| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Genotype 1 and Genotype 4 Hepatitis C Virus Infection |
| Infezione cronica da virus HCV genotipo 1 e 4 |
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| E.1.1.1 | Medical condition in easily understood language |
| Hepatitis C Virus Infection |
| Epatite C |
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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 | LLT |
| E.1.2 | Classification code | 10019751 |
| E.1.2 | Term | Hepatitis C virus |
| E.1.2 | System Organ Class | 100000004848 |
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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 as follows:
• To determine the antiviral efficacy of LDV/SOF FDC as measured by the proportion of subjects who attain SVR at 12 weeks after discontinuation of therapy (SVR12)
• To evaluate the safety and tolerability of each treatment regimen as assessed by review of the accumulated safety data
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Gli obiettivi primari di questo studio sono i seguenti:
• Determinare l’efficacia antivirale della compressa di ledipasvir/sofosbuvir (LDV/SOF) in combinazione a dose fissa (FDC) come misurato dalla percentuale di soggetti che raggiungono una risposta virale sostenuta (RVS) a 12 settimane dopo la sospensione del trattamento (RVS12)
• Valutare la sicurezza e la tollerabilità di ciascun regime terapeutico quando valutato mediante la revisione dei dati di sicurezza accumulati
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are as follows:
• To evaluate the kinetics of circulating HCV RNA during treatment and after treatment discontinuation
• To evaluate the emergence of viral resistance to SOF and LDV during treatment and after treatment discontinuation
• To characterize steady state pharmacokinetics (PK) of study drug
• To determine the proportion of subjects who attain SVR at 4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24)
The exploratory objectives of this study are:
• To identify or validate genetic markers that may be predictive of the natural history of disease, response to therapy and/or tolerability of medical therapies through genetic discovery research (e.g., pharmacogenomics), in subjects who provide their separate and specific consent
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Gli obiettivi secondari di questo studio sono i seguenti:
• Valutare la cinetica circolatoria dell’HCV RNA durante il trattamento e dopo l’interruzione del trattamento
• Valutare la comparsa di resistenza virale a SOF e LDV durante il trattamento e dopo l’interruzione del trattamento
• Caratterizzare la farmacocinetica (FC) allo stato stazionario del farmaco in studio
• Determinare la percentuale di soggetti che presenteranno una RVS alle settimane 4 e 24 dopo l’interruzione della terapia (RVS4 e RVS24)
Gli obiettivi esplorativi del presente studio sono:
• 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
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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 |
Pharmacogenomics (PG) Substudy
Pharmacogenomics sub study to identify or validate genetic markers that may be predictive of the natural history of disease, response to therapy and/or tolerability of medical therapies through genetic discovery research (e.g., pharmacogenomics), in subjects who provide their separate and specific consent |
Sottostudio di Farmacogenomica (PG)
Sottostudio di Farmacogenomica per 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
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| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1) Willing and able to provide written informed consent.
2) Male or female, age ≥ 18 years.
3) Body mass index (BMI) ≥ 18 kg/m2
4) Have received a kidney transplant more than 6 months before the Baseline visit
5) HCV RNA ≥ the lower limit of quantitation (15 IU/mL) at Screening
6) HCV genotype 1 or 4 at Screening as determined by the Central Laboratory. Any non definitive results will exclude the subject from study participation.
7) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy
1) HCV treatment status of one of the following:
a) HCV Treatment-naïve: No prior exposure to any IFN, RBV, or other approved or experimental HCV-specific DAA agent
b) HCV Treatment-Intolerant: Subjects that discontinued HCV treatment due to development or significant worsening of a treatment related adverse event
c) HCV Treatment-Experienced: Virologic failure during or after treatment. Subjects in this category must not have discontinued prior therapy due to an adverse event.
8) Have demonstrated absence of cirrhosis or have compensated 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) Fibroscan® (in countries where locally approved) showing cirrhosis or results > 12.5 kPa
iii) FibroTest® score of > 0.75 AND an AST: platelet ratio index (APRI) of > 2 during Screening
b) Absence of cirrhosis is defined as no evidence of cirrhosis and any one of the following:
i) Liver biopsy within 2 years of Screening showing absence of cirrhosis
ii) Fibroscan® (in countries where locally approved) within 6 months of Baseline/Day 1 with a result of ≤ 12.5 kPa
iii) FibroTest® score of ≤ 0.48 AND APRI of ≤ 1 during Screening
9) Liver imaging within 6 months prior to Baseline/Day 1 is required in subjects with cirrhosis to exclude hepatocellular carcinoma (HCC)
10) Screening ECG without clinically significant abnormalities
11) Subjects must have 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 cells/μL
e) HbA1c ≤ 10%
f) Creatinine clearance (CLcr) ≥ 40 mL /min, as calculated by the Cockcroft Gault equation {2202}
g) Hemoglobin ≥ 10 g/dL
h) Albumin ≥ 3g/dL
i) INR ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR.
12) Females of childbearing potential (as defined in Appendix 4) must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Baseline/Day 1 prior to enrollment.
13) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 4.
14) Male subjects must agree to refrain from sperm donation from the date of screening until 90 days after their last dose of study drug.
15) Subject must be of generally good health, with the exception of chronic HCV infection and renal disease, as determined by the Investigator.
16) Subject must be able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments, including all required post treatment visits. |
• Indice di massa corporea (BMI) ≥ 18 kg/m2;
• I soggetti hanno ricevuto trapianto di rene più di sei mesi prima della visita di baseline;
• Valori di HCV RNA ≥ 15 UI/ml allo screening;
• Infezione da HCV genotipo 1 o 4 allo screening;
• Assenza di 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 |
Subjects who meet any of the following exclusion criteria will not to be eligible for participation in this study.
1) Current or prior history of any of the following:
a) Clinically-significant illness (other than HCV and kidney disease) 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). The presence of varices will be accepted
e) Solid organ transplantation other than kidney.
f) Significant cardiac disease.
g) Psychiatric hospitalization and/or suicide attempt within the last 2 years. Subjects with psychiatric illness (without the prior mentioned conditions) that is well controlled on a stable treatment regimen for at least 6 months prior to enrollment or has not required medication in the last 6 months may be included.
h) Malignancy within 5 years prior to screening, with the exception of specific cancers that are entirely 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) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
3) Pregnant or nursing female or male with pregnant female partner.
4) Chronic liver disease of a non HCV etiology (e.g., hemochromatosis, Wilson’s disease, alpha 1 antitrypsin deficiency, cholangitis).
5) In the opinion of the Investigator, clinically-relevant alcohol or drug abuse within 12 months of Screening. A positive drug screen during Screening will exclude subjects unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by the Investigator.
6) Planned or anticipated second kidney transplant.
7) Use of any prohibited concomitant medications as described in Section 5.4 .
8) Known hypersensitivity to LDV, SOF, or formulation excipients.
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Anamnesi concomitante o antecedente di una delle seguenti condizioni:
• 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 oltre che al rene;
o malattia cardiaca significativa;
o ospedalizzazione psichiatrica, tentativo di suicidio negli ultimi 2 anni.
• Infezione da HBV o da HIV;
• Infezione cronica epatica di eziologia diversa da HCV;
• Pianificata o anticipato trapianto del secondo rene.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ (15 IU/mL) 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. The proportion of subjects with eGFR < 30 mL/min during study will be also evaluated. Safety endpoints will be summarized by treatment arms as the number (proportion) of subjects with events or abnormalities for categorical data or as an 8-number summary (n, mean, standard deviation, median, Q1, Q3, minimum, maximum) for continuous data. |
• l’end point primario di efficacia e la SVR12 (HCV RNA <LLOQ (15 IU/mL) 12 settimane dopo la fine della terapia nella popolazione del Full Analysis Set (FAS)
• l’end point primario di sicurezza è ogno evento avverso che conduca alla terminazione permante dell’assunzione del farmaco sperimentale. Verrà valutata inoltre la proporzione di soggetti con eGRF < 30 mL/min. Gli endpoint di sicurezza saranno analizzati per numero e percentuale di soggetti con eventi o anomalie per i valori categorici o per sommario a 8 cifre (n, media, deviazione standard, mediana, Q1, Q3, minimo, massimo) per i dati continui per ogni gruppo di trattamento. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy: 12 weeks post last treatment dose
Safety: Continuous throughout the duration of the study |
• Efficacia: 12 settimane dopo l’ultima dose di trattamento
• Sicurezza: continuativo durante la durata dello studio
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| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include the proportion of subjects with HCV RNA < LLOQ at 4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24), and the proportion of subjects with virologic failure.
Additional efficacy evaluations may include HCV RNA change from Baseline/Day 1, ALT normalization and viral kinetic parameters. |
• Gli end point secondari di efficacia includono la proporzione di soggetti con HCV RNA < LLOQ a 4 e 24 settimane dal termine della terapia (SVR4 and SVR24), e la proporzione di soggetti con fallimento virologico.
• Valutazioni aggiuntive di efficacia potrebbero includere modifiche al HCV RNA dalla visita di Baseline/Giorno 1, normalizzazione delle ALT e parametri cinetici virali.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoints will be assessed at 4 and 24 weeks following therapy
On treatment assessments will be conduced at screening, Day-1, Week 1, 2, 4, 8, 12, 16 and 24
Post treatment visits will occur at Weeks 4, 12 and 24 post treatment |
• gli end point secondari di efficacia verranno valutati a 4 e 24 settimane dopo il trattamento
valutazioni durante il trattamento saranno condotte allo screening, al giorno 1, alle settimane 1,2,4,8,12,16 e 24. Le visite post trattamento saranno effettuate alle settimane 4, 12 e 24 dopo il 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) | 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 | 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 | 2 |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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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| Last Subject Last Visit |
| Ultima visita dell'ultimo paziente |
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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 | 3 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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