Pilot Study, Comparative, Single-center, Randomized, Crossover, Double-blind, Against Placebo, Testing the Effectiveness of Triheptanoin Oil in Alternating Hemiplegia of Childhood

Study Overview
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Brief Summary
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The purpose of this project is to study the efficacy of triheptanoin oil in patients with Alternating Hemiplegia of Childhood (AHC) due to ATP1A3 gene mutation.

Detailed Description
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The clinical spectrum of Alternating Hemiplegia of Childhood (AHC) is wide and characterized by the association of permanent and paroxysmal (palsy, dystonia, ocular, epileptic, dysautonomic events) neurological events, with onset in childhood. Most of AHC patients carry mutations in the ATP1A3 gene. This gene encodes the Na+/K+ ATPase witch is a transmembrane ion pump generating chemical and electrical gradient of sodium and potassium across the plasma membrane. Those paroxystic events in AHC patients with mutations in the ATP1A3 gene could be associated with a glucidic/energetic metabolism or intracerebral excitability disorder. Triheptanoin is a triglyceride, whose derivatives pass the blood - brain barrier and enhance the Krebs cycle functions. Triheptanoin could therefore allow energy supply to the brain, which is essential for the functioning of the Na+/ K+ ATPase that consumes a significant amount of energy in the brain. The investigators goal is to do a pilot study to test the effectiveness on paroxystic manifestations and the safety of triheptanoin in a small group of patients with Alternating Hemiplegia of Childhood secondary to ATP1A3 mutations.

Official Title
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Etude Pilote, Comparative, Monocentrique, randomisée, en Cross Over, en Double Aveugle, Contre Placebo, Testant l'efficacité de l'Huile triheptanoïne Dans Les Hémiplégies Alternantes de l'Enfant HEMIHEP

Conditions
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Alternating Hemiplegia of Childhood

Intervention / Treatment
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* Drug: Triheptanoin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: AHC with mutation in ATP1A3 gene Age ≥ 15 years and 3 months ≥ 6 neurological paroxystic events during the last 3 months prior to the beginning of the study No specific diet Covered by french social security Patients who freely agree to participate in this study and understand the nature, risks and benefits of this study and give their written informed consent. (In addition to the requirement for the consent of parents or the legal representative, adolescents can provide additional informed consent to participate in clinical trials) Exclusion Criteria: Age < 15 years and 3 months Evidence of psychiatric disorder Comorbid medical condition that would render them unsuitable for the study, e.g. HIV, diabetes Pregnant or parturient or lactating women Absence of double effective contraception at the women old enough to procreate Unwillingness to be informed in case of abnormal MRI Absence of signed informed consent No covered by french social security Persons deprived of their liberty by judicial or administrative decision Person subject to an exclusion period for another research Subjects with exclusion criteria required by french law

Ages Eligible for Study
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Minimum Age: 15 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Triheptanoin<br>Triheptanoin/ Placebo Randomized to receive active Triheptanoin first for 12 weeks. At cross-over, participants will receive placebo for 12 weeks. Each drug will be dispensed successively. A one-month wash out period is planned for 4 weeks between triheptanoine and placebo phases. | Drug: Triheptanoin<br>* Triheptanoin is a triglyceride composed of three heptanoate (C7 fatty acid) esters. Triheptanoin is manufactured by chemical synthesis from glycerol and heptanoic acid. Triheptanoin is a liquid, intended for oral (PO) administration. Participants will be given approximately 1g/kg of Triheptanoin divided at least in three doses (at 8 am, 12 noon, and 8 pm). A one-day titration period will be used, using 0.5 g/kg increments before arriving at the full dose.<br>* Other names: glycerol triheptanoate;|
| Placebo Comparator: Placebo<br>Placebo / Triheptanoin Randomized to receive active Placebo first for 12 weeks. At cross-over, participants will receive Triheptanoin for 12 weeks. Each drug will be dispensed successively. A one-month wash out period is planned for 4 weeks between placebo and triheptanoin phases. | Drug: Placebo<br>* Placebo is a oily liquid, intended for oral (PO) administration. Participants will be given approximately 1g/kg of Placebo divided at least in three doses (at 8 am, 12 noon, and 8 pm). A one-day titration period will be used, using 0.5 g/kg increments before arriving at the full dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of neurologic paroxystic events report in patient diary | visit 1 at day 0, visit 2 at week 12, visit 3 at week 16, visit 4 at week 28 | 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite score allying the number of neurological paroxystic events, their duration and severity. | visit 1 at day 0, visit 2 at week 12, visit 3 at week 16, visit 4 at week 28 | 7 months | 
| Clinical Global Impression Scales - Improvement | visit 2 at week 12, visit 4 at week 28 | 7 months | 
| The Short Form (36) Health Survey | visit 1 at day 0, visit 2 at week 12, visit 3 at week 16, visit 4 at week 28 | 7 months | 
| Brain 31phosphorus magnetic resonance spectroscopy | Ratio of Inorganic Phosphate (Pi) over Phosphocreatine during visual stimulation visit 2 at week 12, visit 4 at week 28 | 7 months | 
| Clinical Safety as measured by questionnaire | visit 2 at week 12, visit 4 at week 28 | 7 months | 
| Biological Safety as measured by acylcarnitine profile, organic acid dosage | visit 2 at week 12, visit 4 at week 28 | 7 months |