Clinical Trials Register

Summary
EudraCT Number:	2013-001640-56
Sponsor's Protocol Code Number:	PI12/01866
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-09-16
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

2013-001640-56

A.3

Full title of the trial

Crossover clinical trial, randomized, double blind, placebo controlled trial. Modulation of cellular mediators and repair endothelial damage in patients with chronic renal disease through inhibition of xanthine oxidase.

Ensayo clínico cruzado, randomizado, doble ciego y controlado con placebo. Modulación de los mediadores de daño y reparación endotelial en pacientes con enfermedad renal crónica a través de la inhibición de la xantino-oxidasa.

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

PI12/01866

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	Fundación Para la Investigación Biomédica de Córdoba
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 Economía y Competitividad
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	Fundación Para la Investigación Biomédica de Córdoba
B.5.2	Functional name of contact point	Isabel Bejerano Blazquez
B.5.3	Address:
B.5.3.1	Street Address	Avd. Menéndez Pidal s/n (Edif. Consultas Externas nivel -1, Despacho CEIC)
B.5.3.2	Town/ city	Córdoba
B.5.3.3	Post code	14004
B.5.3.4	Country	Spain
B.5.4	Telephone number	+0034957011226
B.5.5	Fax number	+0034957012938
B.5.6	E-mail	isabel.bejerano@imibic.org

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	Alopurinol
D.2.1.1.2	Name of the Marketing Authorisation holder	NORMON
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	Alopurinol
D.3.2	Product code	616789
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.3.8	INN - Proposed INN	ALLOPURINOL
D.3.9.1	CAS number	315-30-0
D.3.9.3	Other descriptive name	ALLOPURINOL
D.3.9.4	EV Substance Code	SUB05338MIG
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	100
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	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	MALTODEXTRINE
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	MALTODEXTRINE
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.3.8	INN - Proposed INN	MATODEXTRINE
D.3.9.1	CAS number	9050-36-6
D.3.9.3	Other descriptive name	MALTODEXTRINE
D.3.9.4	EV Substance Code	SUB22106
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	100
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

Patients with chronic kidney disease and asymptomatic hyperuricemia on the balance of mechanisms of vascular injury and repair.

Pacientes con enfermedad renal crónica e hiperuricemia asintomática podría reducir la microinflamación.

E.1.1.1

Medical condition in easily understood language

Patients with chronic kidney disease and asymptomatic hyperuricemia on the balance of mechanisms of vascular injury and repair.

Pacientes con enfermedad renal crónica e hiperuricemia asintomática podría reducir la microinflamación.

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10007648
E.1.2	Term	Cardiovascular disease, unspecified
E.1.2	System Organ Class	100000004849

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 study the effect of inhibiting xanthine oxidase with allopurinol in patients with chronic kidney disease in asymptomatic hyperuricemia endothelial injury and vascular repair mechanisms, evaluating the plasma concentration of angiogenic factors, microparticles of endothelial cells and the cell number circulating endothelial progenitor.

Estudiar el efecto de la inhibición de la xantina oxidasa con alopurinol en pacientes con enfermedad renal crónica e hiperuricemia asintomática en la lesión endotelial y los mecanismos de reparación vascular, evaluando la concentración plasmática de los factores angiogénicos, micropartículas de células endoteliales y el número de células progenitoras endoteliales circulantes.

E.2.2

Secondary objectives of the trial

To study the effect of inhibition of xanthine oxidase with allopurinol in patients with
chronic kidney disease and asymptomatic hyperuricemia on the following variables:
- Oxidative stress - Microinflammation - Endothelial dysfunction - Blood Pressure -
Glomerular filtration ratio - Microalbuminuria / proteinuria

Estudiar el efecto de la inhibición de la xantina oxidasa con alopurinol en pacientes
con enfermedad renal crónica e hiperuricemia asintomática en las siguientes
variables: - Estrés oxidativo, midiendo producción de radicales libres y la actividad
de la xantino-oxidasa. - Microinflamación, midiendo perfil de citoquinas y monocitos
CD14+ CD16+ - Disfunción endotelial: medida mediante la vasodilatación
dependiente de endotelio usando Láser Doppler con el sistema Periflux System
5000. - Presión Arterial: medida mediante monitorización de presión arterial de 24
horas. - Filtrado glomerular, evaluado por MDRD - Microalbuminuria, evaluado por
el cociente albúmina/creatinina en orina.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patient willing and able to give informed consent for participation in the study.
- Ability to understand study procedures and to comply with it for the duration of the study.
- Subjects of both sexes, the age range between 18 and 70 years old.
- Serum uric acid than 7 mg / dl.
- Estimated glomerular filtration rate by MDRD abbreviated formula less than 60 ml / min/1.73m2 and above 15 ml/min/1.73m2.
- Stability of renal function (serum creatinine increase without exceeding 50% in the three months before the start of the study).
- Clinically stable in terms of no hospitalizations or cardiovascular events in the 3 months before the study began.

- Paciente dispuesto y capaz de dar su consentimiento informado para la participación en el estudio.
- Capacidad para comprender los procedimientos del estudio y para cumplir con ello durante la duración del estudio.
- Sujetos de ambos sexos, el rango de edad entre 18 y 70 años de edad.
- Concentración sérica de ácido úrico superior a 7 mg / dl.
- Tasa de filtrado glomerular estimado por fórmula abreviada MDRD inferior a 60 ml / min/1.73m2 y superior a 15 ml/min/1.73m2.
- Estabilidad de la función renal (creatinina sérica basal sin incremento superior a un 50% en los 3 meses antes del inicio del estudio).
- Clínicamente estable en términos de no hospitalizaciones ni eventos cardiovasculares en los 3 meses antes del inicio del estudio.

E.4

Principal exclusion criteria

- Drop active in the 60 days prior to study initiation.
- Use of allopurinol within 60 days preceding baseline
- Active infections within 30 days prior to baseline.
- Patients with systemic inflammatory disease.
- Infection with HIV, Hepatitis C and Hepatitis B.
- History of cancer within 5 years prior to the first dose of study medication.
- Chronic liver disease.
- Immunosuppressive therapy.
- Pregnant women, breastfeeding, or planning to become pregnant.
- Allergy or sensitivity to allopurinol.
- Addiction to drugs or alcohol, in the opinion of the investigator, may interfere with compliance with study requirements.
- Inability or unwillingness of the individual or legal guardian or representative to give written informed consent.

- Gota activa en los 60 días anteriores al inicio estudio.
- Uso de alopurinol dentro de los 60 días anteriores inicio del estudio
- Infecciones activas dentro de los 30 días anteriores al inicio del estudio.
- Pacientes con enfermedad inflamatoria sistémica.
- Infección por VIH, virus de la Hepatitis C o Hepatitis B.
- Historia de cáncer dentro de los 5 años anteriores a la primera dosis de la medicación del estudio.
- Hepatopatía crónica.
- Terapia inmunosupresora.
- Mujeres embarazadas, en lactancia, o con planes de quedar embarazadas.
- Alergia o sensibilidad a alopurinol.
- Adicción a drogas o alcohol que, en opinión del investigador, podría interferir con el cumplimiento de los requisitos de estudio.
- Incapacidad o falta de voluntad del individuo o tutor legal o representante para dar consentimiento informado por escrito.

E.5 End points

E.5.1

Primary end point(s)

Microinflammation: C-ReactiveProtein, IL-1, IL-6, CD14+ CD16+ monocytes Oxidative stress and cellular damage markers: Reactive oxygen species (ROS).
Transmembrane mitochondrial potential loss. To characterize the DNA damage associated with an increase in ROS activity, we will analyze 84 genes involved in signaling pathways of DNA damage. These genes are primarily related to intracellular signaling pathway ATR / ATM, as well as markers associated with genomic damage that will result in cell cycle arrest, apoptosis, and stabilization and repair the cellular genome. This study will be done through microarray (Human DNA Damage Signaling RT ² Profiler ? PCR Array, abiosciences) Endothelial dysfunction: Endothelium-dependent vasodilation will be assessed by measuring the change in skin blood flow using Laser Doppler Flowmetry technique with Periflux System 5000. Lesion / repair vascular mechanism: ICAM, VCAM, VEGF,
endothelial cell microparticles, endothelial progenitor circulating cells.

- Microinflamación: proteína C reactiva, citoquinas proinflamatorias, monocitos
CD14+ CD 16+ - Estrés oxidativo: especies reactivas de oxígeno.
- Disfunción endothelial: Vasodilatación dependiente de endotelio en respuesta a
isquemia-reperfusión medida mediante cambios en flujo capilar usando láser-doppler con Periflux System 5000.

E.5.1.1

Timepoint(s) of evaluation of this end point

after each patient visits

Después de la visita del paciente

E.5.2

Secondary end point(s)

Blood pressure: Assessed by 24 hours ambulatory blood pressure monitoring.
Estimated Glomerular filtration rate: Assessed by MDRD-4 and Cockroft-Gault.
Microalbuminuria / proteinuria: Assessed by urinary albumina/creatinine ratio and
urinary protein / creatinine ratio, in the first morning void.

- Monitorización ambulatoria de presión arterial de 24 horas. - Filtrado glomerular
estimado mediante MDRD-4 y Cockroft-Gault. - Microalbuminuria / proteinuria:
evaluada mediante el cálculo del ratio albumina/creatinina y proteina / creatinina en
la primera orina de la mañana.

E.5.2.1

Timepoint(s) of evaluation of this end point

after each patient visits

Después de la visita del paciente

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

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

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

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

LVLP

Ultima visita 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

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

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)

Normal treatment of that condition

Tratamiento habitual

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

2014-01-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-05

P. End of Trial
P.	End of Trial Status	Ongoing

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