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| Home > Publications Database > Efficacy and tolerability of D-β-hydroxybutyrate ester in patients with amyotrophic lateral sclerosis (KETO-ALS)–a randomised, placebo-controlled, double-blind study |
| Home > Publications Database > Efficacy and tolerability of D-β-hydroxybutyrate ester in patients with amyotrophic lateral sclerosis (KETO-ALS)–a randomised, placebo-controlled, double-blind study |
| Journal Article | DZNE-2026-01134 |
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2026
Elsevier
Amsterdam
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Please use a persistent id in citations: doi:10.1016/j.eclinm.2026.104272
Abstract: 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.
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