| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| chronic hepatitis C |
| epatite cronica da HCV |
|
| E.1.1.1 | Medical condition in easily understood language |
| chronic hepatitis C |
| epatite cronica da HCV |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10019805 |
| E.1.2 | Term | Hepatobiliary disorders |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10021881 |
| E.1.2 | Term | Infections and infestations |
| 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 evaluate the proportion of subjects with sustained viral response 12 (SVR 12) weeks after cessation of treatment in HCV-Infected Patients, with non- severe fibrosis, with or without insulin resistance (IR) and/or diabetes mellitus (DM) treated with EBR/GZR Fixed-Dose Combination for 8 Weeks in G1b Treatment-Na¿ve. . |
| Valutare la proporzione di soggetti con risposta virologica sostenuta 12 settimane(SVR12) dopo la cessazione di un trattamento con Elbasvir/Grazoprevir, in dose fissa combinata, per 8 settimane in pazienti con infezione da HCV, di genotipo 1b (G1b), naive a precedenti trattamenti, con basso grado di fibrosi F0-F2, con o senza insulino resistenza (IR) e diabete mellito (DM). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety/tolerability of EBR/GZR treatment
To determine the proportion of subjects who attain SVR at 24 weeks after cessation of treatment (SVR24)
To evaluate the proportion of subjects with virologic failure
To evaluate the emergence of viral resistance to EBR/GZR at failure
To evaluate insulin resistance using homeostatic model assessment of insulin resistance (HOMA-IR) at baseline and follow-up week 12 (exploratory analysis)
Comparisons between clinically relevant subgroups (including IR and DM) according SVR12 and SVR24 (exploratory analysis
|
Valutare la sicurezza e la tollerabilit¿ del trattamento con EBR / GZR
Determinare la proporzione di soggetti che raggiungono l'SVR a 24 settimane dopo la cessazione del trattamento (SVR24)
Valutare la proporzione di soggetti con fallimento virologico
Valutare l'insorgenza di resistenza virale a EBR / GZR in caso di fallimento
Valutare la resistenza all'insulina mediante la valutazione del modello omeostatico della resistenza all'insulina (HOMA-IR) al basale e alla 12¿ settimana di follow-up
Confronti tra sottogruppi clinicamente rilevanti (inclusi IR e DM) secondo SVR12 e SVR24 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Willing and able to provide written informed consent
• Male or female, age = 18 years
• Chronic HCV infection (= 6 months) documented by prior medical history or liver biopsy, only genotype 1b virus. (Positive for anti HCV antibody, HCV RNA, or an HCV genotype)
• Treatment-naïve with no prior exposure to any IFN, RBV, or approved or experimental HCV-specific DAA
• Non severe fibrosis (F= 2) according to Metavir score if a biopsy was performed or elasticity measured by Fibroscan® lower than 9.5 kPa or Fibrotest® lower than 0.59 or Fibrometer® lower than 0.63 if Fibroscan® cannot be performed.
• Patients who are HBV core antibody positive. These patients should be monitored for hepatitis flare or HBV reactivation during HCV treatment and post treatment follow-up. Appropriate patient management for HBV infection as clinically indicated should be initiated as recommended by the European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol (2017).
• Females of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1 prior to enrollment
• Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use 2 effective method(s) of contraception from at least two weeks prior to Day 1 through 14 days after the last dose of study drugs.
• A female subject who is not of reproductive potential is eligible without requiring the use of contraception. A female subjects who is not of reproductive potentials is defined as one who has either 1) reached natural menopause (defined as 12 months with no menses without an alternative medical cause), 2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy, or 3) bilateral tubal ligation.
• A male subject who is not of reproductive potential is eligible without requiring the use of contraception. A male subject who is not of reproductive potential is defined as: one who has undergone a successful vasectomy. A successful vasectomy is defined as: (1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post vasectomy.
• Lactating females must agree to discontinue nursing before starting study drug
• Subject must be of generally good health, with the exception of chronic HCV infection, and glucose abnormalities as determined by the Investigator
• Subject must be able to comply with the dosing instructions for study drug administration
|
• Capacità e volontà di firmare il consenso informato
• Uomini o donne di età > o uguale a 18 anni
• Infezione cronica da virus HCV genotipo 1b,da almeno 6 mesi, documentata da precedente storia medica o biopsia epatica (positività per anticorpi anti HCV,HCV RNA, o genotipizzazione.HCV).
• Pazienti HCV positivi naive, mai trattati o esposti a terapie con PR(Interferone, Ribavirina) o con i nuovi DAA specifici per l’HCV approvati o sperimentali.
• Fibrosi non severa (F<2) come da Score Metavir.
• Pazienti con HBV core anticorpo positivo. Questi pazienti dovrebbero essere monitorizzati per eventuale riattivazione da HBV durante il trattamento e al follow up post trattamento.
• Le donne in età fertile devono avere un test di gravidanza ematico negativo allo screening ed un test di gravidanza delle urine negativo al 1° giorno di arruolamento.
• Gli uomini e le donne eterosessuali in età fertile devono essere d’accordo nell’utilizzo di due efficaci metodi contraccettivi da almeno due settimane prima dell’arruolamento fino a 14 giorni dopo l’ultima dose del farmaco somministrato nello studio.
• Un soggetto di sesso femminile che non è potenzialmente riproduttiva è elegibile senza necessita di mezzi contraccettivi. Le donne che non sono fertili - come le donne naturalmente in menopausa ( -12 mesi di assenza di ciclo mestruale), le donne sottoposte da almeno 6 settimane ad una ovoectomia bilaterale anche senza isterectomia, e le donne sottoposte ad intervento di chiusura delle tube di Falloppio).
• Gli uomini che non sono potenzialmente riproduttivi sono elegibili senza necessità di usare mezzi contraccettivi. Gli uomini non potenzialmente riproduttivi sono coloro che sono stati sottoposti a vasectomia ( documentata al microscopio con azospermia o documentata da più di due anni senza gravidanza nonostante l’attività sessuale).
• Le donne in allattamento devono essere d’accordo a interrompere l’allattamento prima di essere arruolate.
• I soggetti devono essere in buona salute ad eccezione della infezione cronica da HCV e delle anomalie glucidiche come stabilito dal protocollo di studio.
• I soggetti devono essere in grado di seguire le istruzioni di somministrazione del farmaco dello studio.
|
|
| E.4 | Principal exclusion criteria |
• Is under the age of legal consent, is mentally or legally incapacitated, has a history of a clinically significant psychiatric disorder which, in the opinion of the investigator, would interfere with the study procedures.
• Current or prior history of any of the following:
o Clinically significant illness (other than HCV) or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol; subjects currently under evaluation for a potentially clinically significant illness (other than HCV) are also excluded
o Gastrointestinal disorder or post-operative condition that could interfere with the absorption of the study drug
o History of decompensation (e.g., clinical ascites, encephalopathy, and/or variceal hemorrhage)
o Solid organ transplantation (including hematopoietic stem cell transplants) other than kidney, cornea and hair.
o Significant cardiac disease
o Unstable psychiatric condition including hospitalization, suicidal attempt, and/or a period of disability as a result of their psychiatric illness within 2 years prior to Screening
o Malignancy within the 5 years prior to Screening, with the exception of specific cancers that have been cured by surgical resection (e.g., basal cell skin cancer, etc.). Subjects under evaluation for possible malignancy are not eligible
o Significant drug allergy (e.g., hepatotoxicity)
• Subject has the following laboratory parameters at Screening:
o ALT > 10 x the upper limit of normal (ULN)
o AST > 10 x ULN
o Direct bilirubin > 1.5 x ULN
o Platelets < 75,000/µL
o Creatinine clearance < 50 mL/min as calculated by the Cockcroft-Gault equation
o Hemoglobin < 10 g/dL
o Albumin < 3 g/dL
o INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regime affecting INR
• Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson's disease, alfa-1 antitrypsin deficiency, cholangitis)
• Infection with human immunodeficiency virus (HIV)
• HBsAg positive patients
• Clinically-relevant alcohol or drug abuse within 12 months of Screening.
• Use of any prohibited concomitant medication listed in the specific SmPC section.
• Known hypersensitivity to the study drug, the metabolites, or formulation excipient
• Is currently participating or has participated in a study with an investigational compound within 30 days of signing informed consent and is not willing to refrain from participating in another study.
• (female) is pregnant, lactating, expecting to conceive or donate eggs, or is of childbearing potential and unwilling to commit to two methods of birth control throughout treatment and after the completion of all treatment (see Inclusion Criteria); or male subject is planning to impregnate or provide sperm donation or has a female sexual partner of childbearing potential and is unwilling to commit to using a two methods of birth control throughout treatment and after the completion of all treatment (see Inclusion Criteria).
• had a life-threatening SAE during the screening period.
• is a member or a family member of the investigational study staff or sponsor staff directly involved with this study.
• has evidence or history of chronic hepatitis not caused by HCV, including but not limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, and autoimmune hepatitis.
• For subjects diagnosed with diabetes mellitus, documented HbA1c >8.5% (to exclude uncontrolled diabetes)
• Has any of the following conditions:
o Subject with a history of gastric surgery (e.g., stapling, bypass) or subject with a history of malabsorption disorders (e.g., celiac sprue disease).
o Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the trial.
o Has exclusionary laboratory values as listed below
• Exclusionary laboratory values:
o hemoglobin < LLN (lower limit of normal) of laboratory reference range
o neutrophils <1.5 x 103/µL (<1.2 x 103/µL for Blacks)
o platelets <75 x 103/µL
o direct bilirubin >1.5 x ULN
o Total Bilirubin >1.6 mg/dL unless history of Gilbert's disease. (If Gilbert's disease is the proposed etiology, this must be documented in the subject's chart)
o Serum Albumin < 3.0 g/dL (lower limit of normal) of laboratory reference range
o creatinine clearance <50 mL/min
o INR >1.5
o ALT >350
o AST >350 |
• Età <18 anni, mentalmente o legalmente incapaci e con storia clinica di malattie psichiatriche che secondo l’opinione dello sperimentatore potrebbero interferire con le procedure dello studio.
• Presenza attuale o pregressa di uno dei seguenti:
o Qualsiasi patologia clinicamente significativa(oltre alla infezione da HCV) che potrebbe interferire con il trattamento del soggetto , o con la compliance al protocollo; anche soggetti che sono in valutazione per la presenza di patologie importanti sono esclusi.
o Disturbi gastrointestinali o condizioni post operatorie che potrebbero interferire con l’assorbimento del farmaco.
o Storia di scompenso epatico (ascite clinica, encefalopatia e/o varici emorragiche)
o Trapianto di organo solido (incluso il trapianto di midollo osseo, oltre che di rene, di cornea e di capelli).
o Malattie cardiache rilevanti.
o Condizioni di instabilità psichiatrica incluso l’ospedalizzazione, l’istinto suicida, e/o un periodo di disabilità come conseguenza di malattia psichiatrica nei due anni precedenti lo screening.
o Tumore maligno nei 5 anni precedenti lo screening ad eccezione di alcuni tumori curati con resezione chirurgica.
o Allergie significative a farmaci (es epatotossicità).
• Soggetti che allo Screening presentano i seguenti parametri di laboratorio:
o ALT > 10 volte il limite superiore della norma (ULN)
o AST > 10 volte il limite superiore della norma (ULN)
o Bilirubina > 1.5 volte il limite superiore della norma (ULN)
o Piastrine < 75.000/µL
o Clearance della creatinina < 50 mL/min come calcolato dalla equazione di Cockcroft-Gault
o Emoglobina < 10 g/dL
o Albumina < 3 g/dL
o INR > 1.5 x ULN
• Malattia epatica cronica con eziologia non da HCV(emacromatosi, malattia di Wilson, deficienza di dell’alfa1 antitripsina, colangite).
• Infezione da HIV virus.
• Pazienti HBsAg-positvi
• Abuso di alcol o droghe nei 12 mesi precedenti lo screening.
• Uso di qualsiasi farmaco controindicato nella RCP.
• Ipersensibilità nota al farmaco dello studio, ai suoi metaboliti o agli eccipienti.
• Partecipazione ad altro protocollo di studio
• Evento avverso serio che ha messo in pericolo la vita del paziente durante il periodo di screening.
• Pazienti familiari dello staff dello sponsor dello studio
• Soggetti con evidenza o storia di epatite cronica non causata da HCV, inclusa la NASH, l’epatite indotta da farmaci e l’epatite autoimmune.
• Soggetti con diabete mellito con HbA1c > 8.5%.
• Soggetti con storia di chirurgia gastrica o con storia di malassorbimento gastrico( celiachia).
• Qualsiasi condizione medica che richieda l’uso di corticosteroidi durante il corso del trial.
• Valori di laboratorio come elementi di esclusione:
o Emoglobina < al di sotto del limite inferiore della norma(<LLN) del range di riferimento del laboratorio.
o Neutrofili <1.5 x 103/µL
o Piastrine <75 x 103/µL
o Bilirubina diretta >1.5 x ULN
o Bilirubina totale >1.6 mg/dL a meno di presenza della malattia di Gilbert.
o Albumina sierica < 3.0 g/dL
o Clearance della creatinina <50 mL/min
o INR >1.5
o ALT >350
o AST >350
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • To evaluate the proportion of subjects with SVR 12 weeks after cessation of treatment in HCV-Infected Patients, with non- severe fibrosis, with or without IR and/or DM treated with EBR/GZR Fixed-Dose Combination for 8 Weeks in G1b Treatment-Naïve [Time Frame: at 12 weeks ] |
| Percentuale di pazienti che raggiungono la SVR12 dopo trattamento con Elbasvir/Grazoprevir in dose fissa combinata, per 8 settimane in pazienti con infezione da HCV Naive G1b, con fibrosi non severa, con o senza insulino resistenza (IR) e/o diabete mellito (DM). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 20 weeks from start of therapy |
| 20 settimane dall'inizio del trattamento |
|
| E.5.2 | Secondary end point(s) |
¿ Evaluation of the safety and tolerability of EBV/GZR treatment by number of patients with treatment-related adverse events reported [Time Frame: 12 weeks after cessation of treatment ]
¿ Proportion of subjects who attain SVR24 [Time Frame: at 24 weeks after cessation of treatment ]
¿ Proportion of subjects with virologic failure [Time Frame: until 12 weeks after cessation of treatment ]
¿ Evaluation of the emergence of viral resistance to EBV/GZR during treatment and until 12 weeks after cessation of treatment in failing patients [Time Frame: until 12 weeks after cessation of treatment ]
¿ Assessments of insulin resistance were measured using HOMA-IR at baseline and follow-up week (FW)12 (exploratory analysis)
¿ Comparisons between clinically relevant subgroups (including IR and DM) according SVR12 and SVR24 (exploratory analysis)
|
Valutare la sicurezza e la tollerabilit¿ del trattamento con EBR / GZR
Determinare la proporzione di soggetti che raggiungono l'SVR a 24 settimane dopo la cessazione del trattamento (SVR24)
Valutare la proporzione di soggetti con fallimento virologico
Valutare l'insorgenza di resistenza virale a EBR / GZR in caso di fallimento
Valutare la resistenza all'insulina mediante la valutazione del modello omeostatico della resistenza all'insulina (HOMA-IR) al basale e alla 12¿ settimana di follow-up
Confronti tra sottogruppi clinicamente rilevanti (inclusi IR e DM) secondo SVR12 e SVR24 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks from start of therapy |
| 24 settimane dall'inizio della terapia |
|
| 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 | 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 | No |
| 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 | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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 | 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
|
|
| 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 | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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