| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C Virus Infection |
| Infezione cronica da virus HCV |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 17.0 |
| 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 |
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| 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 | 10008912 |
| E.1.2 | Term | Chronic hepatitis C |
| 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 |
The primary objectives of this study are:
- To evaluate the efficacy of treatment with SOF/GS-5816 for 12 weeks in subjects with chronic HCV infection as measured by the proportion of subjects with SVR12
- To evaluate the safety and tolerability of treatment with SOF/GS-5816 for 12 weeks |
Gli obiettivi primari del presente studio sono:
• Valutare l’efficacia del trattamento con combinazione a dose fissa (CDF) di sofosbuvir (SOF)/GS-5816 per 12 settimane in soggetti portatori di infezione cronica da HCV in base alla percentuale di soggetti con risposta virologica sostenuta a 12 settimane dopo la cessazione del trattamento (RVS12)
• Valutare la sicurezza e la tollerabilità del trattamento con SOF/GS-5816 per 12 settimane
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
- To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of treatment (SVR4 and SVR24)
- To evaluate the proportion of subjects with virologic failure
- To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of treatment
- To evaluate the emergence of viral resistance to SOF and GS-5816 during treatment and after cessation of treatment
- To characterize steady state pharmacokinetics of study drugs |
Gli obiettivi secondari:
• Determinare la percentuale di soggetti che ottengono una RVS a 4 e 24 settimane dopo la cessazione del trattamento (RVS4 e RVS24)
• Valutare la percentuale di soggetti con fallimento virologico
• Valutare la cinetica dell’RNA virale in circolo durante il trattamento e dopo la sua cessazione
• Valutare la comparsa di resistenza virale nei confronti di SOF e GS-5816 durante il trattamento e dopo la sua cessazione
• Caratterizzare la farmacocinetica allo stato stazionario dei farmaci oggetto di studio
Gli obiettivi esplorativi
• Identificare o validare i marcatori genetici che possono essere predittivi della storia naturale della malattia, della risposta alla terapia e/o della tollerabilità delle terapie mediche sulla base di una ricerca genetica (ad esempio, farmacogenomica), in soggetti che l’autorizzano con consenso separato e specifico
• Verificare gli effetti del trattamento sulla qualità della vita correlata alla salute.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional Pharmacokinetic (PK) Substudy:
All subjects, with a target of up to 50 participants, will be eligible to participate in the PK substudy if consent is obtained. An intensive serial PK sample collection (samples obtained over 24 hours post-dose) will be performed at the Week 2 or Week 4 on-treatment visit to determine the steady-state pharmacokinetics of sofosbuvir (and its metabolites GS-566500 and GS-331007), GS-5816 and GS-5816 metabolites (if appropriate).
Optional Pharmacogenomics (PG) Substudy:
All subjects will be eligible to participate in the PG substudy.
For subjects who provide separate consent for optional genetic testing, an additional blood sample will be obtained for possible genetic discovery research to identify or validate genetic markers (e.g., pharmacogenomics) that may be predictive of the safety and/or tolerability of study drug used in this protocol. This sample is recommended to be collected at the Baseline/Day 1 visit, but may be collected at any time during the study or at a separate post-study visit, if necessary. |
Sottostudio di farmacocinetica (FC)
Tutti i soggetti, con un target massimo di 50 partecipanti, saranno idonei a partecipare al sottostudio di FC a condizione che lo autorizzino. Una raccolta intensiva di campioni seriali (campioni ottenuti nell’arco delle 24 ore post-somministrazione) per l’analisi FC sarà effettuata in occasione della visita in corso di trattamento alla settimana 2 o alla settimana 4 al fine di determinare la farmacocinetica allo stato stazionario di SOF (e dei suoi metaboliti GS-566500 e GS-331007), come anche di GS-5816 e dei suoi metaboliti (ove applicabile).
Studio di farmacogenomica (FG)
I partecipanti che avranno fornito il proprio consenso saranno sottoposti al prelievo di un campione di sangue in occasione della visita prevista al baseline/giorno 1. Se non sarà prelevato in occasione della visita prevista al baseline/giorno 1, il campione potrà essere prelevato in qualsiasi momento durante lo studio.
Studio di registro per le sequenze
I soggetti che non ottengono una RVS potranno essere arruolati in uno studio osservazionale di registro per le sequenze. Lo studio di registro per le sequenze è finalizzato a monitorare la persistenza delle mutazioni di HCV resistenti ai farmaci. Lo studio di registro per le sequenze è descritto in un protocollo separato.
Studio di registro per la RVS
Tutti i soggetti che ottengono una RVS potranno essere arruolati nello studio osservazionale di registro per la RVS. Lo studio di registro per la RVS è finalizzato a valutare la durata della RVS. Lo studio di registro per la RVS è descritto in un protocollo separato.
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| E.3 | Principal inclusion criteria |
1) Willing and able to provide written informed consent
2) Male or female, age greater than or equal to 18 years
3) HCV RNA greater than or equal to 100,000 IU/mL at Screening
4) HCV genotype 1, 2, 4, 5, 6, or indeterminate assessed at Screening by the Central Laboratory.
5) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy
6) Classification as treatment naïve or treatment experienced:
a) Treatment naïve is defined as having never been exposed to approved or experimental HCV-specific direct-acting antiviral agents or prior treatment of HCV with interferon or ribavirin
b) Treatment experienced is defined as prior treatment failure to a regimen containing interferon either with or without RBV that was completed at least 8 weeks prior to Baseline/Day 1. Subject must not have discontinued the prior regimen that resulted in virologic failure due to an adverse event.
i) The subject’s medical records must include sufficient detail of prior virologic failure to allow for categorization of prior response, as either:
(1) Non-Responder: Subject did not achieve undetectable HCV RNA levels while on treatment, or
(2) Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during treatment or within 4 weeks of the end of treatment but did not achieve SVR
7) Cirrhosis Determination (approximately 20% of subjects may have cirrhosis)
a) Cirrhosis is defined as any one of the following
i) Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥5)
ii) FibroTest® score > 0.75 AND an AST:platelet ratio index (APRI) > 2 during Screening
iii) Fibroscan with a result of >12.5 kPa
b) Absence of cirrhosis is defined as any one of the following:
i) Liver biopsy within 2 years of Screening showing absence of cirrhosis
ii) FibroTest® score ≤ 0.48 AND APRI ≤ 1 performed during Screening
iii) Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Baseline/Day 1
In the absence of a definitive diagnosis of presence or absence of cirrhosis by Fibrotest® /APRI using the above criteria, a liver biopsy or fibroscan is required. Liver biopsy results will supersede Fibrotest® /APRI or fibroscan results and be considered definitive.
8) Liver imaging within 6 months of Baseline/Day 1 is required in cirrhotic patients only to exclude hepatocellular carcinoma (HCC)
9) Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Baseline/Day 1 prior to randomization.
10) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
11) Lactating females must agree to discontinue nursing before the study drug is administered
12) Subject must be of generally good health, with the exception of chronic HCV infection, as determined by the Investigator.
13) Subject must be able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments. |
• Valori di HCV RNA ≥ 100,000 IU/mL allo screening;
• Infezione da HCV allo screening genotipo 1, 2, 4, 5, 6 o indeterminato;
• Infezione cronica da HCV (≥ 6 mesi);
• Classificazione come trattamento naïve o già sperimentato;
• Diagnosi di cirrosi (circa il 20% dei soggetti possono avere cirrosi);
• Esami epatici strumentali che escludano nei sei mesi precedenti il basale/giorno 1 la presenza di un epatocarcinoma (HCC) sono richiesti per i pazienti con cirrosi.
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| E.4 | Principal exclusion criteria |
1) Current or prior history of any of the following:
a) 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.
b) Gastrointestinal disorder or post operative condition that could interfere with the absorption of the study drug.
c) Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy.
d) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
e) Solid organ transplantation.
f) Significant pulmonary disease, significant cardiac disease or porphyria.
g) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within the last 5 years. Subjects with psychiatric illness (without the prior mentioned conditions) that is well-controlled on a stable treatment regimen for at least 12 months prior to randomization or has not required medication in the last
12 months may be included.
h) Malignancy within the 5 years prior to screening, with the exception of specific cancers that have been cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for possible malignancy are not eligible.
i) Significant drug allergy (such as anaphylaxis or hepatotoxicity).
2) Screening ECG with clinically significant abnormalities
3) Subjects has the following laboratory parameters at screening:
a) ALT > 10 x the upper limit of normal (ULN)
b) AST > 10 x ULN
c) Direct bilirubin > 1.5 x ULN
d) Platelets < 50,000/uL
e) HbA1c > 8.5%
f) Creatinine clearance (CLcr) < 60 mL /min as calculated by the Cockcroft-Gault equation
g) Hemoglobin < 11 g/dL for female subjects; < 12 g/dL for male subjects.
h) Albumin < 3 g/dL
i) INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR
4) Prior exposure to SOF or other nucleotide analogue HCV NS5B inhibitor or any HCV NS5A inhibitor.
5) Pregnant or nursing female or male with pregnant female partner.
6) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, alfa-1 antitrypsin deficiency, cholangitis).
7) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
8) Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug screen will exclude subjects unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by the investigator.
9) Use of any prohibited concomitant medications
10) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone equivalent > 10 mg/day).
11) Known hypersensitivity to GS-5816, SOF, or formulation excipients.
12) History of clinically significant hemoglobinopathy (e.g., sickle cell disease, thalassemia) |
• patologia clinicamente significativa (differente dall'HCV) oppure ogni altra condizione clinica che possa interferire con il trattamento, la valutazione o l'aderenza al protocollo:
o disordini gastrointestinali o condizioni post operatorie che possano interferire con l'assorbimento dei farmaci in studio;
o difficoltà nel prelievo di sangue e/o difficile accesso venoso per fini di flebotomia;
o decompensazione epatica clinica (per es. ascite, encefalopatia o emorragia di varici);
o trapianto d'organo solido;
o malattia cardiaca significativa;
o ospedalizzazione psichiatrica, tentativo di suicidio, e/ periodo di disabilità a seguito di patologia psichiatrica negli ultimi 5 anni. Possono essere inclusi soggetti con malattia psichiatrica (senza le condizioni precedenti) tenuta sotto controllo con regime di trattamento permanente per almeno 12 mesi prima della randomizzazione o i soggetti che non hanno necessitato di trattamento negli ultimi 12 mesi.
o Neoplasie maligne entro i cinque anni precedenti lo screening, con l'eccezione di tumori specifici che sono stati curati con resezione chirurgica (carcinoma a cellule basali, ecc). Soggetti sottoposti a valutazione di neoplasie maligne non sono eleggibili.
o Allergie significative a farmaci (come anafilassi o epatotossicità).
• ECG allo screening con anormalità significative;
• Soggetti con i seguenti vaori di laboratorio allo screening:
o ALT > 10 volte il limite superiore (ULN)
o AST > 10 x ULN
o Bilirubina diretta > 1.5 x ULN
o piastrine < 50,000/uL
o HbA1c > 8.5%
o Clearance della creatinine (CLcr) < 60 mL /min calcolato in base all’equazione Cockcroft-Gault equation
o Emoglobina < 11 g/dL per soggetti femminili; < 12 g/dL per soggetti maschili
o Albumina < 3 g/dL
o INR > 1.5 x ULN ad eccezione di soggetti coni emofilia nota o in regime costante di anticoagulanti che può alterare il valore di INR
• Precedente esposizione a SOF o altri analoghi inibitori di HCV NS5B o di HCV NS5A
• Infezione da HBV o da HIV;
• Infezione cronica epatica di eziologia diversa da HCV;
• Casi clinici rilevanti negli ultimi 12 mesi di abuso di alcol o droga;
• Uso in concomitanza di farmaci proibiti;
• Uso continuativo di farmaci immunosoppressori somministrati per via sistemica (ad esempio prednisone equivalente > 10 mg die);
• Anamnesi di emoglobinopatia di rilevanza clinica (ad esempio anemia falciforme, talassemia).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after cessation of therapy) in the Full Analysis Set (FAS) population.
The primary safety endpoint is any AE leading to permanent discontinuation of study drug(s). |
• l’end point primario di efficacia e la SVR12 (HCV RNA <LLOQ 12 settimane dopo la fine della terapia) nella popolazione del Full Analysis Set (FAS)
• l’end point primario di sicurezza è ogni evento avverso che conduca alla terminazione permanente dell’assunzione del farmaco sperimentale.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The safety and tolerability endpoints are evaluated during the course of treatment. The efficacy endpoint is evaluated 12 weeks after discontinuation of therapy. |
• Sicurezza e tollerabilità: continuativo durante la durata dello studio
• Efficacia: 12 settimane dopo l’ultima dose di trattamento
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| E.5.2 | Secondary end point(s) |
- The proportion of subjects with: HCV RNA < LLOQ at 4 and 24 weeks after cessation of therapy (SVR4 and SVR24)
- The proportion of subjects with HCV RNA < LLOQ on treatment
- HCV RNA change from Baseline/Day 1
- The proportion of subjects with virologic failure |
• Proporzione di soggetti con HCV RNA < LLOQ a 4 e 24 settimane dal termine della terapia (SVR4 and SVR24)
• Proporzione di soggetti con HCV RNA < LLOQ durante il trattamento
• Cambiamenti al HCV RNA dalla visita basale/giorno 1
• Proporzione di soggetti con fallimento virologico.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The efficacy endpoints are evaluated 4 and 24 weeks after discontinuation of therapy.
The other endpoints are evaluated during the course of treatment. |
• gli end point secondari di efficacia verranno valutati a 4 e 24 settimane dopo il trattamento
• gli altri end point verranno valutati nel corso del trattamento. |
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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 | 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 | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Australia |
| Belgium |
| Canada |
| France |
| Germany |
| Hong Kong |
| Italy |
| New Zealand |
| United Kingdom |
| United States |
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| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| 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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