A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood

Elodie Hainque, Samantha Caillet, Sandrine Leroy, Constance Flamand-Roze, Isaac Adanyeguh, Fanny Charbonnier-Beaupel, Maryvonne Retail, Benjamin Le Toullec, Mariana Atencio, Sophie Rivaud-Péchoux, Vanessa Brochard, Florence Habarou, Chris Ottolenghi, Florence Cormier, Aurélie Méneret, Marta Ruiz, Mohamed Doulazmi, Anne Roubergue, Jean-Christophe Corvol, Marie Vidailhet, Fanny Mochel, Emmanuel Roze, Elodie Hainque, Samantha Caillet, Sandrine Leroy, Constance Flamand-Roze, Isaac Adanyeguh, Fanny Charbonnier-Beaupel, Maryvonne Retail, Benjamin Le Toullec, Mariana Atencio, Sophie Rivaud-Péchoux, Vanessa Brochard, Florence Habarou, Chris Ottolenghi, Florence Cormier, Aurélie Méneret, Marta Ruiz, Mohamed Doulazmi, Anne Roubergue, Jean-Christophe Corvol, Marie Vidailhet, Fanny Mochel, Emmanuel Roze

Abstract

Background: Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations.

Methods: We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects.

Results: In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated.

Conclusions: Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting.

Trial registration: The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.

Trial registration: ClinicalTrials.gov NCT02408354.

Keywords: Alternating hemiplegia of childhood; Crossover trial; Triheptanoin.

Conflict of interest statement

Authors’ information

Sandrine Leroy carried out the biostatistical analysis.

Ethics approval and consent to participate

The study protocol was approved by a local ethics committee (CPP Paris VI), and written informed consent was obtained from all the participants or their legal guardians. The study has been registered with clinicaltrials.gov (NCT002408354) the 03/24/2015.

Consent for publication

Not applicable (manuscript contains no individual person’s data).

Competing interests

Elodie Hainque, Samantha Caillet, Sandrine Leroy, Constance Flamand-Roze, Isaac Adanyeguh, Fanny Charbonnier-Beaupel, Maryvonne Retail, Benjamin Le Toullec, Anne Roubergue, Mariana Atencio, Sophie Rivaud-Péchoux, Vanessa Brochard, Florence Habarou, Chris Ottolenghi, Florence Cormier, Mohamed Doulazmi and Marta Ruiz declare that they have no competing interests.

Aurélie Méneret has received travel funding from Zambon.

Jean-Christophe Corvol has stock options at B&A Therapeutics; has received research grants from the French Ministry of Health, ANR, Michael J Fox Foundation, Actelion and Ipsen; participated in scientific advisory boards for BMS, Zambon, Pfizer, Amarantus, Abbvie and Clevexel; and received travel grants from Abbvie and Teva.

Fanny Mochel holds a patent on the use of triheptanoin in Huntington disease and GLUT1 deficiency syndrome. She has received research support from Ultragenyx and honorarium on advisory boards from Ultragenyx and AlfaSigma.

Marie Vidailhet has received grant from Merz and travel grants from MDS and EAN.

Emmanuel Roze has received research support from Merz-Pharma, Orkyn, Aguettant, IP santé, Ultragenix and UCB pharma; served on scientific advisory boards for Orkyn, Ultragenix, Retrophin and Merz-pharma; received speech honoraria from Orkyn, Aguettant, Merz-Pharma and Ultragenix; and received travel funding from the Dystonia Coalition, the Dystonia Medical Research Foundation, the Movement Disorders Society, and the European Academy of Neurology.

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Figures

Fig. 1
Fig. 1
Flow chart of trial participants

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