Efficacy and tolerability of D-β-hydroxybutyrate ester in patients with amyotrophic lateral sclerosis (KETO-ALS)–a randomised, placebo-controlled, double-blind study

Background Hypermetabolism and weight loss are prominent features of amyotrophic lateral sclerosis (ALS). Here, we sought to target the energy deficit in ALS by applying oral ketone bodies as high-energetic substrates. Methods Patients with probable or definite ALS were enrolled to this randomised, placebo-controlled, parallel-group, double-blind, monocentre phase 2 trial. Eligible patients had a decline of ALS functional rating scale revised (ALSFRS-R) of at least 0.33 points/month. They were randomly assigned (1:1) to receive D-β-hydroxybutyrate ester (βHB, 30 g/day) or placebo. Primary endpoint was change of neurofilament light chain (NfL) per month, measured as slope over 6 months. Multiple linear regressions models were applied to adjust for NfL, age, BMI, and slow vital capacity (SVC) at baseline. The trial is registered with clinicaltrials.gov, number NCT04820478. Findings Between April 5, 2022, and February 12, 2025, 81 patients were randomly assigned to receive βHB (n = 40) or placebo (n = 41) and included in the intention-to-treat analysis. In the unadjusted analysis, the primary endpoint NfL slope was negative, showing a decline of −0.5 pg/mL/month (IQR −3.2 to 2.0, minimum −11.2, maximum 10.4) in the βHB group and a stable course of 0.0 pg/mL/month (IQR −1.7 to 3.3, minimum −6.2, maximum 49.0) in the placebo group (p = 0.094). In the adjusted analysis, the NfL slope showed a benefit for the βHB group (−1.5 pg/ml/month in βHB vs. +2.8 pg/ml/month in placebo, mean difference −4.2 pg/ml/month, 95% CI - ∞ to −1.1, p=0.014). When using a mixed effect model, this effect was not statistically different (−0.4 pg/ml/month in βHB vs. +0.3 pg/ml/month in placebo, mean difference −0.7 pg/ml, month, p=0.30). In the unadjusted analysis, ALSFRS-R showed a faster decline in the verum group (−1.4 points/month (IQR −2.1 to −0.6) vs. −0.8 points/month (IQR −1.2 to −0.2), p=0.020). No significant difference between βHB and placebo was found regarding clinical endpoints such as ALSFRS-R or BMI in the adjusted analysis. βHB was well tolerated, with similar frequency of adverse events across both groups. Interpretation Whether the effects on NfL can be confirmed and translated into meaningful clinical effects, remains to be clarified by a larger phase 3 trial with extended treatment duration. βHB was well tolerated. Funding This was an investigator-initiated study, funded by a private donation.