Triheptanoin Did Not Show Benefit versus Placebo for the Treatment of Paroxysmal Movement Disorders in Glut1 Deficiency Syndrome: Results of a Randomized Phase 3 Study

Background Paroxysmal movement disorders are common in Glut1 deficiency syndrome (Glut1DS). Not all patients respond to or tolerate ketogenic diets. Objectives The objective was to evaluate the effectiveness and safety of triheptanoin in reducing the frequency of disabling movement disorders in patients with Glut1DS not receiving a ketogenic diet. Methods UX007G‐CL301 was a randomized, double‐blind, placebo‐controlled, phase 3 crossover study. After a 6‐week run‐in, eligible patients were randomized 1:1 to the first sequence (triheptanoin/placebo or placebo/triheptanoin) titration plus maintenance, followed by washout and the opposite sequence titration plus maintenance. The placebo (safflower oil) matched the appearance, taste, and smell of triheptanoin. Open‐label triheptanoin was administered in the extension. The frequency of disabling paroxysmal movement disorder events per 4 weeks (recorded by diary during maintenance; primary endpoint) was assessed by Wilcoxon rank‐sum test. Results Forty‐three patients (children, n = 16; adults, n = 27) were randomized and treated. There was no difference between triheptanoin and placebo in the mean (interquartile range) number of disabling paroxysmal movement disorder events (14.3 [4.7–38.3] vs. 11.8; [3.2–28.7]; Hodges‐Lehmann estimated median difference: 1.46; 95% confidence interval, −1.12 to 4.36; P = 0.2684). Treatment‐emergent adverse events were mild/moderate in severity and included diarrhea, vomiting, upper abdominal pain, headache, and nausea. Two patients discontinued the study because of non‐serious adverse events that were predominantly gastrointestinal. The study was closed early during the open‐label extension because of lack of effectiveness. Seven patients continued to receive triheptanoin compassionately. Conclusion There were no significant differences between the triheptanoin and placebo groups in the frequency of disabling movement disorder events during the double‐blind maintenance period.