Efficacy of Phosphatidylserine Enriched With n-3 PUFA Supplementation on ADHD in Children With Epilepsy

Study Overview
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Brief Summary
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Our project aims to develop a new therapeutic approach in epilepsy-associated attention disorders in children, through evaluation of the clinical impact of dietary n-3 fatty acids, containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) conjugated to a phospholipid vector. The primary objective is to evaluate the efficacy of a PUFA supplementation (PS-Omega 3), after 12 weeks of treatment, on attention disorders in children with epilepsy. Secondary objectives include: To evaluate the impact of a supplementation of PS-Omega 3 on quality of life. To evaluate the impact of a supplementation of PS-Omega 3 on serum and erythrocyte lipid profiles. To assess the tolerance of a supplementation of PS-Omega 3. To assess the impact of a supplementation of PS-Omega 3 on the frequency of seizures. To describe the impact of a supplementation of PS-Omega 3, at 24 weeks, on attention disorders in children with epilepsy, on quality of life, and on serum and erythrocyte lipid profiles. This study will recruit 272 subjects aged 6- 16 years, suffering from epilepsy (any type) and attention deficit hyperactivity disorder (ADHD) (inattentive or combined type) according to DSM V criteria in 12 clinical sites in France.

Official Title
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Efficacy of Phosphatidylserine Enriched With Polyunsaturated n-3 Fatty Acid Supplementation on Attention Deficit Disorders in Children With Epilepsy. A Randomized Double-blind Placebo-controlled Trial

Conditions
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Attention Deficit Disorder With Hyperactivity, ADHD Inattention or Mixed Type, Epilepsy, Child

Intervention / Treatment
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* Drug: Vayarin®, supplementation of n-3 PUFA
* Drug: PLACEBO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 6 to 15 years and 11 months. Children of either sex (male/female) suffering from epilepsy regardless of syndrome classification. Subjects on a stable dose of antiepileptic drugs (AED) for at least one month prior to inclusion and subjects for whom no change is considered a priori for the three months following the inclusion. Diagnosis of ADHD inattention or mixed type according to the DSM V criteria. Subjects must agree to study participation and their parents/legal guardian must provide written inform consent prior to participation in the study. Exclusion Criteria: Subjects less than 6 years or older than 16 years old AED not stable for at least one month and/or a change in AED is expected in the three months following inclusion. Diagnosis of ADHD hyperactivity type exclusive according to DSM V criteria. Mental retardation defined by a score < 70 on the verbal comprehension and perceptual reasoning Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV), performed within 18 months prior to inclusion or at V1. Diagnosis of a psychiatric comorbidity other than ADHD according to the DSM V criteria, including: pervasive developmental disorders including autism disorders; bipolar disordersand psychotic disorders. Children suffering from diabetes, any type. Use of psychoactive drugs in ADHD within the previous month: Methylphenidate, Amphetamine, Atomoxetine, Modafinil and Antidepressants whatever the class. Use of dietary supplementation, other than vitamins, within the last 3 months. Use of ketogenic diet within the last 3 months. Allergy to fish or other sea products. Soy allergy. Absence of coverage by social security.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PS-OMEGA 3, capsules twice daily<br>Vayarin®, supplementation of n-3 PUFA: each capsule contains 8.5 mg of docosahexaenoic acid (DHA), 21.5 mg of eicosapentaenoic acid (EPA) and 75 mg of phosphatidylserine. | Drug: Vayarin®, supplementation of n-3 PUFA<br>* Two capsules will be swallowed twice daily, 20 to 30 minutes prior to breakfast and dinner, during 12 weeks, between visit 1 and visit 2. At the end of this period, active product will be continued, at the same dose, for a 12 week-open label period. All patients will be administered the active product.<br>|
| Placebo Comparator: PLACEBO, capsules twice daily<br>The placebo will be made of cellulose and a small amount of fish powder to maintain the double-blind in odor and taste. The supplementation in n-3 PUFA in the placebo group may be considered as negligible. Placebo will be administered as indistinguishable capsules, identical to the active product. | Drug: PLACEBO<br>* Two capsules will be swallowed twice daily, 20 to 30 minutes prior to breakfast and dinner, during 12 weeks, between visit 1 and visit 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of the ADHD-rating scale IV inattentive subscore in subjects assigned to supplementation of PS-Omega 3 in comparison with the placebo group after 12 weeks of treatment. | The ADHD Rating Scale-IV quantifies each of the 18 symptoms of ADHD on a 0 to 3 scale, with a maximum score of 54 points. Nine of the 18 items score for inattention while the nine others assess hyperactivity with a maximum of 27 points each. The discriminative value of these two subscales was validated, allowing their individual use. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of the ADHD Rating Scale-IV total score in the PS-Omega 3 group compared with the placebo group after 12 weeks of treatment. | The ADHD Rating Scale-IV quantifies each of the 18 symptoms of ADHD on a 0 to 3 scale, with a maximum score of 54 points. | 12 weeks | 
| Reduction of TOVA total score in the PS-Omega 3 group compared with the placebo group after 12 weeks of treatment. | The TOVA (Test of Variables of Attention) is a computerized tool assessing the capacity of attention and impulse control. This test has been validated as a diagnostic tool in ADHD. | 12 weeks | 
| Proportion of subjects with a normalized TOVA score in the PS-Omega 3 group compared with the placebo group after 12 weeks of treatment. | The TOVA (Test of Variables of Attention) is a computerized tool assessing the capacity of attention and impulse control. This test has been validated as a diagnostic tool in ADHD. | 12 weeks | 
| Change in quality of life score in the PS-Omega 3 group compared with the placebo group after 12 weeks of treatment. | Quality of life assessed by the EFIQUACEE questionnaire (Echelle Française d'Impact et de Qualité de Vie Chez l'Enfant atteint d'Epilepsie). The EFIQUACEE questionnaire is a unique quality of life scale for children suffering from epilepsy. It is validated in French language. | 12 weeks | 
| Evolution of plasma lipid profiles in subjects assigned to supplementation of PS-Omega 3 in comparison with the placebo group after 12 weeks of treatment. | Plasma levels before and after 12 weeks of treatment: total lipid mass ; total phospholipids ; individual phospholipids including: lysophosphatidylcholin, phosphatidylcholin, sphingomyelin, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, diphosphatidylglycerol, lysophosphatidylethanolamine ; total triglycerides ; fatty acids profiles in phospholipids; fatty acids profiles in triglycerides ; fatty acids profiles in cholesterol esters. | 12 weeks | 
| Evolution of eythrocytes lipid profiles in subjects assigned to supplementation of PS-Omega 3 in comparison with the placebo group after 12 weeks of treatment. | Quantification of, in erythrocyte membrane, before and after 12 weeks of treatment: total lipid mass ; total phospholipids ; individual phospholipids including: lysophosphatidylcholin, phosphatidylcholin, sphingomyelin, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, diphosphatidylglycerol, lysophosphatidylethanolamine ; total triglycerides ; fatty acids profiles in phospholipids; fatty acids profiles in triglycerides ; fatty acids profiles in cholesterol esters. | 12 weeks | 
| Tolerance of a supplementation of PS-Omega 3. | Tolerance analysis of the supplementation of PS-Omega 3: interrogatoire, phone calls, clinical examinations, adverse events reported throughout the study. | 36 weeks | 
| Number of subjects with a reduction in the frequency of seizures ≥ 50%, in the PS-Omega 3 group compared with the placebo group after 12 weeks of treatment. |  | 12 weeks | 
| After 24 weeks of treatment, description of the total score of ADHD Rating Scale. |  | 24 weeks | 
| After 24 weeks of treatment, description of the total score of TOVA. |  | 24 weeks | 
| After 24 weeks of treatment, proportion of subjects with a normalized TOVA score. |  | 24 weeks | 
| After 24 weeks of treatment, change in quality of life score (EFIQUACEE questionnaire). |  | 24 weeks | 
| After 24 weeks of treatment, plasma lipid levels before and after treatment. | Plasma levels before and after 24 weeks of treatment: total lipid mass ; total phospholipids ; individual phospholipids including: lysophosphatidylcholin, phosphatidylcholin, sphingomyelin, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, diphosphatidylglycerol, lysophosphatidylethanolamine ; total triglycerides ; fatty acids profiles in phospholipids; fatty acids profiles in triglycerides ; fatty acids profiles in cholesterol esters. | 24 weeks | 
| After 24 weeks of treatment, erythrocyte lipid levels before and after treatment. | Quantification of, in erythrocyte membrane, before and after 24 weeks of treatment: total lipid mass ; total phospholipids ; individual phospholipids including: lysophosphatidylcholin, phosphatidylcholin, sphingomyelin, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, diphosphatidylglycerol, lysophosphatidylethanolamine ; total triglycerides ; fatty acids profiles in phospholipids; fatty acids profiles in triglycerides ; fatty acids profiles in cholesterol esters. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epilepsy, Attention Deficit Disorders, VAYARIN, Children, Polyunsaturated n-3 fatty acid supplementation