Clinical Trials Register

Summary
EudraCT Number:	2014-001739-35
Sponsor's Protocol Code Number:	SOFT-preOLT
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:	2014-07-08
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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-001739-35

A.3

Full title of the trial

An Open-Label Study to Explore the Clinical Efficacy of Sofosbuvir With Ribavirin Administered Pre-Transplant in Preventing Hepatitis C Virus (HCV) Recurrence Post-Transplant in HIV-HCV infected patients

Studio in aperto per valutare l’efficacia clinica di sofosbuvir, somministrato in associazione a ribavirina in fase pre-trapianto, nel prevenire recidive post-trapianto dell’infezione da virus dell’epatite C (HCV) in soggetti con infezione HIV-HCV.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.4.1

Sponsor's protocol code number

SOFT-preOLT

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Università di Modena e ReggioEmilia
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Gilead Scinces srl
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Università di Modena e ReggioEmilia
B.5.2	Functional name of contact point	Researcher
B.5.3	Address:
B.5.3.1	Street Address	via del Pozzo, 71
B.5.3.2	Town/ city	Modena
B.5.3.3	Post code	41124
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390594225318
B.5.5	Fax number	+390594222604
B.5.6	E-mail	giovanni.guaraldi@unimore.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Sovaldi
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead Sciences International Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Rebetol
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Limited
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical condition(s) being investigated

Individuals with HIV-HCV co-infection and end-stage liver disease, with an indication for liver transplantation

Individui con co-infezione HCV-HIV e malattia epatica allo stadio terminale, con indicazione al trapianto di fegato

E.1.1.1

Medical condition in easily understood language

Individuals with HIV-HCV co-infection and end-stage liver disease, with an indication for liver transplantation

Individui con co-infezione HCV-HIV e malattia epatica allo stadio terminale, con indicazione al trapianto di fegato

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	HLT
E.1.2	Classification code	10057212
E.1.2	Term	Hepatitis viral infections
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine if the administration of a combination of sofosbuvir and ribavirin to HIV-HCV co-infected subjects prior to undergoing liver transplantation for up to 48 weeks (or the time of transplant) can prevent post-transplant HCV re-infection as determined by a sustained post-transplant virological response (HCV RNA <LLoQ) at 12 weeks post-transplant

Determinare se la somministrazione di una combinazione di sofosbuvir e ribavirina in soggetti con coinfezione HIV-HCV prima di trapianto epatico per un periodo massimo di 48 settimane (o comunque fino alla data del trapianto) è in grado di prevenire la re-infezione da HCV post-trapianto come determinato da una risposta virologica sostenuta (HCV RNA <LLoQ) a 12 settimane post-trapianto.

E.2.2

Secondary objectives of the trial

-To determine virological response in the pre-transplat period at 12 weeks after the end of treatment or at the day of liver transplantation
-To determine the proportion of patients who get out from the transplant list due to resolution of end stage liver disease after completion of treatment
-To assess safety and tolerability
-To evaluate the HCV RNA Viral Kinetic during the treatment phase and following liver transplant and correlate results with the duration of treatment prior to liver transplant (LT).
-To determine concentrations of SOF in the liver explants in a subset of patients who cease sofosbuvir therapy within 24 hours of LT.
-To explore the presence of HCV RNA in the liver explants and to assess HCV sequences and to correlate with plasma HCV RNA kinetics during therapy, duration of therapy, duration of plasma HCV RNA negativity and cytokine mRNA expression in the liver
- To assess patient and graft survival at 24 and 48 weeks post tranplant

Determinare:
- risposta virologica pre-trapianto a 12 sett. dopo la fine della terapia (TP) o al trapianto
- proporzione di paz. che escono dalla lista trapianti per risoluzione della malattia epatica
- sicurezza e tollerabilità durante la TP e FU
- cinetica di HCV RNA durante la TP e in seguito al trapianto, e correlazione con la durata pre-trapianto della TP
- presenza/assenza di HCV RNA negli espianti di fegato e correlazione con HCV RNA durante la TP, la durata della TP e persistenza di un valore negativo di HCV RNA plasmatico.
- conc. di sof negli espianti di fegato in un sottogruppo di pazienti che cessano la TP con sof entro 24 h dal trapianto.
- presenza di HCV RNA negli espianti di fegato, valutare le sequenze di HCV e di correlare con cinetica virale HCV RNA durante la TP, la durata del TP, durata della negatività di HCV RNA plasmatico e di espressione di mRNA di citochine nel fegato
- il paziente e la sopravvivenza del graft a 24 e 48 settimane post-trapianto

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Males or females at least 18 years old at Screening. Subjects or their heterosexual partner(s) must either be of non-childbearing potential or they must use effective contraception from 2 weeks before the initiation of therapy until 6 months after the last dose of study medication.
2.HIV-HCV Co-infection documented with HIV-Ab and HCV RNA positivity
2.1Chronic HCV-infection, any genotypes, documented by at least one measurement of serum HCV RNA above the lower limit of quantification (LLoQ) measured during Screening
2.2 Chronic HIV infection undergoing antiretroviral therapy for at least 6 month with HIV Viral Load < 40 copies/ml
3. End stage Liver disease (ESLD) or HCC secondary to HCV meeting the MILAN criteria with a MELD between 15 and 35 and waiting list for OLT
4. Subjects must be naïve to treatment with NS5B polymerase inhibitors for chronic HCV infection.
5. A body mass index (BMI) of >=18 kg/m2.
6. Able to effectively communicate with the Investigator and other center personnel. Willing to give written informed consent and comply with the study restrictions and requirements.

1 . Maschi o femmine di almeno 18 anni al momento dello screening . Soggetti o loro partner eterosessuali ( s ) devono essere o non fertili o devono utilizzare un contraccettivo efficace da 2 settimane prima dell'inizio della terapia fino a 6 mesi dopo l'ultima dose del farmaco in studio .
2 . HIV -HCV co- infezione documentata da HIV - Ab ed HCV RNA positività
2.1 infezione cronica da HCV, qualsiasi genotipo, documentata da almeno una misurazione di siero HCV RNA sopra del limite inferiore di quantificazione ( LLOQ ) misurata durante Screening
2 . 2 infezione cronica da HIV in terapia antiretrovirale da almeno 6 mesi con carico virale HIV < 40 copie / ml
3 . stadio terminale della malattia epatica o HCC secondaria ad HCV che soddisfano i criteri di Milano con un MELD tra 15 e 35 e in lista d'attesa per trapianto di fegato
4 . Soggetti devono essere naïve al trattamento con gli inibitori della polimerasi NS5B per l'infezione cronica da HCV .
5 . Un indice di massa corporea (BMI) di >= 18 kg/m2 .
6 . Grado di comunicare efficacemente con il ricercatore e del personale del centro . Disposti a dare il consenso informato scritto e rispettare le limitazioni di studio e requisiti.

E.4

Principal exclusion criteria

1. Any transplant patient who has agreed to a liver transplant from a live donor.
2. Patients requiring planned induction therapy with biologics post-transplantation or with a post-transplantation immunosuppressive regimen not consistent with:
o Solumedrol/Prednisone
o Tacrolimus (maintaining a serum level of 5-12 ng/mL)
3. Chronic medical conditions, especially if treated with medications (such as hypertension), must be stable at the time of screening and first dose.
4. Clinically significant ECG findings at screening, screening QTc ≥ 500 ms (cirrhotic), or a personal or family history of Torsades de pointes
5. History of major organ transplantation with an existing functional graft.
6. Active substance abuse which, in the opinion of the investigator, would make the candidate inappropriate for participation in this study.
7. Abnormal hematological and biochemical parameters, including:
a.neutrophil count <1000 cells/mm3
b. Hgb <8 g/dL without erythroid stimulating agents or blood transfusion
c. platelet count ≤10 000 cells/mm3
d. ALT or AST ≥10 times ULN
e. sodium <130 mmol/L
f. serum bilirubin > 30 mg/dL
g. serum albumin < 2.0 g/dL
h. INR >2
8. History of clinically significant drug allergy to nucleoside/nucleotide analogs.
9. Participation in any other clinical trial within 3 months prior to screening visit and during the study
10. History of having received any systemic antineoplastic or immunomodulatory treatment (including radiation) within 3 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study (excluding a local regional therapy such as TACE).
11. Treatment with TACE or RFA within 30 days prior to the first dose.
12. Pregnant/Breastfeeding women or males whose partners are currently pregnant.
13. Poor venous access making the patient unable to complete the required laboratory testing schedule.

1 . pazienti in attesa di trapianto di trapianto che abbiano accettato un trapianto di fegato da donatore vivo .
2 pazienti che necessitano di terapia di induzione pianificata con farmaci biologici post- trapianto o con una terapia immunosoppressiva post- trapianto non rappresentata da:
o Solumedrol / Prednisone
o Tacrolimus ( mantenendo un livello sierico di 5-12 ng / mL )
3 . Condizioni mediche croniche , soprattutto se trattata con farmaci ( come l'ipertensione ) , devono essere stabili al momento dello screening e della prima dose .
4 . Risultati clinicamente significativi all'ECG allo screening , screening QTc ≥ 500 ms ( cirrosi ), o storia personale o familiare di torsioni di punta
5 . precedente trapianto di organi maggiore con un innesto funzionale esistente .
6 . Abuso di sostanze attive che , a giudizio dello sperimentatore , renderebbero il candidato inadeguato per la partecipazione a questo studio .
7 parametri ematologici e biochimici anomali , tra cui:
un . neutrofili < 1.000 cellule/mm3
b . Hb < 10 g / dL senza agenti eritroidi stimolanti o trasfusioni di sangue
c . conta piastrinica ≤ 20 000 cellule/mm3
d . ALT o AST ≥ 10 volte ULN
e. sodio < 130 mmol / L
f . bilirubina sierica > 30 mg / dL
g . albumina sierica < 2,0 g / dL
h . INR > 2
8 . Storia clinicamente significativa di allergia ai farmaci nucleosidici / nucleotidici analoghi .
9 . Partecipazione a qualsiasi altro studio clinico nei 3 mesi precedenti la visita di screening e durante lo studio
10 . Precedente trattamento con antineoplastici sistemici o immunomodulatori ( compreso radiazione ) nei 3 mesi precedenti la prima dose di farmaco in studio o l'aspettativa che tale trattamento sarà necessaria in qualsiasi momento durante lo studio ( escludendo una terapia locale regionale come TACE ) .
11 . Trattamento con TACE o RFA nei 30 giorni precedenti la prima dose .
12 . Donne in gravidanza / allattamento al seno o maschi le cui partner sono attualmente in stato di gravidanza .
13 . Scarso accesso venoso che rende il paziente non in grado di completare il programma di prove di laboratorio richieste .

E.5 End points

E.5.1

Primary end point(s)

Sustained post-transplant virological response (HCV RNA <LLoQ) at 12 weeks post-transplant

Risposta virologica sostenuta post-trapianto (HCV RNA <LLOQ) a 12 settimane post-trapianto

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks post-transplant

12 settimane post-trapianto

E.5.2

Secondary end point(s)

- HCV RNA <LLoQ in the pre-transplant period at 12 weeks after the end of treatment (48 weeks) or at the day of liver transplantation
-patients proportion who get out from the transplant list
- assess clinical and laboratory AE and SAE
- HCV RNA viral kinetic during treatment and in the liver explants

- HCV RNA <LLOQ nel periodo pre-trapianto a 12 settimane dopo la fine del trattamento (48 settimane) o al giorno del trapianto di fegato
- proporzione pazienti che escono dalla lista di trapianto
- Valutazione di AE e SAE clinici e di laboratorio
- cinetica virale di HCV RNA durante il trattamento e nel fegato espiantato

E.5.2.1

Timepoint(s) of evaluation of this end point

12 weeks after the end of treatment or at the day of liver transplantation

12 settimane dopo la fine del trattamento o al giorno del trapianto di fegato

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

last visit of last patient enrolled

ultima visita dell'ultimo paziente arruolato

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

none

nessuna

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-08-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-05-29

P. End of Trial
P.	End of Trial Status	Completed

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