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

Abstract

BackgroundBased 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.MethodsWe 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.ResultsIn 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.ConclusionsTriheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting.Trial registrationThe study has been registered with clinicaltrials.gov (NCT002408354) the 03/24/2015.

Triheptanoin: First Approval

“…An open-label clinical trial using brain magnetic resonance spectroscopy in patients with Huntington's disease found that triheptanoin can improve brain energy metabolism (with apparent improvements in motor function) [39]. Other clinical trials found that triheptanoin may have some efficacy in reducing the frequency of focal seizures in adult patients with refractory epilepsy [14] but does not reduce the occurrence of paroxysmal events in alternating hemiplegia of childhood [15].…”

“…In addition to development in LC-FAOD, phase II trials have been conducted, are ongoing, or are planned (by Ultragenyx and/or other organizations/institutions), to investigate triheptanoin in a range of other indications, including glucose transporter type 1 deficiency syndrome (GLUT1DS; De Vivo disease) [11,12], Huntington's disease [12], glycogen storage disease type V (GSD-V; McArdle's disease) (NCT02919631; NCT02432768), refractory epilepsy [13,14], alternating hemiplegia of childhood [15], adult polyglucosan body disease [16] and Rett syndrome (NCT02696044). After a phase III crossover trial conducted by Ultragenyx to investigate triheptanoin in GLUT1DS failed to meet its primary and key secondary endpoints [17], development of triheptanoin by Ultragenyx in GLUT1DS was discontinued [although phase II trials (NCT03301532 and NCT03181399) by other parties are continuing in this indication].…”

Therapeutic potential of triheptanoin in metabolic and neurodegenerative diseases

“…[59][60][61] Triheptanoin failed to improve paroxysmal episodes in patients with alternating hemiplegia of childhood related to ATP1A3 variants. 37 The ability of triheptanoin to improve bioenergetics in other conditions 33,36,56,60 but was ineffective in this disorder, supports that the hypothesis that Na+/K+ ATPase dysfunction rather than lack of energetic intermediates leads to impaired sodiumdependent brain glucose transportation in this condition. 37 Studies in rats have demonstrated that pretreatment with triheptanoin prior to middle cerebral artery occlusion protected against oxidative stress 62 and no physiologic effect was observed.…”

“…Triheptanoin failed to improve paroxysmal episodes in patients with alternating hemiplegia of childhood related to ATP1A3 variants . The ability of triheptanoin to improve bioenergetics in other conditions but was ineffective in this disorder, supports that the hypothesis that Na+/K+ ATPase dysfunction rather than lack of energetic intermediates leads to impaired sodium‐dependent brain glucose transportation in this condition …”

“…Treatment of disorders associated with impaired CNS glucose metabolism with anaplerotic substrates such as acetyl‐CoA and propionyl‐CoA has been proposed to bypass this block . In particular, heptanoate from triheptanoin can directly be metabolised to its end products in the brain, or in peripheral tissues that can be delivered to the brain as even or odd chain ketone bodies . A traditional ketogenic diet in G1D has been helpful in seizures control, but is suboptimal in controlling the associated movement disorder .…”