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    Summary
    EudraCT Number:2016-003489-25
    Sponsor's Protocol Code Number:GS-US-337-4063
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-02-15
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-003489-25
    A.3Full title of the trial
    A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Ledipasvir/Sofosbuvir in Subjects with Genotype 1, 4, 5 and 6 Chronic HCV Infection Who are on Dialysis for End Stage Renal Disease
    Studio di fase 2, multicentrico, in aperto per valutare l¿efficacia e la sicurezza di Ledipasvir/Sofosbuvir in soggetti con infezione cronica da HCV di genotipo 1, 4, 5 e 6 che sono in dialisi per nefropatia allo stadio terminale
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial investigating the safety and efficacy of a drug combination Ledipasvir/Sofosbuvir for Subjects with hepatitis C who are on dialysis for kidney disease.
    Studio clinico per valutare l¿efficacia e la sicurezza della combinazione dei medicinali Ledipasvir/Sofosbuvir in soggetti con epatite C che sono in dialisi per malattia renale
    A.3.2Name or abbreviated title of the trial where available
    A trial investigating the safety and efficacy of a drug combination Ledipasvir/Sofosbuvir for Subjec
    Studio clinico per valutare l¿efficacia e la sicurezza della combinazione dei medicinali Ledipasvir/
    A.4.1Sponsor's protocol code numberGS-US-337-4063
    A.5.4Other Identifiers
    Name:NumeroIND;ClinicalTrials.govIDNumber:Numero IND: 115268 Clinical Trials.gov ID: NCT0303
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGILEAD SCIENCES INCORPORATED
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGilead Sciences, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGilead Sciences International Ltd.
    B.5.2Functional name of contact pointClinical Trials Mailbox
    B.5.3 Address:
    B.5.3.1Street AddressGranta Park
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeCB21 6GT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 1223 897 284
    B.5.5Fax number+44 1223 897 284
    B.5.6E-mailclinical.trials@gilead.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Harvoni
    D.2.1.1.2Name of the Marketing Authorisation holderGilead Sciences International Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLedipasvir
    D.3.9.1CAS number 1256388-51-8
    D.3.9.2Current sponsor codeGS-5885
    D.3.9.4EV Substance CodeSUB120165
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number90
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSofosbuvir
    D.3.9.1CAS number 1190307-88-0
    D.3.9.2Current sponsor codeGS-7977
    D.3.9.4EV Substance CodeSUB121170
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Hepatitis C virus infection
    Infezione da epatite C cronica
    E.1.1.1Medical condition in easily understood language
    Hepatitis C
    Epatite C
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10008912
    E.1.2Term Chronic hepatitis C
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10019744
    E.1.2Term Hepatitis C
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To evaluate the antiviral efficacy of treatment with LDV/SOF for 8,12, or 24 weeks in
    subjects with chronic hepatitis C virus (HCV) infection who are on dialysis for ESRD, as
    measured by the proportion of subjects with sustained viral response 12 weeks after cessation
    of treatment (SVR12)
    - To evaluate the safety and tolerability of each treatment regimen
    - Valutare l¿efficacia antivirale del trattamento con ledipasvir/sofosbuvir (LDV/SOF) per 8, 12 o 24 settimane in soggetti affetti da infezione cronica da virus dell¿epatite C (Hepatitis C Virus, HCV) che sono in dialisi per nefropatia allo stadio terminale (End Stage Renal Disease, ESRD), misurata in base alla percentuale di soggetti con risposta virale prolungata a 12 settimane (sustained viral response at 12 weeks, SVR12) dopo la cessazione del trattamento
    - Valutare la sicurezza e la tollerabilit¿ di ciascun regime di trattamento
    E.2.2Secondary objectives of the trial
    - To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of each study treatment regimen (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 LDV and SOF during treatment and after
    cessation of treatment
    - To evaluate the steady-state pharmacokinetics of LDV and SOF and its metabolites in
    subjects who are on dialysis for ESRD
    - Determinare la percentuale di soggetti che raggiungono l¿SVR a 4 e a 24 settimane dopo la cessazione di ciascun regime di trattamento dello studio (SVR4 e SVR24)
    - Valutare la percentuale di soggetti con mancata risposta virologica
    - Valutare la cinetica dell¿RNA circolante di HCV durante il trattamento e dopo la cessazione del trattamento
    - Valutare l¿insorgenza della resistenza virale a LDV e SOF durante il trattamento e dopo la cessazione del trattamento
    - Valutare la farmacocinetica allo stato stazionario di LDV e SOF e dei suoi metaboliti in soggetti che sono in dialisi per ESRD
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Pharmacogenomics
    Version: Amndt 1.0
    Date: 29/11/2016
    Title: Pharmacogenomics (PG) Substudy
    Objectives: In consenting participants, blood sample should be drawn at the Baseline/Day 1 visit. If not obtained at Baseline/Day1 visit, the sample may be drawn at any time during the study.

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Pharmacokinetic (PK) Substudies
    Subjects may consent to participate in either or both PK substudies.

    Intensive PK Substudy
    In consenting participants (target n=15), serial blood samples will be collected once at the Week 6, 8, or 12 on treatment visit at the following timepoints:
    0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose
    Plasma concentrations of LDV and SOF and its metabolites will be determined and PK
    parameters will be estimated as appropriate.

    Hemodialysis PK Substudy
    In consenting participants, (target n=10), blood samples will be collected at one hemodialysis
    session between Week 6 and Week 12, inclusive (as appropriate based on treatment regimen). A single blood sample will be collected within 10
    minutes before hemodialysis initiates. During hemodialysis, a single sample will be collected from both the arterial and venous sides of the dialyzer approximately 1 hour prior to conclusion of hemodialysis. Finally, a single blood sample will be collected within 10 minutes after hemodialysis concludes. Plasma concentrations of SOF and LDV and its metabolites will be determined and hemodialysis extraction ratio will be estimated as
    appropriate. Plasma concentrations of LDV and SOF and its metabolites will be determined and hemodialysis extraction ratio and fraction of dose
    removed by dialysis will be estimated as ppropriate.

    Farmacogenomica
    Versione: Amndt 1.0
    Data: 29/11/2016
    Titolo: Sottostudio di farmacogenomica (Pharmacogenomics, PG)
    Obiettivi: Nei partecipanti consenzienti, deve essere prelevato un campione di sangue alla visita Basale/Giorno 1. Se non viene acquisito alla visita Basale/Giorno 1, il campione pu¿ essere prelevato in qualsiasi momento durante lo studio.

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sottostudi farmacocinetici (pharmacokinetic, PK): (intensivo e di emodialisi)
    I soggetti possono acconsentire a partecipare a uno o entrambi i sottostudi PK.
    Sottostudio di PK intensiva
    Nei partecipanti consenzienti (target n = 15), saranno prelevati campioni di sangue seriali alle visite in corso di trattamento una volta alle Settimane 6, 8 o 12 (se applicabile) ai seguenti time point:
    ¿ 0 (pre-dose-5 minuti), 0.25, 0.5, 1, 2, 4, 6, 8, 10 e 12 ore post-dose
    Saranno determinate le concentrazioni plasmatiche di LDV e SOF e dei suoi metaboliti e saranno stimati i parametri PK a seconda dei casi.

    Sottostudio PK di emodialisi
    Nei partecipanti consenzienti (target n = 10), saranno prelevati campioni di sangue in occasione di una sessione di emodialisi tra la Settimana 6 e la Settimana 12, comprese (a seconda dei casi sulla base del regime di trattamento). Entro 10 minuti dall¿inizio dell¿emodialisi sar¿ prelevato un singolo campione di sangue. Durante l¿emodialisi, verr¿ prelevato un singolo campione di sangue sia dall¿accesso venoso che arterioso del dializzatore circa 1 ora prima della conclusione dell¿emodialisi.. Infine, verr¿ prelevato un singolo campione di sangue entro 10 minuti dopo la conclusione dell¿emodialisi.
    Saranno determinate le concentrazioni plasmatiche di LDV e SOF e dei suoi metaboliti e sar¿ appropriatamente stimato il rapporto di estrazione dell¿emodialisi.

    E.3Principal 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) Chronic HCV infection (= 6 months) as documented by prior medical history or liver biopsy
    4) HCV RNA = LLOQ at screening
    5) Genotype 1,4, 5 and 6 HCV as determined at Screening
    6) End stage renal disease (ESRD) requiring peritoneal dialysis (PD) or hemodialysis (HD)
    7)he most recent HCV treatment must have been completed at least 8
    weeks prior to Screening.
    8) Subjects must have a determination of treatment experience (treatment naïve vs. treatment experienced). Treatment naïve is defined as having never been exposed to an approved or experimental HCV-specific direct acting antiviral agents or prior treatment of HCV with interferon or ribavirin. All other patients will be considered treatment experienced.
    9) Subjects must have appropriate testing for determination of cirrhosis status.
    a) Presence of cirrhosis is defined as any one of the following:
    i) Fibroscan with a result of > 12.5 kPa
    ii) Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score = 5)
    iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score = 0.75 at screening
    b) Absence of cirrhosis is defined as any one of the following:
    i) Fibroscan with a result of = 12.5 kPa within = 6 months of Baseline/Day 1
    ii) Liver biopsy performed within 2 years of Screening showing absence of cirrhosis
    iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score < 0.75 at screening
    10) Liver imaging within 6 months of Baseline/Day 1 is required in cirrhotic subjects only, to exclude HCC
    11) Subjects with HIV-1 coinfection may be eligible, provided they satisfy these additional inclusion criteria:
    i) Completed at least 3 months of any prior HIV ARV therapy and maintained HIV RNA<50 copies/mL (or <LLOQ if the local laboratory assay’s LLOQ is 50 = copies/mL) and CD4 T-cell count > 100 cells/mm3 prior to Screening. Subjects with an isolated or
    unconfirmed HIV RNA >50 copies/mL (or >LLOQ if the local laboratory assay’s LLOQ
    is 50= copies/mL) are not excluded ii) On a stable ARV regimen for = 8 weeks prior to Screening and is expected to continue
    the current ARV regimen through the end of study.
    12) A negative serum pregnancy test is required for female subjects (unless permanently sterile
    or greater than two years post-menopausal).
    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) Lactating females must agree to discontinue nursing before the study drug is administered.
    15) Subject must be able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments
    Per essere eleggibili a partecipare a questo studio i soggetti devono soddisfare tutti i criteri di inclusione seguenti.
    1) Volontà e capacità di dare il proprio consenso informato scritto
    2) Maschio o femmina, età = 18 anni
    3) Infezione cronica da virus dell’epatite C (Hepatitis C Virus, HCV) (= 6 mesi) documentata da anamnesi pregressa o biopsia epatica
    4) RNA dell’HCV = limite inferiore di quantificazione (lower limit of quantification, LLOQ) allo screening
    5) HCV genotipo 1, 4, 5 e 6 determinato allo Screening
    6) Malattia renale in stadio terminale (End stage renal disease, ESRD) che richiede dialisi peritoneale (peritoneal dialysis, PD) o emodialisi (hemodialysis, HD)
    7) L’ultimo trattamento per HCV deve essere stato completato almeno 8 settimane prima dello screening
    8) I soggetti devono avere una determinazione dell’esperienza di trattamento (naïve al trattamento rispetto a pretrattati). Naïve al trattamento viene definito come il non essere mai stati esposti ad agenti antivirali ad azione diretta approvati o sperimentali che agiscono specificatamente contro l’HCV o trattamento pregresso di HCV con interferone o ribavirina. Tutti gli altri pazienti saranno considerati come pretrattati.
    9) I soggetti devono sottoporsi a un esame appropriato per determinare lo stato di cirrosi.
    a) La presenza di cirrosi è definita come una delle seguenti condizioni:
    i) Fibroscan con un risultato > 12,5 kPa
    ii) Biopsia epatica che mostri presenza di cirrosi (per es. punteggio Metavir = 4 o punteggio Ishak = 5)
    iii) In assenza di biopsia epatica o disponibilità di Fibroscan, punteggio FibroTest® = 0,75 allo screening
    b) L’assenza di cirrosi è definita come una delle seguenti condizioni:
    i) Fibroscan con un risultato = 12,5 kPa entro = 6 mesi dal basale/Giorno 1
    ii) Biopsia epatica effettuata entro 2 anni dallo Screening che mostri assenza di cirrosi
    iii) In assenza di biopsia epatica o disponibilità di Fibroscan, punteggio FibroTest® < 0,75 allo screening
    10) La diagnostica per immagini del fegato entro 6 mesi dal basale/Giorno 1 è richiesta solo nei soggetti cirrotici al fine di escludere la presenza di carcinoma epatocellulare (hepatocellular carcinoma, HCC)
    11) I soggetti con co-infezione da HIV-1 possono essere idonei, a condizione che soddisfino questi criteri di inclusione supplementari:
    i) Aver completato almeno 3 mesi di qualsiasi pregressa terapia ARV per l’HIV e aver mantenuto un RNA di HIV <50 copie/ml (o <LLOQ, se l’LLOQ del test di laboratorio locale è = 50 copie/ml) e la conta dei linfociti T CD4 > 100 cellule/mm3 prima dello screening. I soggetti con un RNA di HIV isolato o non confermato > 50 copie/ml (o >LLOQ, se l’LLOQ del test di laboratorio locale è = 50 copie/ml) non sono esclusi
    ii) Avere un regime stabile di ARV per = 8 settimane prima dello screening e previsione di proseguire il regime attuale di ARV fino alla fine dello studio (vedere criterio di esclusione 7).
    12) Per i soggetti di sesso femminile è necessario che un test di gravidanza sul siero dia risultato negativo (a meno che non siano permanentemente sterili o in post-menopausa da più di due anni).
    13) I soggetti di sesso maschile e femminile in età fertile che hanno rapporti eterosessuali devono accettare di utilizzare il/i metodo/i di contraccezione specificato/i nel protocollo, come descritto nell’Appendice 4.
    14) I soggetti femminili che allattano devono accettare di interrompere l’allattamento prima della somministrazione del farmaco in studio
    15) Il soggetto deve essere in grado di rispettare le istruzioni relative al dosaggio per la somministrazione del farmaco in studio e deve essere in grado di portare a termine il programma delle valutazioni dello studio.
    E.4Principal exclusion criteria
    Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
    1) Current or prior history of any of the following:
    a) Clinically-significant illness (other than HCV, HIV and kidney disease or co-morbidities
    associated with ESRD except as noted below) 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
    or ESRD) are also excluded.
    b) Current or prior history of significant cardiac disease including or resulting in:
    ¿ Hospital admission for significant cardiovascular disease (myocardial infarction,
    unstable angina, heart failure, hypertensive emergency) or has had a cardiovascular
    procedure (e.g. CABG or PTCA), within 6 months of Screening
    ¿ Cardiomyopathy with ejection fraction <50%
    c) Gastrointestinal disorder or postoperative condition that could interfere with the
    absorption of the study drug.
    d) Difficulty with blood collection and/or poor venous access for the purposes of
    phlebotomy.
    e) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
    f) Solid organ transplantation other than failed kidney transplants (current use of =5 mg/day
    of prednisone, or equivalent dose of corticosteroid, allowed).
    g) Significant pulmonary disease
    h) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of
    their psychiatric illness within the last 2 years.
    i) 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
    2) Screening ECG with clinically significant abnormalities
    3) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease,
    alfa-1 antitrypsin deficiency, cholangitis).
    5) Opportunistic infection (Appendix 5) within 6 months prior to Screening
    6) Infection (other than HIV or HCV) requiring parenteral therapy within 30 days prior to
    baseline.
    7) Life threatening SAE during the screening period
    8) 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. For subjects receiving ritonavir boosted atazanavir
    regimen, a direct bilirubin > 1.5 x ULN will be allowed if < 25% of the total bilirubin
    d) Platelets < 25,000/µL
    e) HbA1c > 9%
    f) Hemoglobin < 9 g/dL
    g) Albumin < 2.8 g/dL
    h) INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant
    regimen affecting INR
    i) Hepatitis B surface antigen positive
    9) Prior exposure to any HCV NS5A inhibitor.
    10) Male with pregnant female partner.
    11) Females who may wish to become pregnant and/or plan to undergo egg harvesting during the
    course of the study and up to 30 days of the last dose of study drug
    12) Males who may wish to donate sperm during the course of the study until at least 30 days
    after the last dose of study drug.
    13) 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.
    14) Use of any prohibited concomitant medications as described in Section 5.4.
    15) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone
    equivalent > 10 mg/day).
    16) Known hypersensitivity to LDV, SOF, the metabolites, or formulation excipient.
    17) For subjects with HIV-1 coinfection only:
    ¿ HIV-1 RNA >50 copies/mL
    ¿ CD4 T-cell count <100 cells/mm3
    ¿ HIV-2 positive test
    I soggetti che rispondono a uno qualsiasi dei seguenti criteri di esclusione non sono idonei per essere arruolati nel presente studio.
    1) Anamnesi attuale o pregressa per una qualsiasi delle seguenti condizioni:
    a) Malattia clinicamente significativa (diversa dall’HCV, dall’HIV e dalla malattia renale o co-morbidità associate all’ESRD ad eccezione di quanto indicato di seguito) o altre patologie mediche maggiori che potrebbero interferire con il trattamento del soggetto, la valutazione o la conformità al protocollo; sono esclusi anche i soggetti attualmente in corso di valutazione per la presenza di una malattia che può potenzialmente essere clinicamente significativa (diversa dall’HCV o dall’ESRD).
    b) Anamnesi attuale o pregressa di malattia cardiaca significativa che include o che porta a:
    • Ricovero ospedaliero per malattia cardiovascolare significativa (infarto del miocardio, angina instabile, insufficienza cardiaca, emergenza ipertensiva) o procedura cardiovascolare (es. bypass aortocoronarico [Coronary artery bypass graft, CABG] o angioplastia coronarica transluminale percutanea [Percutaneous transluminal coronary angioplasty, PTCA]) effettuata entro 6 mesi dallo Screening.
    • Cardiomiopatia con frazione di eiezione < 50%.
    c) Patologia gastrointestinale o condizione post-operatoria che potrebbe interferire con l’assorbimento del farmaco in studio.
    d) Problemi con i prelievi di sangue e/o accesso venoso difficile ai fini della flebotomia.
    e) Decompensazione epatica clinica (per es. ascite, encefalopatia o emorragia variceale).
    f) Trapianto di organo solido diverso da trapianto renale non riuscito (è consentito l’uso corrente di =5 mg/giorno di prednisone o una dose equivalente di corticosteroidi).
    g) Malattia polmonare significativa.
    h) Ricovero psichiatrico, tentativo di suicidio e/o periodo di invalidità conseguente alla malattia psichiatrica negli ultimi 2 anni.
    i) Malignità nei 5 anni precedenti lo screening, con l’eccezione di tumori specifici curati mediante resezione chirurgica (carcinoma cutaneo basocellulare ecc.). I soggetti in corso di valutazione per una possibile malignità non sono idonei.
    2) ECG eseguito allo screening con anomalie clinicamente significative.
    3) Epatopatia cronica con eziologia diversa dall’HCV (per es. emocromatosi, malattia di Wilson, deficit di alfa-1 antitripsina, colangite).
    4) Infezione con virus dell’epatite B (Hepatitis B Virus, HBV).
    5) Infezione opportunistica (Appendice 5) nei 6 mesi precedenti lo screening.
    6) Infezione (diversa dall’HIV o HCV) che richiede una terapia parenterale nei 30 giorni precedenti il basale.
    7) Evento avverso serio (SAE) che mette in pericolo di vita durante il periodo di screening.
    8) I soggetti che hanno i seguenti parametri di laboratorio allo screening:
    a) ALT > 10 X il limite superiore della norma (ULN)
    b) AST > 10 X ULN
    c) Bilirubina diretta > 1,5 x ULN. Per i soggetti che ricevono un regime a base di atazanavir potenziato con ritonavir, una bilirubina diretta > 1,5 x ULN sarà autorizzata se < 25% della bilirubina totale
    d) Piastrine < 25.000/µl
    e) HbA1c > 9%
    f) Emoglobina < 9 g/dl
    g) Albumina < 2,8 g/dl
    h) Rapporto internazionale normalizzato (International Normalized Ratio, INR) > 1,5 x ULN, a meno che il soggetto non presenti emofilia nota o è in regime anticoagulante stabile che influisce sull’INR
    i) Antigene di superficie dell’epatite B positivo
    9) Esposizione pregressa a qualsiasi inibitore di NS5A dell’HCV.
    10) Uomo con compagna incinta.
    11) Donne che desiderano rimanere incinta e/o prevedono di sottoporsi a prelievo di ovuli nel corso dello studio e fino a 30 giorni dall’ultima dose del farmaco in studio.
    12) Uomini che desiderano donare sperma nel corso dello studio fino a 30 giorni dopo l’ultima dose di farmaco in studio.
    13) Abuso di alcool o droghe clinicamente significativo entro 12 mesi dallo screening. La positività allo screening per droghe determinerà l’esclusione dei soggetti a meno che non possa essere spiegata da un farmaco prescritto; diagnosi e prescrizione devono essere approvati dallo Sperimentatore.
    14) Uso di qualsiasi farmaco concomitante vietato come descritto nella Sezione 5.4.
    15) Uso cronico di agenti immunosoppressori somministrati per via sistemica (per es. equivalente del prednisone > 10 mg/giorno).
    16) Nota ipersensibilità a LDV, SOF, ai metaboliti o agli eccipienti della formulazione.
    17) Solo per i soggetti con co-infezione da HIV-1:
    • RNA di HIV-1 > 50 copie/ml
    • Conta dei linfociti T CD4 <100 cellule/mm3
    • Test positivo all’HIV-2
    E.5 End points
    E.5.1Primary end point(s)
    The primary end point is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of treatment) in the Full Analysis Set (FAS) population.
    The primary safety endpoint is any AE that led to permanent discontinuation of study drug.
    L’endpoint di efficacia primario dello studio è la SVR12 in tutti i soggetti arruolati e trattati.
    L'endpoint primario di sicurezza è un qualsiasi AE che ha portato alla sospensione permanente del farmaco in studio.
    E.5.1.1Timepoint(s) of evaluation of this end point
    SVR 12 weeks
    SVR12 settimane
    E.5.2Secondary end point(s)
    Secondary endpoints include the following:
    ¿ The proportion of subjects with HCV RNA < LLOQ at 4 and 24 weeks after cessation of treatment (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
    ¿ The proportion of subjects who develop viral resistance to LDV and SOF during treatment
    and after cessation of treatment
    ¿ The steady-state pharmacokinetics of LDV and SOF and its metabolites
    Gli endpoint secondari sono i seguenti:
    ¿ La percentuale di soggetti con HCV RNA <LLOQ a 4 e 24 settimane dopo la sospensione del trattamento (SVR4 e SVR24)
    ¿ La percentuale di soggetti con HCV RNA <LLOQ in trattamento
    ¿ Cambiamento HCV RNA dal basale / Giorno 1
    ¿ La percentuale di soggetti con fallimento virologico
    ¿ La percentuale di soggetti che sviluppano resistenza virale a LDV e SOF durante il trattamento e dopo l'interruzione del trattamento
    ¿ La farmacocinetica allo steady-state di LDV e SOF e dei suoi metaboliti
    E.5.2.1Timepoint(s) of evaluation of this end point
    ¿ SVR 4 and 24 weeks
    ¿ PK Day 7
    ¿ SVR 4 e 24 settimane
    ¿ PK giorno 7
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Taiwan
    United States
    Belgium
    Germany
    Italy
    Switzerland
    E.8.7Trial 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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 95
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    -
    -
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-05-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-04
    P. End of Trial
    P.End of Trial StatusCompleted
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