Clinical Trials Register

Summary
EudraCT Number:	2014-005523-27
Sponsor's Protocol Code Number:	CIRROXABAN
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:	2015-07-10
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

2014-005523-27

A.3

Full title of the trial

Multicenter prospective randomized trial of the effect of rivaroxaban on survival and development of complications of portal hypertension in patients with cirrhosis

Estudio prospectivo multicéntrico, aleatorizado del efecto de Rivaroxaban sobre la supervivencia y el desarrollo de complicaciones de la hipertensión portal en pacientes con cirrosis

A.3.1

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

Multicenter prospective randomized trial of the effect of rivaroxaban on survival and development of complications of portal hypertension in patients with cirrhosis

Estudio prospectivo multicéntrico, aleatorizado del efecto de Rivaroxaban sobre la supervivencia y el desarrollo de complicaciones de la hipertensión portal en pacientes con cirrosis

A.3.2

Name or abbreviated title of the trial where available

CIRROXABAN

A.4.1

Sponsor's protocol code number

CIRROXABAN

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	INSTITUTO DE INVESTIGACIONES BIOMEDICAS AUGUST PI I SUNYER (IDIBAPS)
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	Instituto Carlos III
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	CTU Clinic (Clinical Trial Unit)
B.5.2	Functional name of contact point	Jaime Camacho
B.5.3	Address:
B.5.3.1	Street Address	Villarroel 170
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08036
B.5.3.4	Country	Spain
B.5.4	Telephone number	349322754004386
B.5.5	Fax number	34932279877
B.5.6	E-mail	jcamacho@clinic.ub.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	Xarelto 10 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
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	Rivaroxaban
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.3.8	INN - Proposed INN	RIVAROXABAN
D.3.9.1	CAS number	366789-02-8
D.3.9.2	Current sponsor code	BAY 59-7939
D.3.9.4	EV Substance Code	SUB29263
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	10
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Liver cirrhosis

Cirrosis hepatica

E.1.1.1

Medical condition in easily understood language

Liver cirrhosis

Cirrosis hepatica

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

Survival free of: transplant and decompensations / complications of PHT.

Supervivencia libre de trasplante y de presentar descompensaciones/complicaciones de la HTP.

E.2.2

Secondary objectives of the trial

1. To evaluate the efficacy in preventing portal thrombosis (PT).
2. To evaluate the efficacy in preventing complications of portal hypertension (PHT)
3. To evaluate the safety of rivaroxaban in patients with liver cirrhosis (LC)
4. To evaluate the incidence of HCC.
5. To assess the effect on liver fibrosis by non-invasive methods.
6. To evaluate the effect on hepatocellular function (Child-Pugh and MELD)
7. To correlate levels of anti-Xa and Rivaroxaban on efficacy and safety
8. To evaluate the effect of Rivaroxaban on HVPG (in a Substudy: CIRROXABAN-CATSHEP, in 65 patients).
9. To assess if Rivaroxaban reduces bacterial translocation and proinflammatory cytokines. Correlation with clinical findings.

1. Evaluar la eficacia en la prevención de trombosis portal (TP).
2. Evaluar la eficacia en la prevención de complicaciones de la hipertensión portal (HTP)
3. Evaluar la seguridad de Rivaroxaban en pacientes con cirrosis hepática (CH)
4. Evaluar la incidencia de HCC.
5. Evaluar el efecto sobre la fibrosis hepática mediante métodos no invasivos.
6. Evaluar el efecto sobre función hepatocelular (Child-Pugh y MELD)
7. Correlacionar niveles de anti-Xa y de Rivaroxaban con eficacia y seguridad
8. Evaluar el efecto de rivaroxaban sobre HVPG (en un Subestudio CIRROXABAN-CATSHEP de 65 pacientes).
9. Evaluar si Rivaroxaban disminuye la traslocación bacteriana y las citoquinas proinflamatorias. Correlación con los eventos clínicos.

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

CIRROXABAN-CATSHEP
Version 1.0, dated January 8, 2015
To evaluate the effect of Rivaroxaban on HVPG in 65 patients.

Version 1.0 de fecha 8 de Enero de 2015
Evaluar el efecto de Rivaroxaban sobre HVPG en 65 pacientes.

E.3

Principal inclusion criteria

a. Aged between 18 and 75 years of both sexes.
b. Clinical and / or laboratory criteria, ultrasound and / or liver biopsy compatible with the diagnosis of viral cirrhosis (If HBV: HBV-DNA must be negative; if HCV: SVR should be at least for 6 months prior to enrollment); alcohol (in the last 6 months: in men less than 60 g daily intake in women less than 40 g); NASH and cryptogenic.
c. Presence of clinically significant portal hypertension (CSPHT) defined by clinical criteria (presence of esophageal varices or ascites), elastography (liver Fibroscan® ? 21 kPa) or hemodynamic (HVPG ? 10 mmHg)
d. Mild to moderate hepatic impairment defined by Child-Pugh of 7-10 points.
e. Written informed consent to participate in the study

a. Edad comprendida entre 18 y 75 años de ambos sexos.
b. Criterios clínicos y/o analíticos, ecográficos y/o biopsia hepática compatibles con el diagnóstico de cirrosis hepática víricas (Si VHB: deben ser DNA-VHB negativo, si VHC: deben estar en SVR al menos desde 6 meses antes a su inclusión); alcohol (en los últimos 6 meses en hombres menos de 60 g de consumo diario o 40 g en mujeres); NASH y criptogenéticas.
c. Presencia de hipertensión portal clínicamente significativa (HTPCS) definida por criterios clínicos (presencia de varices esofágicas o ascitis), elastográfia (Fibroscan ® hepático ? 21 Kpa) o hemodinámicos (GPVH ? 10 mmHg)
d. Insuficiencia hepática leve-moderada definida por Child-Pugh de 7 a 10 puntos.
e. Consentimiento informado por escrito para participar en el estudio

E.4

Principal exclusion criteria

a. Any previous or current thrombosis in splenoportal axis (must be ruled out by US-Doppler earlier than one month after randomization; if doubts: AngioCT or AngioMRI if required).
b. Background of hepatic encephalopathy grade II or higher
c. Ascites that required prior practice of paracentesis in the last year
d. Indication for use of anticoagulant and / or antiplatelet therapy for any reason.
e. Hypersensitivity to the active ingredient or to excipients
f. Active bleeding, clinically significant, or risk of major bleeding.
g. Pregnancy and lactation.
h. HCC or malignant neoplasia at the time of inclusion.
i. Any comorbidity involving a therapeutic limitation and/or a life expectancy <12 months.
j. Existence of risk bleeding esophageal varices or prior variceal bleeding. They may not be included untill full treatment (stable beta blockers dosage or eradication trough varices ligation).
k. Pregnancy or lactation.
l. Severe thrombocytopenia <40,000 platelets / dl.
m. Kidney failure (creatinine clearance <15ml / min).
n. TIPS or portosystemic shunt carrier.
o. Child-Pugh score greater than 10.
p. In HCV liver cirrosis patients: not carrying at least six months in SVR. In HBV liver cirrosis patients: HBV DNA is not negative .
q. Active alcoholism (60 g / day in men and 40 in women)
r. Use of potent inhibitors of cytochrome CYP450 3A4 (ketoconazole, protease inhibitor antiretroviral treatment in HIV patients) or cytochrome inductors (rifampicin. Phenytoin ...).
s. Participation in another clinical trial

a. Cualquier trombosis previa o actual del eje espleno portal (debe descartarse en una US-Doppler no anterior a un mes de la aleatorización; si dudas se requerirá AngioTAC o AngioRNM).
b. Antecedentes de encefalopatia hepática grado II o superior
c. Ascitis previa que haya requerido la práctica de paracentesis evacuadora en el último año
d. Indicación de uso de tratamiento anticoagulante y/o antiagregante por cualquier motivo.
e. Hipersensibilidad al principio activo o a alguno de los excipientes.
f. Hemorragia activa, clínicamente significativa, o riesgo de hemorragia mayor.
g. Embarazo y lactancia.
h. Hepatocarcinoma o neoplasia maligna en el momento de inclusión.
i. Cualquier comorbilidad que conlleve una limitación terapéutica y/o un pronóstico de vida <12 meses.
j. Existencia de varices esofágicas de riesgo ó hemorragia por varices previas. No podrán ser incluidos hasta estar con tratamiento completo (Dosis estable de BetaBloqueantes o erradicación de las varices si ligadura).
k. Embarazo o lactancia
l. Plaquetopenia severa < 40.000 plaquetas/dl.
m. Insuficiencia Renal (aclaramiento de creatinina <15ml/min).
n. Ser portador de TIPS o shunt portosistémico.
o. Child-Pugh superior a 10.
p. Pacientes con CH-VHC que no lleven al menos 6 meses en SVR. En C. hepática VHB que el DNA del VHB no sea negativo.
q. Alcoholismo activo (más de 60 g/dia en hombres y 40 en mujeres)
r. Uso de inhibidores potentes del citocromo CYP450 3A4 (ketoconazol, inhibidores de la proteasa -tratamiento con antiretrovirales pacientes HIV) o de inductores del Citocromo (rifampicina. Fenitoina...).
s. Participación en otro ensayo clínico

E.5 End points

E.5.1

Primary end point(s)

1. Survival free of transplant.

1. Supervivencia libre de trasplante.

E.5.1.1

Timepoint(s) of evaluation of this end point

At month 24

En el mes 24.

E.5.2

Secondary end point(s)

Key secondary enpoints:
1. Bleeding episode due to portal hypertension.
2. Hepatic encephalopathy grade II or higher.
3. Ascitic decompensation: In patients without ascites, decompensation defined as "de novo" clinically detectable ascites; whereas in those with previous ascites is considered end-point for worsening ascites if required: a) perform two or more evacuative paracentesis in the following six months, or b) the completion of a TIPS.
Secondary enpoints:
1. Development of portal vein thrombosis detected by ultrasound and confirmed by CT angiography or MRI ngiography.
2. Development of complications of portal hypertension (anamnesis, physical examination, ultrasound and fibrogastroscopy).
3. Security of rivaroxaban in patients with liver cirrhosis. History and clinical evaluation of bleeding and monitoring of hematocrite. Evaluation of liver function.
4. Incidence of HCC by semiannual ultrasound.
5. To correlate levels of Rivaroxaban and antiXa to the efficacy and safety of the drug.
Rivaroxaban 6. Effect on hepatic venous pressure gradient (HVPG) Determination of HVPG at baseline and 12 months rivaroxaban or placebo (in a Substudy CIRROXABAN-CATSHEP of 65 patients).
7. Effect of rivaroxaban on liver fibrosis assessed by liver elastography measured by FibroScan and / or ARFI at baseline and every six months conditions. Effect on fibroscan and / or splenic ARFI.
8. Effect of Rivaroxaban on hepatocellular function estimated by the Child-Pugh scores and MELD.
9. Assess Rivaroxaban reduces bacterial translocation and proinflammatory cytokines. Correlation with clinical events.

Variables secundarias clave:
1. Episodio de hemorragia por hipertensión portal.
2. Encefalopatía hepática grado II o superior.
3. Descompensación ascítica: En pacientes sin ascitis, se considerará descompensación la aparición de ascitis de novo clínicamente detectable; mientras que en aquellos con ascitis previa se considerará end-point por empeoramiento de las ascitis si se requiere: a) realizar dos o más paracentesis evacuadoras en los siguientes 6 meses, o b) la realización de un TIPS.
Variables secundarias:
1. Desarrollo de trombosis portal detectada en ecografía y confirmada por angioTAC o AngioRNM.
2. Desarrollo de complicaciones de la hipertensión portal (anamnesis; exploración física, ecografía y Fibrogastroscopia).
3. Seguridad de Rivaroxaban en pacientes con cirrosis hepática. Anamnesis y evaluación clínica de hemorragia y seguimiento de hematocrito. Evaluación de función hepática.
4. Incidencia de HCC mediante ecografías semestrales.
5. Correlacionar niveles de antiXa y de Rivaroxaban con la eficacia y la seguridad del fármaco.
6. Efecto de Rivaroxaban sobre el gradiente de presión venosa hepática (GPVH) Determinación del GPVH basalmente y a los 12 meses de Rivaroxaban o placebo (en un Subestudio CIRROXABAN-CATSHEP de 65 pacientes).
7. Efecto de Rivaroxaban sobre la fibrosis hepática evaluada mediante elastografía hepática medida por FibroScan y/o ARFI en condiciones basales y semestralmente. Efecto sobre el fibroscan y/o ARFI esplénico.
8. Efecto de Rivaroxaban sobre la función hepatocelular estimada mediante los scores de Child-Pugh y MELD.
9. Evaluar si Rivaroxaban disminuye la traslocación bacteriana y las citoquinas proinflamatorias. Correlación con los eventos clínicos.

E.5.2.1

Timepoint(s) of evaluation of this end point

At month 24

En el mes 24.

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

E.6.5

Efficacy

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

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

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

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:

160

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

160

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

160

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

Ninguno

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

2015-07-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-04-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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