precedenti
12. terapia sistemica con antineoplastici o immunomodulatori nei 6 mesi precedenti
13. retinopatie
14. patologie della tiroide
15. storia o altra evidenza di malattia grave o di qualsiasi altra condizione che renderebbe il paziente, a giudizio del ricercatore, non adatto per lo studio.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Strength and quality of HBV-specific T cell responses after 24 weeks of PEG-IFN add-on compared to baseline and to the control arm treated with NUC alone. |
| Intensità e qualità delle risposte T linfocitarie specifiche per HBV dopo 24 settimane di PEG-IFN aggiunto alla terapia con NUC rispetto al basale e al braccio di controllo trattato con solo NUC. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| months 7-13 after the start of the study |
| mesi 7-13 dall’avvio dello studio |
|
| E.5.2 | Secondary end point(s) |
• level of improvement of HBV-specific T cell responses after additional 24 weeks of PEG-IFN therapy (48 weeks total) compared to the 24 weeks data;
• mean change in serum HBsAg at week 48 of PEG-IFN add-on compared to baseline and to the control arm treated with NUC alone;
• level of correlation between decline in serum HBsAg and improvement of HBV-specific T cell responses;
• changes in Treg and NK cell activity after 24 and 48 weeks of PEG-IFN add-on compared to baseline and to the control arm treated with NUC alone.
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• livello di miglioramento delle risposte delle cellule T specifiche per HBV dopo ulteriori 24 settimane di terapia con PEG-IFN (48 settimane totali) rispetto ai dati relativi alle 24 settimane;
• variazione media nel livello serico di HBsAg alla settimana 48 di PEG-IFN aggiunto alla terapia con NUC rispetto al basale e al braccio di controllo trattato con solo NUC;
• livello di correlazione tra la caduta di HBsAg serico e il miglioramento delle risposte delle cellule T specifiche per HBV;
• variazioni nell'attività delle cellule Treg e NK dopo 24 e 48 settimane di PEG-IFN aggiunto alla terapia con NUC rispetto al basale e al braccio di controllo trattato con solo NUC.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| months 13-25 after the start of the study |
| mesi 13-25 dall’avvio dello studio |
|
| 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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Characterization of the mechanisms of functional recovery of T-lymphocytes in the course of antiviral therapy. |
| Caratterizzazione dei meccanismi di recupero funzionale T-linfocitario in corso di terapia antivirale. |
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| 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) | No |
| 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 | 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 | No |
| 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 | 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
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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 | |
| E.8.9.1 | In the Member State concerned months | 25 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 25 |
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