Clinical Trials Register

Summary
EudraCT Number:	2011-006208-11
Sponsor's Protocol Code Number:	1544?H?254
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-02-28
Trial 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

2011-006208-11

A.3

Full title of the trial

A randomized, controlled multicenter clinical trial comparing endoscopic band ligation versus oral carvedilol in the primary
prophylaxis of esophageal variceal bleeding in patients with cirrosis

Ensayo clínico multicéntrico, aleatorizado y controlado que compara la ligadura endoscópica con banda con el carvedilol oral en la profilaxis primaria de la hemorragia de varices esofágicas en pacientes con cirrosis

A.3.1

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

Study comparing the use of a medical procedure (endoscopic band ligation) versus a drug treatment (carvedilol) to prevent bleeding of esophageal varices in patients with liver disease.

Estudio que compara el uso de un procedimiento médico (ligadura endoscópica) frente a medicamento (carvedilol) para evitar el sangrado de várices esofágicas en pacientes con enfermedad del hígado.

A.4.1

Sponsor's protocol code number

1544?H?254

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	CAIBER
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	MINISTERIO DE SANIDAD Y POLITICA SOCIAL
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	CAIBER
B.5.2	Functional name of contact point	UCICEC ALBACETE
B.5.3	Address:
B.5.3.1	Street Address	C/ HERMANOS FALCÓ Nº 37, HOSPITAL GENERAL DE ALBACETE, UNIDAD DE INVESTIGACIÓN, CAIBER
B.5.3.2	Town/ city	ALBACETE
B.5.3.3	Post code	02008
B.5.3.4	Country	Spain
B.5.4	Telephone number	34967597375
B.5.5	Fax number	3493227 98 77
B.5.6	E-mail	ilmartinezg@sescam.jccm.es

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	Carvedilol ratiopharm 6,25 mg comprimidos recubiertos con película EFG
D.2.1.1.2	Name of the Marketing Authorisation holder	Ratiopharm España, 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	Carvedilol ratiopharm 6,25 mg comprimidos recubiertos con película EFG
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	72956-09-3
D.3.9.3	Other descriptive name	CARVEDILOL
D.3.9.4	EV Substance Code	SUB06153MIG
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	6.25
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

Esophageal variceal bleeding in patients with cirrhosis

Hemorragia de várices esofáficas en pacientes con cirrosis

E.1.1.1

Medical condition in easily understood language

Bleeding of varices of Esophagus in patients with hepatic disease

Sangrado de várices de esófago en pacientes con enfermedad hepática

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

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 evaluate whether carvedilol improves bleeding free survival in patients with cirrhosis and medium or large esophageal varices when compared with endoscopic band ligation.

Evaluar si el carvedilol mejora la supervivencia libre de sangrado en pacientes con cirrosis y varices esofágicas medianas o grandes, en comparación con la ligadura endoscópica con banda.

E.2.2

Secondary objectives of the trial

1. To evaluate whether carvedilol, as compared to endoscopic band ligation,
a) improves survival
b) decreases the incidence of variceal bleeding and of bleeding from non-variceal sources
c) decreases the development of other complications of portal hypertension (ascites, spontaneous bacterial peritonitis, bacterial infections, hepatorrenal syndrome, and hepatic encephalopathy).
2. To compare the incidence of portal vein thrombosis between both treatment arms.
3. To compare the rate of adverse events.
4. To compare the costs of both treatments.

1. Evaluar si el carvedilol, en comparación con la ligadura endoscópica con banda:
a) mejora la supervivencia
b) disminuye la incidencia de hemorragia por varices y de hemorragias de origen no varicoso
c) disminuye el desarrollo de otras complicaciones de la hipertensión portal (ascitis, peritonitis bacteriana espontánea, infecciones bacterianas, síndrome hepatorrenal y encefalopatía hepática).
2. Comparar la incidencia de trombosis venosa portal entre ambos brazos de tratamiento.
3. Comparar la tasa de eventos adversos.
4. Comparar costes de ambos tratamientos.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

? Age from 18 to 80 years.
? Liver cirrhosis diagnosed by liver biopsy or unequivocal clinical, analytical or radiologic criteria
? Presence of esophageal varices or gastroesophageal varices type GOV1, medium or large in size (>5 mm)
? Ability to understand study procedures and to comply with them for the entire length of the study.

? Edad entre 18 y 80 años.
? Cirrosis hepática diagnosticada por biopsia hepática o por criterios clínicos, analíticos o radiológicos inequívocos.
? Presencia de varices esofágicas o gastroesofágicas tipo GOV1, medianas o grandes (> 5 mm)
? Capacidad para entender los procedimientos del estudio y para cumplir con ellos durante toda la duración del mismo.

E.4

Principal exclusion criteria

? Previous esophageal variceal bleeding.
? Pregnant or lactating patients
? Known hypersensibility to carvedilol
? Contraindications to carvedilol.
? Patients already taking beta-blockers
? Previous endoscopic band ligation or endoscopic injection sclerotherapy
? Total portal vein thrombosis or portal vein cavernoma
? Hepatocellular carcinoma out of Milano criteria
? End-stage liver disease as indicated by a Child-Pugh score over 13.
? Extrahepatic malignancy that significantly affects survival
? Previous TIPS or porto-caval shunt

? Sangrado previo de várices esofágicas.
? Pacientes embarazadas o en período de lactancia.
? Hipersensibilidad conocida a carvedilol
? Contraindicaciones para el carvedilol.
? Pacientes que ya toman beta-bloqueantes.
? Previa ligadura endoscópica con banda o escleroterapia por inyección endoscópica.
? Trombosis venosa portal total o cavernoma de la vena porta
? Carcinoma hepatocelular que no cumple los criterios de Milano.
? Enfermedad hepática terminal (puntuación Child-Pugh > 13).
? Tumor maligno extrahepático que afecta significativamente a la supervivencia
? TIPS o derivación porto-cava previa.

E.5 End points

E.5.1

Primary end point(s)

Time to first variceal bleeding or death.

Tiempo hasta el primer sangrado de várices o muerte.

E.5.1.1

Timepoint(s) of evaluation of this end point

In every follow up visit (V1-V7)

En todas las visitas de seguimiento (V1-V7)

E.5.2

Secondary end point(s)

1.Time to variceal bleeding.
2. Time to death.
3. Time to death or liver transplantation.
4. Incidence of clinical decompensation (development of ascites, spontaneous bacterial peritonitis, bacterial infections, hepatorenal syndrome or hepatic encephalopathy).
5. Incidence of portal vein thrombosis, assessed by abdominal Doppler-ultrasound.
6. Proportion of patients with adverse events.
7. Proportion of patients with severe adverse events.
8. Costs of the Management of the patients.

1. Tiempo hasta el sangrado de várices.
2. Tiempo hasta la muerte.
3. Tiempo hasta la muerte o el trasplante hepático.
4. Incidencia de descompensación clínica (desarrollo de ascitis, peritonitis bacteriana espontánea, infecciones bacterianas, síndrome hepatorrenal o encefalopatía hepática).
5. Incidencia de trombosis de la vena porta, evaluada por Doppler abdominal.
6. Proporción de pacientes con acontecimientos adversos.
7. Proporción de pacientes con acontecimientos adversos graves.
8. Costes del manejo de los pacientes.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. In every follow up visit (V1-V7)
2. In every follow up visit (V1-V7)
3. In every follow up visit (V1-V7)
4. In every follow up visit (V1-V7)
5. V2-V7
6. V0-V7
7. V0-V7
8. In every follow up visit (V1-V7)

1. En todas las visitas de seguimiento (V1-V7)
2. En todas las visitas de seguimiento (V1-V7)
3. En todas las visitas de seguimiento (V1-V7)
4. En todas las visitas de seguimiento (V1-V7)
5. V2-V7
6. V0-V7
7. V0-V7
8. En todas las visitas de seguimiento (V1-V7)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Ligadura endoscópica por banda

Endoscopic band ligation

E.8.2.4

Number of treatment arms in the trial

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

LVLS

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:

290

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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