| 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 |
| epatite virale |
| epatite virale |
|
| 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 | 10019744 |
| E.1.2 | Term | Hepatitis C |
| 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 is to demonstrate that in treatment-naïve chronic hepatitis C genotype 1 patients i) Fixed-duration triple therapy with DEB025 600 mg BID / 600 mg QD plus peg- IFNα2a/RBV for 48 weeks leads to a superior SVR24 rate as compared to peg- IFNα2a/RBV for 48 weeks AND/OR ii) Response-guided triple therapy with either 24 or 48 weeks with DEB025 400 mg BID plus peg-IFNα2a/RBV leads to a superior SVR24 rate as compared to peg-IFNα2a/RBV for 48 weeks AND/OR iii) Response-guided triple therapy with either 24 or 48 weeks with DEB025 600 mg BID / 600 mg QD plus peg-IFNα2a/RBV leads to a superior SVR24 rate as compared to peg- IFNα2a/RBV for 48 weeks. |
| Obiettivo primario: dimostrare nei pazienti con epatite cronica C genotipo 1 naive che: i) la triplice terapia con DEB025 600 mg QD in associazione a PEG-IFN-α2a e RBV per una durata di trattamento prestabilita di 48 settimane (comprensive della loading dose*) permetta di ottenere un tasso di SVR24 superiore rispetto al trattamento con PEG-IFN-α2a e RBV per 48 settimane; E/O ii) la triplice terapia per un periodo di tempo sia di 24 che di 48 settimane, in base alla risposta al trattamento (response-guided therapy), con DEB025 400 mg BID in associazione a PEG-IFN-α2a e RBV permetta di ottenere un tasso di SVR24 superiore rispetto al trattamento con PEG-IFN-α2a e RBV per 48 settimane E/O Per favore ved. sinossi in italiano |
|
| E.2.2 | Secondary objectives of the trial |
| The key secondary objectives include evaluating whether response-guided triple therapy with DEB025 600 mg BID / 600 mg QD plus peg-IFNα2a/RBV or DEB025 400 mg BID plus peg- IFNα2a/RBV has similar efficacy as the fixed duration triple therapy in terms of proportion of patients achieving SVR24. These analyses will be conducted at a descriptive level. 2.3 Other Secondary objectives • To evaluate the proportions of patients who achieve the following virologic response in each treatment arm: • RVR4LOQ: “Rapid Virologic Response by LOQ”: serum HCV RNA < LOQ (limit of quantification) after 4 weeks of treatment • RVR4LOD: “Rapid Virologic Response by LOD”: serum HCV RNA < LOD (limit of detection) after 4 weeks of treatment • EVR: “Early Virologic Response”: HCV RNA decrease ≥ 2 log10 or HCV RNA < LOQ (limit of quantification) after 12 weeks of treatment • PLEASE SEE PROTOCOL |
| Obiettivo secondario principale: esplorare se con un periodo di trattamento più corto (24 settimane) guidato dalla risposta al trattamento in corso di trattamento (response-guide therapy) si possa ottenere un tasso di SVR24 simile a quello ottenuto con la triplice terapia (DEB025 in associazione a PEG-IFN-α2a + RBV) per 48 settimane Per maggiori dettagli consultare il capitolo 3 del protocollo originale. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Eligible patients have to fulfill all of the following criteria: 1. Written informed consent obtained before performance of any study-related assessment; 2. Males or females aged ≥18 and ≤ 70 years; 3. Body Mass Index ≥ 18 and ≤ 36 kg/m2; 4. Chronic hepatitis C virus infection diagnosed : • Positive for anti-HCV antibody, or HCV RNA or an HCV genotype test at least 6 months before screening, with positive HCV RNA and anti-HCV antibody tested at the time of screening, OR • Positive for anti-HCV antibody and HCV RNA at the time of screening with a liver biopsy within 3 years before randomization, consistent with chronicity of HCV infection (presence of fibrosis); 5. Serum HCV RNA ≥ 1000 IU/ml (3 log10) assessed by qPCR (quantitative polymerase chain reaction) or equivalent, no upper limit; 6. Infection with HCV genotype 1; mixed infections with other genotypes will not be eligible; 7. No previous treatment for Hepatitis C virus infection – i.e. HCV treatment naïve; 8. One of the following liver evaluation: • A liver biopsy within 3 years prior to baseline. If cirrhosis has been previously diagnosed with a biopsy there is no need to repeat the biopsy. • Transient elastography (FibroScan) within 6 months prior to baseline. 9. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception to be eligible. The contraceptive regimen must be maintained during the treatment period and for 7 months after the last DEB025 or RBV dose. Highly effective contraception is defined as either: 1. Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. 2. Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment 3. Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female study subjects, the vasectomised male partner should be the sole partner for that patient. 4. Use of a combination of two of the following methods (a+b during treatment, a+b or a+c or b+c after discontinuation of DEB025): a. Placement of - an intrauterine device (IUD) or - an intrauterine system (IUS) b. Barrier methods of contraception: - Condom with spermicide or - Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository - c. Only 4 weeks after permanent discontinuation of DEB02/placebo: Use of oral, injected or implanted hormonal methods of contraception. Women are considered not to be of child bearing potential (thus eligible without contraception) if they: • are post menopausal as defined as at least 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms), or PLEASE SEE PROTOCOL |
| criteri di inclusione principali • Donne e uomini tra i 18 e i 70 anni d’età che abbiano firmato il consenso informato scritto prima di qualsiasi valutazione prevista dallo studio • Diagnosi di epatite cronica C in base a: • positività agli anticorpi per HCV o HCV RNA positivo o determinazione del genotipo dell’HCV almeno 6 mesi prima dello screening, in presenza di positività degli anticorpi anti-HCV o HCV RNA positivo al momento dello screening OPPURE • positività degli anticorpi anti-HCV e HCV RNA positivo al momento dello screening in presenza di evidenza di cronicizzazione dell’infezione da HCV (presenza di fibrosi) tramite biopsia epatica effettuata nei 3 anni precedenti la randomizzazione • Infezione da HCV genotipo 1; le infezioni miste o da altri genotipi non sono eleggibili • Disponibilità di una delle seguenti valutazioni epatiche: biopsia epatica effettuata nei 3 anni precedenti il basale o elastografia transiente (FibroScan) effettuata nei 6 mesi precedenti il basale • Livelli sierici di HCV RNA ≥ 1000 IU/ml (3 log10) determinati tramite PCR quantitativa o saggio equivalente • Pazienti che non sono stati precedentemente trattati • I pazienti con cirrosi compensata sono eleggibili a meno che non rientrino in uno dei criteri di esclusione |
|
| E.4 | Principal exclusion criteria |
| Patients fulfilling any of the following criteria are not eligible for inclusion into this study: 1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives of that medication before enrollment, whichever is longer; 2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes; 3. Any medical contraindications to peg-IFNα and/or RBV treatment; 4. Active or suspected cancer, or a history of malignancy where the risk of recurrence is ≥ 20% within 2 years; 5. HBsAg positive; 6. HIV positive; 7. Elevated (>ULN) total bilirubin level documented on more than one (>1) occasion during the past 6 months 8. Documented history of Gilbert’s disease 9. Presence or history of hepatic decompensation, defined by any of the following: • Grade 3 or 4 esophageal or gastric varices, history of upper gastrointestinal bleeding or patients needing primary prophylaxis for varices bleeding • Ascites • Signs of hepatic encephalopathy • Serum albumin < 35 g/L • Prolonged prothrombin time expressed as international normalized ratio (INR) > 1.5 10. Hepatocellular carcinoma (HCC): • Patients with an alpha-fetoprotein (AFP) level ≥ 5 × ULN are excluded. • A liver imaging assessment not older than 2 months prior to the screening visit, with no evidence for focal lesion(s) suggestive of hepatocellular carcinoma is required. Patients with cirrhosis on biopsy or an elasticity score ≥ 14.8 kPa on FibroScan or an elevated AFP (> ULN) must have either a liver ultrasound with contrast medium, a computed tomographic (CT) scan, or magnetic resonance imaging (MRI) to exclude HCC. • For all other patients a conventional liver ultrasound may be performed to exclude HCC. 11. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL) either at screening or baseline; 12. Men whose female partners are pregnant or intends to become pregnant while the male patient is receiving study treatment or within 7 months of the last DEB025 or RBV dose.; 13. Men UNLESS they are using a condom with spermicide during intercourse while on treatment and for 7 months after the last DEB025 or RBV dose. Male patients should not father a child in this period. 14. Use of any other medication (including over the counter medication and herbal products) within 30 days before baseline or within 5 drug half-lives of that medication (whichever is longer) that are known inhibitors/inducers of cytochrome 450 3A, substrates of cytochrome 450 3A, substrates of P-gp, or substrates/inhibitors of OATPs, MRP2 or BSEP, or are mentioned in the list of; prohibited medications PLEASE SEE PROTOCOL |
| criteri di esclusione principali: • Pazienti che stanno assumendo altri farmaci sperimentali al momento dell’arruolamento o che li hanno assunti nei 30 giorni precedenti l’inizio dello studio o in un periodo di tempo pari a 5 emivite del farmaco, considerando il periodo più lungo • HBsAg positivi • HIV positivi • Anamnesi o evidenza di scompenso epatico • Carcinoma epatocellulare • Elevati livelli di bilirubina totale (>ULN) documentati in almeno 2 momenti durante gli ultimi 6 mesi • Anamnesi di malattia di Gilbert • Pazienti che stanno assumendo o hanno recentemente assunto un qualsiasi farmaco (compresi i farmaci da banco e i prodotti a base di erbe) nei 30 giorni precedenti la visita basale o in un periodo di tempo pari a 5 emivite di un qualsiasi farmaco* noto per essere: un inibitore/induttore del citocromo 450 3A, substrato noto del citocromo 450 3A oppure un substrato per cui ci potrebbe essere una interazione clinica importante con il citocromo 450 3A non ancora analizzata (per es i contraccettivi ormonali) substrato della glicoproteina P di membrana (P-glycoprotein, P-gp) substrato/inibitore di trasportatori anionici organici (organic anion-transporting polypeptide OATPs), substrato/inibitore della multidrug resistance protein-2 (MRP2) substrato/inibitore della pompa di efflusso dei sali biliari (Bile Salt Export Pump, BSEP) o sono indicati nella lista di medicinali proibiti * in caso di somministrazione concomitante si consideri il farmaco con l’emivita più lunga • Donne fisiologicamente in grado di iniziare una gravidanza A MENO CHE non utilizzino metodi contraccettivi ad alta efficacia fino a 7 mesi dopo la fine del trattamento. • Donne in gravidanza o allattamento • Uomini la cui coniuge/partner sia in stato di gravidanza o abbia intenzione di intraprendere una gravidanza in un periodo di tempo comprensivo di 7 mesi dopo la fine del trattamento. Uomini che siano d’accordo nell’utilizzare adeguati metodi contraccettivi fino a 7 mesi dopo la fine del trattamento. • Anamnesi di patologia psichiatrica severa o non controllata, in particolare depressione, compreso precedente ospedalizzazione o precedenti tentativi di suicidio. Anamnesi di patologia psichiatrica moderata, in particolare depressione, negli ultimi 5 anni • Titolo degli anticorpi antinucleo (ANA) ≥ 1:160 allo screening e/o evidenza alla biopsia epatica di epatite autoimmune • Consumo di alcool > 20 g al giorno per le donne e > 30 g al giorno per gli uomini • Anamnesi di trapianto d’organo con organo funzionante, eccetto trapianto di cornea e di capelli |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy assessment will be the HCV RNA in serum (IU//ml) 24 weeks after end of treatment. |
| l’endpoint primario di efficacia è la risposta virologica sostenuta (SVR24) definita come HCV RNA non determinabile (< LOD*) 24 settimane dopo la fine del trattamento. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks after end of treatment. |
| 24 settimane dopo la fine del trattamento. |
|
| E.5.2 | Secondary end point(s) |
| 1) Rapid Virological response by limit of detection (RVR4LOD), Rapid Virological response by limit of quantification (RVR4LOQ) – defined as serum HCV RNA below LOD or LOQ respectively after 4 weeks of treatment 2)-Early Virological Response (EVR): serum HCV RNA reduction by at least 2Log10 or serum HCV RNA below LOQ 12 weeks after treatment start -partial Early Virological Response (pEVR): serum HCV RNA reduction by at least 2Log10 but still detectable 12 weeks after treatment start -complete Virological Response (cEVR): serum HCV RNA below LOD 12 weeks after treatment start -eRVRLOD: RVR4LOD achieved and maintained 12 weeks after treatment start -eRVRLOQ: RVR4LOQ achieved and maintained 12 weeks after treatment start 3)-End of treatment response (ETR) – defined as HCV RNA undetectable by limit of detection, -Sustained Virological Response Week 12 (SVR12) defined as serum HCV RNA undetectable by limit of detection (LOD) 12 weeks after treatment completion - Sustained Virological Response Week 48 (SVR48) defined as serum HCV RNA undetectable by limit of detection (LOD) 48 weeks after treatment completion 4)Change in liver enzyme (ALT and bilirubin) and hematological patient profiles (platelets, neutrophils, hemoglobin) during treatment phase. |
| Risposta virologica rapida, definita come HCV RNA sierico < LOD dopo 4 settimane di trattamento (RVR4LOD) Risposta virologica rapida, definita come HCV RNA sierico < LOQ* dopo 4 settimane di trattamento (RVR4LOQ) Relapse, definito come HCV RNA misurabile nelle 24 settimane di follow-up dopo la fine del trattamento dopo aver raggiunto l’ETR* Breakthrough virologico, definito come aumento in corso di trattamento dell’HCV RNA ≥ 1 log10 sopra il nadir* oppure HCV RNA misurabile in corso di trattamento dopo che precedentemente, sempre in corso di trattamento, era risultato non misurabile. Cambiamento degli enzimi epatici (ALT - bilirubina)/profilo ematologico dei pazienti - |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 1) 4 weeks after treatment start 2) 12 weeks after treatment start 3) at treatment completion whenever it occurs, 12 and 48 weeks after treatment completion 4) 48 weeks |
| Risposta virologica rapida, definita come HCV RNA sierico < LOD dopo 4 settimane di trattamento. Risposta virologica precoce (EVR=Early Virological response) 12 settimane dopo l'inizio del trattamento. Relapse, definito come HCV RNA misurabile nelle 24 settimane di follow-up dopo la fine del trattamento dopo aver raggiunto l’ETR* : 12 e 48 settimane dopo la fine del trattamento. Cambiamento degli enzimi epatici (ALT -bilirubina)/profilo ematologico dei pazienti : 48 settimane - |
|
| 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 | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| - Stesso farmaco ad altro dosaggio |
| - same IMP used at different dosage |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Hong Kong |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Taiwan |
| Thailand |
| United States |
| Vietnam |
|
| 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
|
| LPLV : 30/APR/2013 |
| • data di fine studio (LPLV): 30 aprile 2013 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 22 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 23 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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