Clinical Trials Register

Summary
EudraCT Number:	2011-005825-36
Sponsor's Protocol Code Number:	MAFRI-2
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:	2012-02-06
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

2011-005825-36

A.3

Full title of the trial

Midrodrine, octeotride and albumin for cirrhotic patients with functional renal impairment

MIDODRINA, OCTEOTRIDA Y ALBÚMINA: EFECTO SOBRE LA FUNCIÓN RENAL DE PACIENTES CON CIRROSIS HEPÁTICA E INSUFICIENCIA RENAL FUNCIONAL

A.3.1

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

Midrodrine, octeotride and albumin for cirrhotic patients with functional renal impairment

MIDODRINA, OCTEOTRIDA Y ALBÚMINA: EFECTO SOBRE LA FUNCIÓN RENAL DE PACIENTES CON CIRROSIS HEPÁTICA E INSUFICIENCIA RENAL FUNCIONAL

A.4.1

Sponsor's protocol code number

MAFRI-2

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	Fundació Clinic per a la Recerca Biomèdica
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	N/A
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	Fundació clinic per a la Recerca Biomèdica
B.5.2	Functional name of contact point	Farmacología Clínica -CTU- Hospital
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	+349322754009838
B.5.5	Fax number	+34932279877
B.5.6	E-mail	acruceta@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	Albúmina Humana Grifols 20% solución para perfusión
D.2.1.1.2	Name of the Marketing Authorisation holder	Instituto Grifols, 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	Albúmina Humana Grifols 20% solución para perfusión
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Albúmina Humana Grifols 20% es una solución que contiene 200 g/l de proteína total, de las cuales al
D.3.9.1	CAS number	46162
D.3.9.2	Current sponsor code	N/A
D.3.9.3	Other descriptive name	HUMAN PLASMA PROTEINS WITH NOT LESS THAN 96% ALBUMIN
D.3.9.4	EV Substance Code	SUB22285
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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	Yes
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	GUTRON 5 mg comprimidos, 5mg
D.2.1.1.2	Name of the Marketing Authorisation holder	NYCOMED SPAIN S.L.;
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	GUTRON 5 mg comprimidos
D.3.2	Product code	441120
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 Buccal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MIDODRINE HYDROCHLORIDE
D.3.9.1	CAS number	3092-17-9
D.3.9.2	Current sponsor code	Gutron
D.3.9.3	Other descriptive name	midodrina
D.3.9.4	EV Substance Code	SUB03291MIG
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	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: 3
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	SANDOSTATIN solución inyectable
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	octeotride
D.3.2	Product code	0078-0180
D.3.4	Pharmaceutical form	Concentrate and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SANDOSTATIN
D.3.9.1	CAS number	79517-01-4
D.3.9.2	Current sponsor code	sandostatin
D.3.9.3	Other descriptive name	OCTREOTIDE ACETATE
D.3.9.4	EV Substance Code	SUB03490MIG
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.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

cirrhotic patients

Cirrosis hepática

E.1.1.1

Medical condition in easily understood language

cirrhotic patients with functional renal impairment

cirrosis hepática más insuficiencia renal

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 the effect of albumin administration, midodrine and octreotide on renal function in patients with liver cirrhosis with serum creatinine above 1.2 mg / dL.

Evaluar el efecto de la administración de albúmina, midodrina y octreotido sobre la función renal en pacientes con cirrosis hepática con creatinina sérica superior a 1,2 mg/dL.

E.2.2

Secondary objectives of the trial

1. To assess the relationship between treatment response and the activity of endogenous vasoactive systems, plasma renin activity, plasma aldosterone, norepinephrine, vasopressin and atrial natriuretic peptide.
2. To assess the relationship between response to treatment with blood pressure changes measured by Holter tension.
3. Evaluate the deterioration of renal function in the short term after stopping treatment in responders.
4. To evaluate the presence of bacterial DNA in blood of patients at different times and its correlation with response to treatment.

1. Evaluar la relación entre la respuesta al tratamiento y la actividad de los sistemas vasoactivos endógenos: actividad de renina plasmática, concentración plasmática de aldosterona, noradrenalina, vasopresina y el péptido natriurético atrial.
2. Evaluar la relación entre respuesta al tratamiento con los cambios de tensión arterial medidos por Holter de tensión.
3. Evaluar el empeoramiento de la función renal a corto plazo tras la suspensión de tratamiento en los pacientes respondedores.
4. Evaluar la presencia de DNA bacteriano en sangre de pacientes en diferentes momentos y su correlación con respuesta al tratamiento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age between 18 and 80 years
- Liver Cirrhosis
- Serum Creatinine greater t han 1,2 mg/dL
- To have given written informed consent

- Edad entre 18 y 80 años
- Cirrosis hepática definida por criterios clínicos, analíticos o histológicos (Anexo IX)
- Insuficiencia renal funcional con una creatinina sérica superior a 1,2 mg/dl.
- Que, adecuadamente informados, otorguen su consentimiento por escrito para participar en el estudio y someterse a las pruebas y exploraciones que ello comporta

E.4

Principal exclusion criteria

- Pregnancy
- Systolic blood pressure ? 150 mmHg and / or diastolic blood pressure ? 90 mmHg
- Previous treatment with transjugular intrahepatic portosystemic shunt (TIPS) or surgical portosystemic shunts
- Use of antibiotics for seven days prior to inclusion in the study, except for prophylactic (ie. prophylaxis of spontaneous bacterial peritonitis)
- Cardiac or respiratory failure
- Positive for the human immunodeficiency virus
- Urinary retention
- Ischemic heart disease or peripheral vascular disease.
- Narrow-angle glaucoma
- Cerebrovascular occlusions
- Aortic Aneurysm
- Thyrotoxicosis
- Pheochromocytoma

- Mujeres embarazadas, en periodo de lactancia, o aquellas que pretendan quedar embarazadas durante el periodo del estudio
- Tensión arterial sístólica ?150 mmHg y/o tensión arterial diastólica ?90 mmHg
- Tratamiento previo con derivación transyugular intrahepática portosistémica (TIPS) o shunts quirúrgicos portosistémicos
- Uso de antibióticos en los siete días anteriores a la inclusión en el estudio, excepto para fines profilácticos (pe. profilaxis de la peritonitis bacteriana espontánea)
- Insuficiencia cardiaca o respiratoria
- Positividad para el virus de la imunodeficiencia humana
- Retención urinaria
- Enfermedad isquémica cardíaca o vascular periférica.
- Glaucoma de ángulo estrecho
- Oclusiones cerebro vasculares
- Aneurisma aórtico
- Tirotoxicosis
- Feocromocitoma

E.5 End points

E.5.1

Primary end point(s)

Change in glomerular filtration rate measured by isotopic tests at 12 weeks of starting treatment.

Cambio en el filtrado glomerular medido mediante pruebas isotópicas a las 12 semanas de iniciar el tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

Change in glomerular filtration rate measured by isotopic tests at 12 weeks of starting treatment.

Cambio en el filtrado glomerular medido mediante pruebas isotópicas a las 12 semanas de iniciar el tratamiento.

E.5.2

Secondary end point(s)

? Changes in plasma renin activity, plasma aldosterone and norepinephrine at 4, 12 and 16 weeks.
? Changes in blood pressure measured by Holter voltage at 4, 12 and 16 weeks.
? Changes in renal function at 4 weeks after cessation of treatment (week 16)

? Cambios en la actividad de renina plasmática, concentración plasmática de aldosterona y noradrenalina a las 4, 12 y 16 semanas.
? Cambios de tensión arterial medidos por Holter de tensión a las 4, 12 y 16 semanas.
? Cambios en la función renal a las 4 semanas tras la suspensión de tratamiento (semana 16)

E.5.2.1

Timepoint(s) of evaluation of this end point

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

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.8.2.4

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

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)

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

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)

N/A

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

2012-04-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-13

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

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