Clinical Trials Register

Summary
EudraCT Number:	2012-002105-22
Sponsor's Protocol Code Number:	EVL-VHC-HVH.12
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-06-25
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

Spain - AEMPS

A.2

EudraCT number

2012-002105-22

A.3

Full title of the trial

Personal monitoring of liver transplant patients infected with Hepatitis C Virus. Pilot study to compare the evolution of Hepatitis C by receiving immunosuppression with tacrolimus in combination with Mycophenolate Mofetil or Everolimus.

Seguimiento personalizado de los pacientes trasplantados hepáticos infectados por el Virus de la Hepatitis C. Estudio piloto para comparar la evolución de la Hepatitis C, según reciban inmunosupresión con Tacrolimus en combinación con Micofenolato Mofetil o Everolimus.

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

EVL-VHC-HVH.12

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	Dra Itxarone Bilbao. Servicio de cirugía hepatobiliopancreatica y trasplantes. HUVH
B.1.3.4	Country	Spain
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	Dra Itxarone Bilbao. Servicio de cirugía hepatobiliopancreatica y trasplantes. HUVH
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Servicio de cirugía hepatobiliopancreatica y trasplantes. HUVH
B.5.2	Functional name of contact point	Dra Itxarone Bilbao
B.5.3	Address:
B.5.3.1	Street Address	Paseo Vall d'Hebron 119-129
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08035
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034932746113
B.5.5	Fax number	0034932746112
B.5.6	E-mail	ibilbao@vhebron.net

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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	Advagraf
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.1	Product name	tacrolimus
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TACROLIMUS
D.3.9.1	CAS number	104987-11-3
D.3.9.4	EV Substance Code	SUB10797MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
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	Certican
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Farmacéutica, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.1	Product name	everolimus
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	159351-69-6
D.3.9.3	Other descriptive name	EVEROLIMUS
D.3.9.4	EV Substance Code	SUB02065MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Cell-Cept
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.1	Product name	micofenolato mofetil
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	115007-34-6
D.3.9.3	Other descriptive name	MYCOPHENOLATE MOFETIL
D.3.9.4	EV Substance Code	SUB03360MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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

Recurrence of hepatitis C post-liver transplantation in patients with hepatitic C.

Recidiva de la hepatitis C post-trasplante hepático en pacientes con hepatitic C.

E.1.1.1

Medical condition in easily understood language

Recurrence of hepatitis C post-liver transplantation in patients with hepatitic C.

Recidiva de la hepatitis C post-trasplante hepático en pacientes con hepatitic C.

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10070678
E.1.2	Term	Hepatitis C recurrent
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10024716
E.1.2	Term	Liver transplantation
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Compare the evolution of hepatitis C recurrence as determined by progression of liver fibrosis (F ? 2, as ranked by ISHAK) a year post-liver transplantation in patients receiving low dose tacrolimus in combination with mycophenolate mofetil vs everolimus.

Comparar la evolución de la recidiva de la hepatitis C determinada por progresión de la fibrosis hepática (F?2, según la clasificación de ISHAK) al año post-trasplante hepático en pacientes que reciben dosis bajas de tacrolimus en combinación con micofenolato mofetil vs everolimus.

E.2.2

Secondary objectives of the trial

1. To assess the viral load of HCV RNA. 2. To characterize the haplotype of each patient. 3. Rate serological markers of hepatic fibrosis 4. To assess the elasticity of the liver parenchyma by FibroScan. 5. To compare the incidence of acute rejection and acute rejection corticoresistente. 6. Compare the time to first acute rejection episode. 7. Compare the need for antiviral therapy post-transplant year. 8. Assess patient survival and graft survival post-transplant year. 9. To evaluate the incidence of patient withdrawals or study discontinuation post-transplant year. 10. To evaluate the incidence of cardiovascular risk factors.

1. Valorar la carga viral RNA del VHC. 2. Caracterizar el haplotipo de cada paciente. 3. Valorar los marcadores serológicos de fibrosis hepática 4. Valorar la elasticidad del parénquima hepático mediante FibroScan. 5. Comparar la incidencia del rechazo agudo y rechazo agudo corticoresistente. 6. Comparar el tiempo hasta el primer episodio de rechazo agudo. 7. Comparar la necesidad de administrar tratamiento antiviral al año post-trasplante. 8. Valorar la supervivencia del paciente y del injerto al año post-trasplante. 9. Valorar la incidencia de retiradas del paciente o interrupción del estudio al año post-trasplante. 10. Valorar la incidencia de los factores de riesgo cardiovascular.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients ? 18 years with HCV RNA-positive 12 months before transplantation, recipients of a first orthotopic liver transplantation.

Pacientes ? 18 años, con RNA-VHC positivo 12 meses antes del trasplante, receptores de un primer trasplante hepático ortotópico.

E.4

Principal exclusion criteria

1. Multi-organ transplant recipients or who have previously received an organ transplant. 2. Patients with split or living donor recipients. 3. Transplant recipients with ABO incompatibility. 4. Patients seropositive for HIV antibodies. 5. Recipients who receive a transplant for fulminant hepatic failure. 6. HCV patients with cirrhosis who received antiviral treatment before transplantation, and have to negative serum HCV-RNA. 7. Patients with known malignancy or history of malignancy except basal cell skin carcinoma and hepatocellular carcinoma meeting the following criteria: absence of vascular invasion, lymph single or less than two inches in diameter or two or three nodules of no more than three inches in diameter (Milan criteria). 8. Patients with a glomerular filtration <60 ml/min/1.73m 2 before transplantation or requiring renal dialysis before transplantation. 9. Patients in whom severe coexisting disease, or suffering any unstable medical condition that could affect the objectives of the study. 10. Patients who have been treated during the month prior to inclusion in the study with a drug or therapy is not recorded (investigational drug) or if such therapy be administered in the post-transplant. 11. Pregnant patients, nursing or of childbearing potential, not using effective contraception.
Exclusion criteria at the time of randomization (day 28 post-transplant): Patients who have not completed the healing process post-transplant month. Patients with a platelet count <50.000/mm3, a WBC count <2000/mm3, active infection requiring ICU admission or threatens vital, requiring intensive care and life support measures.

1. Receptores de un trasplante multiorgánico o que hayan recibido previamente el trasplante de algún órgano. 2. Pacientes con split o receptores de donante vivo. 3. Receptores de un trasplante con incompatibilidad ABO. 4. Pacientes seropositivos para anticuerpos del VIH. 5. Receptores que reciban el trasplante por un fallo hepático fulminante. 6. Pacientes con cirrosis por VHC que hayan recibido tratamiento antiviral antes del trasplante, y que hayan negativizado el ARN-VHC sérico. 7. Pacientes con neoplasia conocida o historia de neoplasia, exceptuando carcinoma cutáneo de células basales y hepatocarcinoma que cumpla los siguientes criterios: ausencia de invasión vascular, nódulo único menor o igual a cinco centímetros de diámetro máximo o dos o tres nódulos de no más de tres centímetros de diámetro (criterios de Milán). 8. Pacientes con un Filtrado Glomerular <60 ml/min/1.73m 2 antes del trasplante, o que requieran diálisis renal antes del trasplante. 9. Pacientes en los que coexista una enfermedad grave, o que sufran alguna situación médica inestable, que pudiera afectar a los objetivos del estudio. 10. Pacientes que hayan sido tratados durante el mes previo a la inclusión en el estudio con algún fármaco o terapia no registrada (fármaco en investigación), o si dicha terapia se va a administrar en el post-trasplante. 11. Pacientes mujeres embarazadas, en periodo de lactancia o potencialmente fértiles, que no utilicen un método anticonceptivo eficaz.
Criterios de exclusión en el momento de la randomización (día 28 post-trasplante): Pacientes que no han completado el proceso de cicatrización al mes post-trasplante. Pacientes con un recuento plaquetar <50.000/mm3, un recuento leucocitario <2.000/mm3, infección activa que requiera ingreso en UCI o suponga una amenaza vital, que requieran cuidados intensivos y medidas de soporte vital.

E.5 End points

E.5.1

Primary end point(s)

Percentage of patients with fibrosis grade ? 2 according to the classification of ISHAK

Porcentaje de pacientes que presenten grado de fibrosis ? 2 según la clasificación de ISHAK

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months after transplantation.

12 meses postrasplante.

E.5.2

Secondary end point(s)

Incidence of biopsy-proven acute rejection. Time to first episode of acute rejection. Time to histologic recurrence of hepatitis C after liver transplantation. Measures of central tendency and viral load of HCV. Patient survival and graft. Incidence of adverse events.

Incidencia de rechazos agudos demostrados por biopsia. Tiempo hasta el primer episodio de rechazo agudo. Tiempo hasta la recidiva histológica de la hepatitis C post-trasplante. Medidas de centralización y dispersión de la carga viral del VHC. Supervivencia del paciente y del injerto. Incidencia de acontecimientos adversos.

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months after transplantation.

12 meses postrasplante.

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

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 the last subject undergoing the trial.

Última visita del último sujeto del ensayo.

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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)

At the end of the study patients will receive the right treatment at the discretion of physician and periodic follow-up with the practice of the center.

Al final del estudio, los pacientes recibirán el tratamiento adecuado a la discreción del médico y el seguimiento periódico, con la práctica del centro.

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

2012-08-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-05-25

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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