Clinical Trials Register

Summary
EudraCT Number:	2021-001989-38
Sponsor's Protocol Code Number:	IMCRELA
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:	2021-06-14
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

2021-001989-38

A.3

Full title of the trial

IMPACT OF THE COMBINED TREATMENT OF THE LIPOSOMATED POLYPHENOLS CÚRCULA AND RESVERATROL® WITH DUTASTERIDE, IN THE CLINICAL IMPROVEMENT OF PATIENTS WITH ALS TREATED WITH RILUZOLE

IMPACTO DEL TRATAMIENTO COMBINADO DE LOS POLIFENOLES LIPOSOMADOS CÚRCULA Y RESVERATROL® CON DUTASTERIDA, EN LA MEJORA CLÍNICA DE PACIENTES CON ELA TRATADOS CON RILUZOL

A.3.1

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

COMPARISON OF THE COMBINED TREATMENT OF THE LIPOSOMATED POLYPHENOLS CÚRCULA AND RESVERATROL® WITH DUTASTERIDE, IN THE IMPROVEMENT OF PATIENTS WITH ELA WHO ARE BEING TREATED WITH RILUZOLE

COMPARACION DEL TRATAMIENTO COMBINADO DE LOS POLIFENOLES LIPOSOMADOS CÚRCULA Y RESVERATROL® CON DUTASTERIDA, EN LA MEJORA DE PACIENTES CON ELA QUE ESTÉN SIENDO TRATADOS CON RILUZOL

A.3.2

Name or abbreviated title of the trial where available

IMCRELA

A.4.1

Sponsor's protocol code number

IMCRELA

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	Facultad de medicina y ciencias de la salud de la Universidad Católica de Valencia
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	FACULTAD DE MEDICINA Y CIENCIAS DE LA SALUD DE LA UNIVERSIDAD CATÓLICA DE VALENCIA
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	FACULTAD DE MEDICINA Y CIENCIAS DE LA SALUD DE LA UNIVERSIDAD CATÓLICA DE VALENCIA
B.5.2	Functional name of contact point	Carlos Barrios
B.5.3	Address:
B.5.3.1	Street Address	2, Quevedo St.
B.5.3.2	Town/ city	Valencia
B.5.3.3	Post code	46001
B.5.3.4	Country	Spain
B.5.6	E-mail	carlos.barrios@ucv.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	Dutasterida
D.2.1.1.2	Name of the Marketing Authorisation holder	Industria Química y Farmacéutica VIR, 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	Dutasterida
D.3.4	Pharmaceutical form	Capsule, soft
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	DUTASTERIDE
D.3.9.1	CAS number	164656-23-9
D.3.9.3	Other descriptive name	DUTASTERIDE
D.3.9.4	EV Substance Code	SUB06430MIG
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	0.5
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.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, soft
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

Amyotrophic Lateral Sclerosis

Esclerosis lateral amiotrófica

E.1.1.1

Medical condition in easily understood language

Amyotrophic Lateral Sclerosis

Esclerosis lateral amiotrófica- ELA

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10002026
E.1.2	Term	Amyotrophic lateral sclerosis
E.1.2	System Organ Class	10029205 - Nervous system 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 functional improvement of the combined treatment with Liposomal Turmeric / Resveratrol® with Dutasteride in comparison with patients in routine clinical practice

Valorar la mejoría funcional del tratamiento combinado con Liposomal Cúrcuma/Resveratrol® con Dutasterida en comparación con pacientes en práctica clínica habitual

E.2.2

Secondary objectives of the trial

•Assess activity at the cognitive and behavioral level in ALS patients, and its effects on the quantity and quality of sleep, after the intervention with the combination of Liposomal Turmeric / Resveratrol® with Dutasteride, at baseline visit, 3 and 6 months.
•Quantify the decrease in oxidative stress, after the intervention with the indicated drug combination, at the baseline visit, 3 and 6 months.
•Quantify the possible decrease in inflammation, after the intervention with the indicated drug combination, at a baseline visit, 3 and 6 months.
•Assess the effects on the intestinal microbiota, after the intervention with the indicated drug combination, related to cognitive and behavioral changes at the beginning, 3 and 6 months.
•Assessment of muscle strength and capacity at baseline visit, 3 and 6 months after onset.
•Assessment of the quantity and quality of sleep, after the intervention with the indicated combination of medications, at a baseline visit, 3 and 6 months.

•Valorar la actividad a nivel cognitivo y conductual en pacientes de ELA, y sus efectos en la cantidad y calidad de sueño, tras la intervención con la combinación de Liposomal Cúrcuma/Resveratrol® con Dutasterida, en visita basal, 3 y 6 meses de inicio del tto.
•Cuantificar la disminución de estrés oxidativo, tras la intervención con la combinación de medicamentos indicado, en visita basal, 3 y 6 meses.
•Cuantificar la posible disminución de inflamación, tras la intervención con la combinación de medicamentos indicado, en visita basal, 3 y 6 meses.
•Valorar los efectos en la microbiota intestinal, tras la intervención con la combinación de medicamentos indicado, relacionados con los cambios cognitivos, y conductuales al inicio, 3 y6 meses.
•Valoracion de la fuerza y capacidad muscular en visita basal, a los 3 y 6 meses de inicio.
•Valoración de la cantidad y calidad de sueño, tras la intervención con la combinación de de medicamentos indicado, en visita basal, 3 y 6 meses.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Male patients over 18 years of age or female patients over 50 years of age who are not fertile, and between 18 and 50 years of age who have accepted the use of contraceptives if they are of childbearing age and renounce becoming pregnant during the intervention.
•Patients diagnosed and symptomatic of ALS for at least 6 months prior to inclusion in the study.
•Patients treated with Riluzole at least one month before inclusion in the study.
•Acceptance of participation in the study by signing the IC form.
•At the discretion of the investigator, the patient must be able to meet the requirements of the study

•Pacientes varones mayores de 18 años ó pacientes mujeres mayores de 50 años no fértiles, y entre 18 y 50 años que hayan aceptado el uso de anticonceptivos si se encuentran en edad fértil renunciando a quedarse embarazadas durante la intervención.
•Pacientes diagnosticados y sintomáticos de ELA desde al menos 6 meses previos a la inclusión en el estudio.
•Pacientes tratados con Riluzol mínimo un mes antes de la inclusión en el estudio.
•Aceptación de participación en el estudio mediante la firma del formulario de CI.
•A criterio del investigador, el paciente debe ser capaz de cumplir con los requisitos del estudio

E.4

Principal exclusion criteria

•Patients with tracheostomy.
•Patients with invasive or non-invasive ventilation with positive ventilatory pressure.
•Participation in any other trial or in the 4 weeks prior to inclusion.
•Gastro-stomized patients.
•We are ill with evidence of dementia.
•We are ill with dependence on alcohol or drug abuse.
•Patients infected with hepatitis B or C, or HIV positive.
•Kidney patients with creatinine 2 times higher than normal markers 30 days before inclusion.
9.Hepatic patients with hepatic markers (ALT, AST) elevated 3 times above normal levels 30 days prior to enrollment.
10.Patients treated with anticoagulants or with hemostatic problems 30 days before inclusion.

•Pacientes con traqueotomía.
•Pacientes con ventilación invasiva o no invasiva con presión ventilatoria positiva.
•Participación en cualquier otro ensayo o en las 4 semanas previas a la inclusión.
•Pacientes gastroestomizados.
•Enfermos con evidencia de demencia.
•Enfermos con dependencia de abuso de alcohol o drogas.
•Pacientes infectados de hepatitis B o C, o HIV positivo.
•Pacientes renales con creatinina 2 veces superior a los marcadores normales30 días antes de la inclusión.
•Pacientes hepáticos con marcadores hepáticos (ALT, AST) elevados 3 veces por encima de los niveles normales 30 días antes de la inclusión.
•Enfermos tratados con anticoagulantes o con problemas hemostáticos 30 días antes de la inclusión.

E.5 End points

E.5.1

Primary end point(s)

Determine functional improvement, understanding as such a statistically significant increase in the mean score obtained on the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRR-R) associated with ALS with respect to the baseline visit, at 3 and 6 months. treatment.

Determinar mejoría funcional entendiendo como tal un aumento estadísticamente significativo de la media de la puntuación obtenida en la escala Escala Amyotrophic Lateral Sclerosis Functional Rating Scale revisada (ALSFRR-R) asociada a la ELA respecto a la visita basal, a los 3 y a los 6 meses del tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

9 months

9 meses

E.5.2

Secondary end point(s)

- Motor Variables: The scales and tests carried out will try to determine improvement in muscular and respiratory activity, which deteriorates due to motor neuron damage.
The tests will be the following:
• Electromyography (EMG). Graphic recording technique of the electrical activity produced by skeletal muscles. EMG can be monitored through electrodes inserted into the muscles (intramuscular electrodes) or through electrodes on the surface of the skin over the muscle (superficial electrodes) with the FREE-EMG 300 Electromyograph (8 CHANNELS). This EMG is electromyographic data acquisition and analysis software. In this version, 8 acquisition channels are considered that allow the acquisition of EMG, Switch and / or Force Cell data. The graphical interface is designed for a 1280 x 1024 screen area.
• TEST MRC 11 –steps-mrc grading scale measures muscle strength
• Measurement of forced vital capacity (FVC): FVC is an indicator of lung capacity and would be obtained by performing spirometry, measuring it using a peak expiratory flow meter.
- Variables for cognitive and behavioral assessment: The assessment of cognitive and behavioral functions will try to determine possible improvements in these functions, linked to the damage that occurs in the frontotemporal area of the cortex in patients with ALS. To carry out these assessments, the following cognitive and behavioral tests will be applied.
The tests will be:
• Edinburgh ELA Cognitive and Behavioral Exam (ECCE)
• A behavioral test-interview with the caregiver that asks questions with a dichotomous answer Y / N about the presence of uninhibited behavior, apathy or behavioral inertia, lack of sympathy or empathy, perseverative, stereotyped, compulsive or ritualistic behavior, as well as hyperorality and alteration of eating behavior. Likewise, it collects 3 questions about the possible presence of psychotic symptoms.
-Variables related to the microbiota: A Clinical Intestinal Microbiome will be carried out, which is an analysis of the bacterial microbiota present in the intestine, from a stool sample. With this test the improvement will be assessed by the percentage of patients who present a increase of Akkermansia muciniphila, bifidobacterium or lactobacillus (the increase of any of the 3, especially the first); or a decrease in Escherichia coli or Ruminococcus torques (either of the two, but especially the second) at baseline, at 3 months (according to the investigator), and at 6 months.
-Variables related to the quantity and quality of sleep:
• Clinical questionnaire for screening of sleep pathologies, hereinafter, sleep test (TS)
• Measurement through diaries (DS) and scales (ES) of multiple quantitative and qualitative sleep variables (Epworth Test (sleepiness) and Pittsburgh Test (sleep quality)).
-Variables related to inflammation and oxidation:
• Quantitative measurement of plasma IL-6 and TNF-alpha.
• Quantitative measurement of plasma CRP.
• Quantitative measurement of plasma haptoglobin.
• Quantitative assessment of TEAC (oxidation).
• Quantitative measurement of plasma 8-oxoG.
• Quantitative measurement of plasma MDA.

- Variables Motoras:Las escalas y pruebas realizadas tratarán de determinar mejoría en la actividad muscular y respiratoria, que se deteriora por el daño de las motoneuronas.
Los tests serán los siguientes:
•Electromiografía (EMG). Técnica de registro gráfico de la actividad eléctrica producida por los músculos esqueléticos. El EMG puede ser monitoreado a través de electrodos insertados dentro de los músculos (electrodos intramusculares) o a través de electrodos en la superficie de la piel sobre el músculo (electrodos superficiales) con Electromiógrafo FREE-EMG 300 (8 CANALES). Este EMG es un software de adquisición y análisis de datos electromiográficos. En esta versión se consideran 8 canales de adquisición que permiten adquirir datos EMG, Switch y/o Celda de Fuerza. La interfaz gráfica está diseñada para un área de pantalla de 1280 x 1024.
•TEST MRC 11 –steps-mrc grading scale mide la fuerza muscular
•Medición de la capacidad vital forzada (CVF): CVF es un indicador de capacidad pulmonar y se obtendría mediante la realización de una espirometría, midiéndolo mediante un medidor de flujo espiratorio máximo.
- Variables para la valoración cognitiva y conductual: La valoración de las funciones cognitivas y conductuales, tratarán de determinar posibles mejoras en estas funciones, vinculadas con los daños que se producen en la zona frontotemporal de la corteza en enfermos de ELA. Para realizar estas valoraciones, se aplicarán los siguientes test tanto cognitivos como conductuales.
Las pruebas serán:
•Examen cognitivo y conductual de ELA de Edimburgo (ECCE)
•Un examen conductual-entrevista con el cuidador que plantea preguntas con respuesta dicotómica S/N sobre la presencia de conducta desinhibida, apatía o inercia comportamental, falta de simpatía o empatía, conducta perseverativa, estereotipada, compulsiva o ritualista, así como hiperoralidad y alteración de la conducta alimentaria. Así mismo, recoge 3 cuestiones sobre la posible presencia de sintomatología psicótica.
-Variables relacionadas con la microbiota: Se realizará un Microbioma Intestinal Clínico, que es un análisis de la microbiota bacteriana presente en el intestino, a partir de una muestra de heces.Con este test se valorará la mejoría mediante el porcentaje de pacientes que presenten un aumento de Akkermansia muciniphila, bifidobacterium o lactobacillus (el aunmento de cualquiera de las 3, especialmente la primera); o una disminución de Escherichia coli o Ruminococcus torques (cualquiera de las dos, pero especialmente la segunda) al inicio, a los 3 meses (a juicio del investigador) y a los 6 meses.
-Variables relacionadas con la cantidad y calidad de sueño:
•Cuestionario clínico para screening de patologías de sueño, en adelante, test de sueño (TS)
•Medición mediante diarios (DS) y escalas (ES) de múltiples variables cuantitativas y cualitativas de sueño (Test Epworth (somnolencia) y Test de Pittsburgh (calidad de sueño)).
-Variables relacionadas con inflamación y oxidación:
•Medición cuantitativa de IL-6 y TNF-alfa plasmáticos.
•Medición cuantitativa de PCR plasmática.
•Medición cuantitativa de haptoglobina plasmática.
•Valoración cuantitativa de TEAC (oxidación).
•Medición cuantitativa de 8-oxoG plasmática.
•Medición cuantitativa de MDA plasmático.

E.5.2.1

Timepoint(s) of evaluation of this end point

9 months

9 meses

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

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

Yes

E.6.13.1

Other scope of the trial description

Low-intervention pilot clinical trial, phase IIb, single-center exploratory, randomized, single-blind, placebo-controlled trial.

Ensayo clínico piloto de baja intervención, fase IIb, unicéntrico de tipo exploratorio, aleatorizado simple ciego controlado con placebo.

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

Yes

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)

Yes

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

LPLV

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:

100

F.1.3

Elderly (>=65 years)

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

100

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

2021-07-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-05-31

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

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