Safety and Efficacy Study of Antioxidants for the Treatment of the Fragile X Syndrome

Fragile X Syndrome Clinical Trial

— SXF-TRA152  

Official title:

Phase II Double-blind Randomized Placebo-controlled 1-way Crossover Trial to Investigate Safety and Efficacy of the Ascorbic Acid and Tocopherol for the Treatment of the Fragile X Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01329770
• Other study ID #: 2009-017837-23
• Status: Completed
• Phase: Phase 2
• First received: March 29, 2011
• Last updated: April 13, 2015
• Start date: December 2010
• Est. completion date: April 2015

Study information

• Verified date: April 2015
• Source: The Mediterranean Institute for the Advance of Biotechnology and Health Research
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial Summary

The Fragile X syndrome (FXS) was first described by Dr. Martin and Dr. Bell in 1943, in families with several patients affected by sex-linked mental disability. This disorder is the most common cause of inherited mental disability. The prevalence of the Fragile X syndrome has been established at 1 in 2,500 males and 1 in 4000 females.

Despite moderate to severe mental retardation, fragile X patients exhibit macroorchidism, an elongated face, long ears, connective tissue dysplasia, hyperactivity, autistic-like and stereotypical behaviours, speech delay and increased sensory sensitivity.

Objective: To evaluate the effect of the combination of the antioxidant Ascorbic acid and tocopherol, as therapy of the Fragile X Syndrome in young males.

Hypothesis: It is proposed that part of the pathophysiology of the central nervous system in the animal model of the fragile X syndrome may be determined by oxidative stress. In addition, Fragile X patients showed a significantly low level of ascorbic acid in plasma. The biochemical characteristics of oxidative stress may be reversed in the FMR1-KO mice, by a chronic treatment with antioxidant compounds such as tocopherol or melatonin, it may also normalize several hallmarks of the Syndrome such as hyperactivity, anxiety and cognitive deficits. The normalization of the oxidative stress is proposed as a new therapeutic pathway to alleviate conditions caused by an excess of free radicals that are crucial in neurodevelopmental diseases such as autism, down syndrome and other diseases of the central nervous system.

Description:

• Objective: To evaluate the effect of the combination of the antioxidant Ascorbic acid and tocopherol, as therapy of the Fragile X Syndrome in young males.

• Design: Pilot clinical trial, Phase II , 6-month randomized, double-blind placebo-controlled one-way crossover clinical trial, with two treatment periods of 12 weeks duration.

• Setting: IMABIS Foundation. Carlos Haya Hospital, Malaga.

• Subjects: Children aged 5-11 years (infants) and 12-18 years (adolescents) diagnosed with Fragile X syndrome.

• Intervention: 30 participants randomly assigned, to receive antioxidant vitamins C (ascorbic acid) and vitamin E (d-alpha-tocopherol) once a day or placebo for 12 weeks double-blind. In Study Period 2, all participants receive (open) active treatment. Outcome measures: improvement in plasma antioxidant levels, oxidative stress (indicated by glutathione status, thiobarbituric acid reacting substances (TBARS) and carbonyl content of proteins) and HPA axis response. Behavioral problems will be studied using "Developmental behavior checklist" and "Teacher`s and Parent´s Questionnaire, C. Keith Conners", also learning improvement will be analyzed using "Wechsler Intelligence Scale for children" at 0, 3, 6 months during the trial and 3 months after completing the treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: April 2015
• Est. primary completion date: April 2015
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 6 Years to 18 Years

Eligibility

Inclusion Criteria:

• Molecular genetics diagnosis of the syndrome (number of CGG repeats in the FMR1 gene over 200).

• Presenting characteristic symptoms of fragile X syndrome.

• Patients older than 6 years and younger that 19 years.

• Signed informed consent by parents and/or legal tutor prior to enrolment in the trial.

• Both parents and patients must commit to participate for the duration of the 30 week trial.

Exclusion Criteria:

• The study excludes individuals with other neurological disorders not linked to the syndrome.

• Patients that have had serious medical problems in the previous 12 months.

• Are taking more than 100mg of vitamin E or vitamin C daily for the past 4 months.

• Have physical problems, mental or sensory impairments that preclude the assessment of effectiveness.

• Hypersensitivity to any component of the preparation.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Fragile X Syndrome
• Syndrome

Intervention

Dietary Supplement:
• Ascorbic Acid (Vitamin C) and Alpha-tocopherol (Vitamin E)
Vitamin E (D-alpha-Tocopherol) 10 mg/kg/day (with a maximum of 600mg/day) Vitamin C (L-Ascorbic Acid) 10 mg/kg/day (with a maximum of 800mg/day) For 12 weeks
• Placebo
Two daily dose of placebo, administered at breakfast and dinner for 12 weeks

Locations

Country	Name	City	State
Spain	Psychiatric Service. Hospital Carlos Haya	Malaga

Sponsors (1)

Lead Sponsor	Collaborator
Yolanda de Diego Otero

Country where clinical trial is conducted

Spain, 

References & Publications (3)

de Diego-Otero Y, Romero-Zerbo Y, el Bekay R, Decara J, Sanchez L, Rodriguez-de Fonseca F, del Arco-Herrera I. Alpha-tocopherol protects against oxidative stress in the fragile X knockout mouse: an experimental therapeutic approach for the Fmr1 deficiency. Neuropsychopharmacology. 2009 Mar;34(4):1011-26. doi: 10.1038/npp.2008.152. Epub 2008 Oct 8. — View Citation

el Bekay R, Romero-Zerbo Y, Decara J, Sanchez-Salido L, Del Arco-Herrera I, Rodríguez-de Fonseca F, de Diego-Otero Y. Enhanced markers of oxidative stress, altered antioxidants and NADPH-oxidase activation in brains from Fragile X mental retardation 1-deficient mice, a pathological model for Fragile X syndrome. Eur J Neurosci. 2007 Dec;26(11):3169-80. Epub 2007 Nov 14. — View Citation

Romero-Zerbo Y, Decara J, el Bekay R, Sanchez-Salido L, Del Arco-Herrera I, de Fonseca FR, de Diego-Otero Y. Protective effects of melatonin against oxidative stress in Fmr1 knockout mice: a therapeutic research model for the fragile X syndrome. J Pineal Res. 2009 Mar;46(2):224-34. doi: 10.1111/j.1600-079X.2008.00653.x. Epub 2008 Dec 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in the baseline Conner's Parent and Teacher Scales at 12 and 24 weeks	Hyperactivity scales: Conners Parent and Teacher Questionnaire, realized before starting treatment, 12 weeks and 24 weeks after beginning the treament.	Baseline, week 12, week 24	No
Secondary	Change in the baseline measure of the Inventory of behaviour development (DBC-P24) at 12 and 24 weeks	Inventory of behaviour development (DBC-P24) will be realized before starting, 12 weeks and 24 weeks after beginning the treatment	Baseline, week 12 and week 24	No
Secondary	Wechsler Intelligence Scale for children	Wechsler Intelligence Scale for children will be used at base line and 12 weeks after beginning the treatment	baseline, week 12 and week 24	No
Secondary	Composite measure of blood and urine.	Safety Evaluation through blood and urine measurement. The following studies will be done at base line, 12 and 24 weeks after beginning the treatment: Hematology; Biochemical; Determination of adrenal axis.; Oxidative status.; Analysis of urine density, pH, protein, glucose, ketone bodies, bilirubin, blood, nitrite, urobilinogen, leukocytes, urinary sediment, sodium, chlorine, potassium.	Baseline, week 12 and week 24	Yes

External Links

•   Foundation IMABIS