Clinical Trials Register

Summary
EudraCT Number:	2015-005460-42
Sponsor's Protocol Code Number:	SXF2-8
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:	2016-04-20
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

2015-005460-42

A.3

Full title of the trial

Phase III clinical trial, double-blind, cross-way, to evaluate the safety and efficacy ascorbic acid (vitamin C) and tocopherol (vitamin E) combination versus placebo for the treatment of cognitive and behavioral disorders in children with fragile x syndrome

ENSAYO CLÍNICO FASE III, DOBLE CIEGO, DE UNA VÍA CRUZADA, PARA EVALUAR LA SEGURIDAD Y LA EFICACIA DE LA COMBINACIÓN DE ÁCIDO ASCÓRBICO (VITAMINA C) Y TOCOFEROL (VITAMINA E) VERSUS PLACEBO PARA EL TRATAMIENTO DE LOS TRASTORNOS COGNITIVOS Y DE COMPORTAMIENTO EN POBLACIÓN INFANTIL CON SÍNDROME X FRÁGIL

A.3.1

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

Clinical trial to evaluate ascorbic acid (vitamin C) and tocopherol (vitamin E) in combination versus placebo for the treatment of cognitive and behavioral disorders in children with fragile x syndrome

Ensayo clínico para evaluar la combinación de vitamina C y E en combinación para el tratamiento de trastornos cognitivos y de comportamiento en niños con síndrome X frágil

A.4.1

Sponsor's protocol code number

SXF2-8

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 Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud
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	Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud
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	Delos Clinical
B.5.2	Functional name of contact point	Clinical Trial Assistant
B.5.3	Address:
B.5.3.1	Street Address	C/ Miguel de Mañara 11 Bajo D
B.5.3.2	Town/ city	Sevilla
B.5.3.3	Post code	41004
B.5.3.4	Country	Spain
B.5.6	E-mail	secretaria@delosclinical.com

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	No
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	Vitamin C
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	Yes
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	Vitamin C
D.3.9.3	Other descriptive name	ACIDUM ASCORBICUM D6
D.3.9.4	EV Substance Code	SUB44467
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	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	No
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	Vitamin E
D.3.4	Pharmaceutical form	Oral solution
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	Vitamin E
D.3.9.1	CAS number	58-95-7
D.3.9.3	Other descriptive name	TOCOPHERYL ACETATE
D.3.9.4	EV Substance Code	SUB15584MIG
D.3.10	Strength
D.3.10.1	Concentration unit	millilitre(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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	Oral solution
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

Fragile x syndrome

Síndrome X frágil

E.1.1.1

Medical condition in easily understood language

Fragile x syndrome

Síndrome X frágil

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10017324
E.1.2	Term	Fragile X syndrome
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To Evaluate the safety, tolerability and efficacy of the combination of two antioxidants ascorbic acid and tocopherol, for the treatment of cognitive and behavioral disorders in children diagnosed of fragile X syndrome.

Evaluación de la seguridad, tolerabilidad y eficacia de la combinación de dos antioxidantes ácido ascórbico y tocoferol, para el tratamiento de trastornos cognitivos y de comportamiento en población infantil diagnosticada de síndrome X frágil.

E.2.2

Secondary objectives of the trial

1. To evaluate the safety and tolerability of Vitamin C 10 mg / kg / day and vitamin E 10 mg / kg / day in the treatment of subjects in the pediatric population diagnosed with Fragile X Syndrome.

2.To evaluate the reduction of the overall clinical severity of pediatric subjects diagnosed with Fragile X Syndrome.

3. To evaluate the improvement of cognitive symptoms associated with pediatric subjects with a diagnosis of fragile X syndrome.

4. To evaluate the overall improvement of sleep in pediatric subjects with a diagnosis of fragile X syndrome.

5. To evaluate the improvement of language in pediatric subjects diagnosed with Fragile X Syndrome.

6. To evaluate the effectiveness of treatment to 32 weeks of pediatric subjects with a diagnosis of fragile X syndrome.

7. To evaluate the improvement of quality of life and health of primary caregivers of pediatric subjects with a diagnosis of fragile X syndrome.

1. Evaluar la seguridad y tolerabilidad de Vitmanina C 10mg/Kg/día y vitamina E 10mg/Kg/día en el tratamiento de sujetos dentro de la población pediátrica con diagnóstico de Síndrome X-frágil.

2. Evaluar la reducción de la severidad clínica global de los sujetos pediátricos con diagnóstico de Síndrome X-frágil.

3. Evaluar la mejora de los síntomas cognitivos asociados a los sujetos pediátricos con diagnóstico de Síndrome X-frágil.

4. Evaluar la mejoría global del sueño en sujetos pediátricos con diagnóstico de Síndrome X-frágil.

5. Evaluar la mejora del lenguaje en los sujetos pediátricos con diagnóstico de Síndrome X-frágil.

6. Evaluar la eficacia en el tratamiento a 32 semanas de sujetos pediátricos con diagnóstico de Síndrome X-frágil.

7. Evaluar la mejora de la calidad de vida y salud de los cuidadores principales de los sujetos pediátricos con diagnóstico de Síndrome X-frágil.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Diagnosis of Fragile X syndrome by genetic testing of molecular biology, with full mutation result methylation.

2. Patients older than 2 years and under 9 years.

3. Signed the informed consent document before starting their participation in the trial.

1. Diagnóstico de Síndrome X frágil por pruebas genéticas de biología molecular, resultado mutación completa con metilación.

2. Tener una edad mayor de 2 años y menor de 9 años.

3. Haber firmado el documento de consentimiento informado, antes de iniciar su participación en el ensayo.

E.4

Principal exclusion criteria

1. Any advanced, severe or unstable disease.

2. Individuals with other psychiatric diagnosed as the first diagnosis.

3. Suffer serious medical problems in the last 12 months.

4. Previous treatment with 100 mg of vitamin E or C a day in the last month.

5. Any physical, mental or sensory impairments that prevent the assessment of effectiveness.

6. Hypersensitivity to any component of the preparation.

7. Liver failure or severe renal or previous history of kidney stones.

8. Any treatment regimen, including treatment with psychotropic drugs and / or anticonvulsant therapy that has not been stable for a period ? 4 weeks prior to randomization.

9. Current treatment with more than two psychoactive drugs, excluding medication used specifically for seizure control.

10. Hypoprothrombinemia secondary to vitamin K deficiency.

11. Sensitivity to any of the compounds of formula treatment.

12. Deficiency of G-6-PD.

13. Use of oral anticoagulants.

14. Suspicion of change the pharmacological or non-pharmacological interventions during the course of the study.

1. Cualquier enfermedad avanzada, severa o inestable.

2. Se excluirán del estudio los individuos con otro diagnostico psiquiátrico como primer diagnóstico.

3. Haber padecido problemas médicos serios en los últimos 12 meses.

4. Estar tomando más de 100mg de vitaminas E o C al día en el último mes.

5. Tener problemas físicos, psíquicos o sensoriales que impidan la evaluación de la efectividad.

6. Hipersensibilidad a alguno de los componentes del preparado.

7. Insuficiencia hepática o renal grave o historia previa de cálculos renales.

8. Cualquier pauta de tratamiento, incluido el tratamiento con psicotrópicos y/o tratamiento anticonvulsivo que no haya sido estable durante un periodo ? 4 semanas antes de la aleatorización.

9. Tratamiento actual con más de dos medicaciones psicoactivas, excluyendo la medicación utilizada específicamente para el control de las convulsiones.

10. Hipoprotrombinemia secundaria a deficiencia de vitamina K

11. Sensibilidad a cualquiera de los compuestos de la fórmula de tratamiento.

12. Deficiencia de G-6-PD.

13. Uso de fármacos anticoagulantes orales.

14. Previsión de iniciar o cambiar las intervenciones farmacológicas o no farmacológicas durante el curso del estudio.

E.5 End points

E.5.1

Primary end point(s)

ICG scale (Guy 1976)

Escala de Impresión Clínica Global (ICG)

E.5.1.1

Timepoint(s) of evaluation of this end point

32 weeks

E.5.2

Secondary end point(s)

- McCarthy test
- TVIP
- ATEC
- Vineland scale
- IDEA
- SDSC
- SF36
- IBP
- GHQ-28
- Nutritional questionnaire
- DBC-P

Test McCarthy
Vocabulario en imágenes Peabody (TVIP)
Lista de chequeo del tratamiento del autismo (ATEC)
Escala de Madurez Social (Vineland)
Inventario de espectro autista (IDEA)
Escala de alteraciones del sueño en niños (SDSC)
Cuestionario sobre estado de salud (SF36)
Índice de Bienestar Psicológico (IBP)
Cuestionario de Salud de Goldberg (GHQ-28).
Cuestionario sobre alimentación
Inventario de comportamientos en el desarrollo (DBC-P).

E.5.2.1

Timepoint(s) of evaluation of this end point

40 weeks

40 semanas

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)

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

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 de último 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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

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)

After clinical trial completion, patients not receiving any study treatment.

Una vez finalizado el ensayo clínico, los pacientes no continuarán recibiendo tratamiento a estudio.

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

2016-07-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-28

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

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