Objective: To assess safety and efficacy of an oral, single, low dose of octanoic acid (OA) in subjects with alcohol-responsive essential tremor (ET). Methods:We conducted a double-blind, placebo-controlled, crossover, phase I/II clinical trial evaluating the effect of 4 mg/kg OA in 19 subjects with ET. The primary outcome was accelerometric postural tremor power of the dominant hand 80 minutes after administration. Secondary outcomes included digital spiral analysis, pharmacokinetic sampling, as well as safety measures.Results: OA was safe and well tolerated. Nonserious adverse events were mild (Common Terminology Criteria for Adverse Events grade 1) and equally present after OA and placebo. At the primary outcome, OA effects were not different from placebo. Secondary outcome analyses of digital spiral analysis, comparison across the entire time course in weighted and nonweighted accelerometry, as well as nondominant hand tremor power did not show a benefit of OA over placebo. The analysis of individual time points showed that OA improved tremor at 300 minutes (dominant hand, F 1,16 5 5.49, p 5 0.032 vs placebo), with a maximum benefit at 180 minutes after OA (both hands, F 1,16 5 6.1, p 5 0.025).Conclusions: Although the effects of OA and placebo at the primary outcome were not different, secondary outcome measures suggest superiority of OA in reducing tremor at later time points, warranting further trials at higher dose levels. Classification of evidence:This study provides Class I evidence that a single 4-mg/kg dose of OA is not effective in reducing postural tremor in patients with ET at a primary outcome of 80 minutes, but is effective for a secondary outcome after 180 minutes. Up to 74% of subjects with essential tremor (ET) reported a significant reduction in tremor intensity after ingesting small amounts of ethanol.1-3 Recently, it was shown that tremor improved up to 50% in patients with ethanol-responsive ET after an ethanol challenge. 4The long-chain alcohol 1-octanol has been demonstrated to effectively alleviate tremor symptoms in ET without causing intoxication or other clinically relevant adverse effects. 5,6 Pharmacokinetic findings suggested that the effect of 1-octanol might be mediated through its metabolite octanoic acid (OA). 7 In the harmaline-induced animal-model of ET, OA reduced tremor in a dose-dependent manner.8 OA was approved by the US Food and Drug Administration as a food additive, received the status GRAS (generally recognized as safe), is used as a component in high-caloric formulas, and has been studied as a component of ketogenic diet for the management of pediatric epilepsy.

Background The Essential Tremor (ET) Rating Assessment Scale (TETRAS) has shown excellent inter- and intra-rater reliability. To assess the scale’s ability to detect changes in tremor severity, we compared TETRAS performance with standard postural tremor accelerometry during a standardized ethanol challenge. Methods Fifteen adult ET patients received a single oral ethanol dose calculated to reach 0.05 g/dl breath alcohol content (brAC) on two different study days. Two investigators independently assessed the effects with accelerometry on one day and with TETRAS on another day. Measurements were taken at 8 time-points (2 time-points baseline and 6 time-points up to 2 hours post ethanol). Further outcome measures included brAC readings at the same time points. Results Because correlation between TETRAS and accelerometry revealed a logarithmic relation, for all comparisons, accelerometry data were log-transformed and a cumulative score logACC(R+L) was calculated. Correlation between logACC(R+L) and TETRAS was significant (r= 0.57, p<0.01). Repeated measures ANOVA for both TETRAS and accelerometry before and after ethanol showed a significant effect of time-point (F=34.6, p<0.01; F=13.5, p<0.01). Corrected post-hoc tests showed a difference between baseline and each of the following 6 time-points. TETRAS and brAC were significantly correlated (r=−0.29, p<0.01). Intra-rater test-retest analysis between baseline measures showed high correlation (ICC=0.974, p<0.001). The ethanol challenge showed excellent reproducibility. Conclusion We demonstrated sensitivity of the TETRAS performance scale to change after a therapeutic intervention. Our study provides responsiveness validity for TETRAS, further establishing its potential as a valid instrument for ET evaluation in both clinical and research settings.