Effect of Triheptanoin on Caudate Atrophy and Motor Scores in Patients With Early-Stage Huntington Disease: A Phase II Study.

Background And Objectives: Brain energy deficiency occurs at the early stage of Huntington disease (HD). Triheptanoin, a drug that targets the Krebs cycle, can restore a normal brain energetic profile in patients with HD. In this study, we aimed at assessing its efficacy on clinical and neuroimaging structural measures in HD.

Methods: We conducted a 6-month bicentric (Paris, Leiden) double-blind randomized controlled trial followed by a 6-month open-label phase, between June 2015 and December 2019. We enrolled 107 patients at the early stage of HD-total motor score (TMS) of the UHDRS between 5 and 40. Participants received triheptanoin 1 g/kg/day or placebo (ratio 1/1). The primary outcome was the rate of caudate atrophy at 6 months using the caudate boundary shift integral (cBSI) method. Main secondary outcomes were cBSI at 12 months, TMS, and diffusion imaging at 6 and 12 months. Analysis was conducted using ANOVA, and data were presented with a 95% CI. To perform a 12-month comparison, we used the placebo arm of a 12-month randomized controlled trial conducted in parallel, using the double robust propensity score method.

Results: One hundred patients were randomized (mean age 49 years, 52% women). Fourteen patients withdrew from the study, including 10 because of gastrointestinal effects. There was no difference in cBSI at 6 months between groups (mean 0.026 [0.018-0.033] vs 0.023 [0.014-0.032]). TMS at 12 months was stable in patients treated with triheptanoin for 12 months (mean 0.6 [-1.1 to 2.1]), whereas it increased in patients initially on placebo (2.5 [1.2-3.8]). Compared with the external placebo control group, caudate atrophy decreased by approximately 50% (0.038 [0.028-0.048] vs 0.070 [0.057-0.082]) and TMS stabilized (0.66 [-1.07 to 2.48] vs 2.65 [1.38-3.89]) in patients treated with triheptanoin for 12 months.

Discussion: There was no effect of triheptanoin on caudate atrophy over 6 months. Compared with the external placebo group, triheptanoin was associated with motor stability and decreased caudate atrophy in patients treated for 12 months, but the post hoc nature of these findings is a major limitation.

Trial Registration Information: clinicaltrials.gov NCT02453061, May 25, 2015. First patient enrolled on June 29, 2015.

Classification Of Evidence: This study provides Class I evidence that triheptanoin does not slow caudate atrophy compared with placebo over 6 months in patients with early HD.