Clinical Trials Register

Summary
EudraCT Number:	2015-003866-96
Sponsor's Protocol Code Number:	BEMI-2015
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:	2016-02-03
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

2015-003866-96

A.3

Full title of the trial

Randomized controlled trial on the safety and efficacy of low molecular weight heparins in the prevention of thrombotic events in hospitalized cirrhotic patients

Estudio controlado y aleatorizado sobre la seguridad y eficacia del uso de heparinas de bajo peso molecular en la prevención de episodios trombóticos en pacientes cirróticos hospitalizados

A.3.1

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

Trial about the prevention of thrombosis in hospitalized cirrhotic patients

Ensayo sobre la prevención de la trombosis en pacientes cirróticos hospitalizados

A.3.2

Name or abbreviated title of the trial where available

BEMI 2015

A.4.1

Sponsor's protocol code number

BEMI-2015

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	ANGELA PUENTE
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	LABORATORIOS ROVI
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	ANGELA PUENTE
B.5.2	Functional name of contact point	ANGELA
B.5.3	Address:
B.5.3.1	Street Address	AV. VALDECILLA SN
B.5.3.2	Town/ city	SANTANDER
B.5.3.3	Post code	39008
B.5.3.4	Country	Spain
B.5.4	Telephone number	00349422025202929
B.5.5	Fax number	0034942202544
B.5.6	E-mail	anpuente@humv.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	HIBOR 3500 UI
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATORIOS FARMACEUTICOS ROVI, SA
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	HIBOR 3500 UI
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BEMIPARIN SODIUM
D.3.9.1	CAS number	9041-08-1
D.3.9.4	EV Substance Code	SUB20549
D.3.10	Strength
D.3.10.1	Concentration unit	ATU anti-thrombin unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3.500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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

Prevention of thrombosis in cirrhotic patients

Prevención de la trombosis en pacientes cirróticos

E.1.1.1

Medical condition in easily understood language

Prevention of thrombosis in cirrhotic patients

Prevención de la trombosis en pacientes cirróticos

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	HLGT
E.1.2	Classification code	10014523
E.1.2	Term	Embolism and thrombosis
E.1.2	System Organ Class	10047065 - Vascular disorders

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 assess the safety and efficacy of prophylactic anticoagulation for the prevention of thrombotic events in hospitalized cirrhotic patients

Evaluar la seguridad y eficacia de la anticoagulación profiláctica para la prevención de eventos tombóticos en pacientes cirróticos hospitalizados

E.2.2

Secondary objectives of the trial

1.To assess prospectively the incidence of thrombotic events in hospitalized
cirrhotic patients. 2. To assess the efficacy of low molecular weight heparin (HIBOR
3.500UI) in preventing thrombotic events in cirrhotic patients hospitalized. 3. To
Identify risk factors for development of portal vein thrombosis and deep vein
thrombosis in hospitalized patients. 4.To evaluate related morbidity and mortality
thromboembolic events. 5. To Assess prophylactic anticoagulation levels by
determining antiXa and antithrombin III. 6. To study the expression profile and
functionality of the family of Toll-like receptors, I-FABP / IL6-IL8 / NO, endothelin
and LPS-binding protein. 7. To evaluate the effect on liver fibrosis (by FibroScan®)
and serum TGFB 8. To study the hepatocellular function estimated by the
Child-Pugh scores and MELD

1.Evaluar de forma prospectiva la incidencia de fenómenos trombóticos en
pacientes cirróticos hospitalizados. 2.Evaluar la eficacia del uso de heparina de
bajo peso molecular (HIBOR 3.500UI) en la prevención de eventos trombóticos en
pacientes cirróticos hospitalizados. 3.Identificar factores de riesgo de desarrollo de
trombosis portal y trombosis venosa profunda en pacientes hospitalizados.
4.Evaluar la morbimortalidad relacionada con los fenómenos tromboembólicos.
5.Evaluar los niveles de anticoagulación profiláctica mediante la determinación de
antiXa y antitrombina III. 6.Estudiar el perfil de expresión y funcionalidad de la
familia de receptores de tipo Toll, I-FABP/IL6-IL8/NO, endotelina y LPS-binding
protein. 7.Evaluar el efecto sobre la fibrosis hepática (mediante Fibroscan® ) y
TGF? sérico 8.Evolución de la función hepatocelular estimada mediante los scores
de Child-Pugh y MELD

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Applicants must meet all the following: 1) Liver cirrhosis of any etiology diagnosed
by biopsy or after clinical, laboratory and ultrasound criteria; 2) Admission to
hospital more than 3 days of their liver decompensation (ascites, encephalopathy,
upper gastrointestinal bleeding or low controlled, spontaneous bacterial peritonitis)
3) signed written consent.4) women in childbearing age with use of effective
contraception

Se deberán cumplir todos los siguientes: 1) Cirrosis hepática de cualquier etiología
diagnosticada por biopsia previa o por criterios clínicos, analíticos y ecográficos; 2) Ingreso hospitalario superior a 3 días por descompensación de su hepatopatía
(ascitis, encefalopatía, hemorragia digestiva alta o baja controlada, peritonitis
bacteriana espontánea) 3) Consentimiento firmado por escrito, 4)Mujeres en edad
fértil con uso de método anticonceptivo eficaz

E.4

Principal exclusion criteria

One or more of the following: 1) Age <18 and> 80 years; 2) contraindication to
heparin treatment of low molecular weight, 3) uncontrolled bleeding 4) Any
comorbidity involving a therapeutic limitation and / or a life expectancy <6 months;
5) concomitant antiplatelet therapy (aspirin, clopidogrel, ticlopidine, dipyridamole,
sulfinpyrazone, dextran 40, or other anticoagulants 6) and continued concomitant
NSAIDs, salicylates, corticosteroids; 7) existence of clinically significant esophageal
varices / severe gastropathy of portal hypertension without their having been
previously treated with primary / secondary prophylaxis (endoscopic variceal ligation
/ non-cardioselective beta-blockers); 8) refusal to participate in the study or to sign
the informed consent; 9) Pregnancy and lactation; 10) HIV infection; 11) severe
thrombocytopenia <20,000 platelets / dl, 12) Failure to severe with lower clearance
30ml / min Renal 13) portal vein thrombosis or peripheral thrombosis diagnosed on
admission, 14) Presence of previously known procoagulant factor

Uno o más de los siguientes: 1) Edad <18 y >80 años; 2) contraindicación a
tratamiento heparinas de bajo peso molecular, 3) Hemorragia no controlada 4)
Cualquier comorbilidad que conlleve una limitación terapéutica y/o un pronóstico de
vida <6 meses; 5) tratamiento concomitante con antiagregantes (ácido
acetilsalicilico, clopidogrel, ticlopidina, dipiridamol, sulfinpirazona, dextrano 40, u
otros anticoagulantes 6) tratamiento concomitante y continuado de antiinflamatorios
no esteroideos, salicilatos, corticoides; 7) existencia de Varices esofágicas
clínicamente significativas/ gastropatía severa de la Hipertensión portal sin que
hayan sido tratatadas previamente con profilaxis primaria/secundaria (Ligadura
endoscópica de varices/ betabloqueantes no cardioselectivos) ; 8) Negativa a
participar en el estudio, o afirmar el consentimiento informado; 9) Embarazo o
lactancia; 10) Infección por el VIH; 11) plaquetopenia severa < 20.000 plaquetas/dl,
12) Insuficiencia Renal grave con aclaramiento inferior a 30ml/min, 13) Trombosis
portal o TVP diagnosticadas al ingreso, 14) Presencia de factor procoagulante
previamente conocido.

E.5 End points

E.5.1

Primary end point(s)

Security prophylactic anticoagulation with Bemiparin (HIBOR®) for the prevention of
vein thrombosis in patients with prolonged hospitalization

Seguridad de la anticoagulación profiláctica con Bemiparina (HIBOR®) para la
prevención de la trombosis venosa profunda/ trombosis portal en pacientes
cirróticos con hospitalización prolongada

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months

3 meses

E.5.2

Secondary end point(s)

Related peripheral and portal thrombosis

Aparición de trombosis portal o perfiferica

E.5.2.1

Timepoint(s) of evaluation of this end point

3 months

3 meses

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

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

Yes

E.8.2.3.1

Comparator description

ningún procedimiento

non procedure

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

LVLS

ULTIMA VISITA DEL ULTIMO PACIENTE

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

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:

200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

225

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

2016-04-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-02-01

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