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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Fragile X Syndrome

Intervention / Treatment
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* Dietary Supplement: Ascorbic Acid (Vitamin C) and Alpha-tocopherol (Vitamin E)
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ascorbic Acid and alpha-tocopherol<br>Two daily doses of the combination of antioxidants, administered at breakfast and dinner | Dietary Supplement: Ascorbic Acid (Vitamin C) and Alpha-tocopherol (Vitamin E)<br>* 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<br>|
| Placebo Comparator: Placebo<br>Two daily doses of placebo, administered at breakfast and dinner | Dietary Supplement: Placebo<br>* Two daily dose of placebo, administered at breakfast and dinner for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurodevelopmental disability, Hyperactivity, Anxiety, Cognitive problems, Behavioural symptoms, Fragile X syndrome, Autism, inherited Genetic condition