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Randomized Controlled Trial
. 2021 Dec 1;4(12):e2135841.
doi: 10.1001/jamanetworkopen.2021.35841.

Safety and Efficacy of Acetyl-DL-Leucine in Certain Types of Cerebellar Ataxia: The ALCAT Randomized Clinical Crossover Trial

Katharina Feil  1   2   3 , Christine Adrion  4 , Sylvia Boesch  5 , Sarah Doss  6   7 , Ilaria Giordano  8 , Holger Hengel  9 , Heike Jacobi  8   10 , Thomas Klockgether  8 , Thomas Klopstock  1   11   12 , Wolfgang Nachbauer  5 , Ludger Schöls  9   13 , Katharina Marie Steiner  14 , Claudia Stendel  1   11 , Dagmar Timmann  14 , Ivonne Naumann  2 , Ulrich Mansmann  4 , Michael Strupp  1   2 ; ALCAT Study Group
Affiliations
Randomized Controlled Trial

Safety and Efficacy of Acetyl-DL-Leucine in Certain Types of Cerebellar Ataxia: The ALCAT Randomized Clinical Crossover Trial

Katharina Feil et al. JAMA Netw Open. .

Abstract

Importance: Cerebellar ataxia is a neurodegenerative disease impairing motor function characterized by ataxia of stance, gait, speech, and fine motor disturbances.

Objective: To investigate the efficacy, safety, and tolerability of the modified essential amino acid acetyl-DL-leucine in treating patients who have cerebellar ataxia.

Design, setting, and participants: The Acetyl-DL-leucine on Cerebellar Ataxia (ALCAT) trial was an investigator-initiated, multicenter, double-blind, randomized, placebo-controlled, clinical crossover trial. The study was conducted at 7 university hospitals in Germany and Austria between January 25, 2016, and February 17, 2017. Patients were aged at least 18 years and diagnosed with cerebellar ataxia of hereditary (suspected or genetically confirmed) or nonhereditary or unknown type presenting with a total score of at least 3 points on the Scale for the Assessment and Rating of Ataxia (SARA). Statistical analysis was performed from April 2018 to June 2018 and January 2020 to March 2020.

Interventions: Patients were randomly assigned (1:1) to receive acetyl-DL-leucine orally (5 g per day after 2 weeks up-titration) followed by a matched placebo, each for 6 weeks, separated by a 4-week washout, or vice versa. The randomization was done via a web-based, permuted block-wise randomization list (block size, 2) that was stratified by disease subtype (hereditary vs nonhereditary or unknown) and site.

Main outcomes and measures: Primary efficacy outcome was the absolute change of SARA total score from (period-dependent) baseline to week 6.

Results: Among 108 patients who were randomly assigned to sequence groups (54 patients each), 55 (50.9%) were female; the mean (SD) age was 54.8 (14.4) years; and the mean (SD) SARA total score was 13.33 (5.57) points. The full analysis set included 105 patients (80 patients with hereditary, 25 with nonhereditary or unknown cerebellar ataxia). There was no evidence of a difference in the mean absolute change from baseline to week 6 in SARA total scores between both treatments (mean treatment difference: 0.23 points [95% CI, -0.40 to 0.85 points]).

Conclusions and relevance: In this large multicenter, double-blind, randomized, placebo-controlled clinical crossover trial, acetyl-DL-leucine in the investigated dosage and treatment duration was not superior to placebo for the symptomatic treatment of certain types of ataxia. The drug was well tolerated; and ALCAT yielded valuable information about the duration of treatment periods and the role of placebo response in cerebellar ataxia. These findings suggest that further symptom-oriented trials are needed for evaluating the long-term effects of acetyl-DL-leucine for well-defined subgroups of cerebellar ataxia.

Trial registration: EudraCT 2015-000460-34.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Feil reported receiving funding for a research project from Boehringer Ingelheim outside the submitted work. Dr Boesch reported receiving grants from the European Friedreich Ataxia Consortium for Translational Studies (EFACTS), FP7 Health (HEALTH-F2-2010-242193), and E-Rare-3 Clinical Research for New Therapeutic Uses of Already Existing Molecules (Repurposing) in Rare Diseases (E-Rare-3JTC2016); Dr Boesch also reported serving on the advisory board for Stada, Abbvie, and Ipsen; she also reported receiving honoraria from Ipsen, Allergan, Merz, Abbvie, and Reata outside the submitted work. Dr Doss reported receiving funding for unrelated research from Actelion and Teva and speaker honoraria from Actelion. Dr Klopstock reported receiving grants from German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]), the German Federal Ministry of Education and Research (Bundesministerium fuer Bildung und Forschung [BMBF]), and the European Commission outside the submitted work; he also reported receiving grants, personal fees, and nonfinancial support from ApoPharma Inc, Retrophin Pharmaceuticals, Santhera Pharmaceuticals, GenSight Biologics and Stealth Biotherapeutics outside the submitted work; and he is a member of the European Reference Network for Rare Neurological Diseases (ERN-RND)–Project ID No 739510. Dr Klockgether reported receiving grants from the European Research Area Network for Research Programmes on Rare Diseases (E-Rare) during the conduct of the study; personal fees from Biohaven, UCB, Roche, uniQure, Novartis, and Bayer; and grants from the National Institutes of Health, the BMBF under the EU Joint Programme–Neurodegenerative Disease Research (JPND), the German Federal Ministry of Health, and BMBF outside the submitted work and he is a member of the ERN-RND–Project ID No 739510. Dr Schöls reported receiving funding from the DFG, the BMBF, and the European Commission outside the submitted work; and he is a member of the European Reference Network for Rare Neurological Diseases (ERN-RND)–Project ID No 739510. Dr Steiner reported receiving grants from the DFG and from the German Heredo-Ataxia Foundation during the conduct of the study. Dr Timmann reported receiving funding from the DFG, Deutsche Heredo-Ataxie Gesellschaft (DHAG), and Bernd Fink Foundation. Dr Strupp reported being the joint chief editor of the Journal of Neurology, editor in chief of Frontiers of Neuro-otology, and section editor of F1000; Dr Strupp also reported receiving speaker’s honoraria from Abbott, Actelion, Auris Medical, Biogen, Eisai GmbH, Grünenthal, GlaxoSmithKline, Hennig Pharma, Interacoustics, MSD Sharp & Dohme, Mylan, Otometrics, Pierre Fabre, TEVA GmbH, and UCB SA Belgium; and he reported being a paid consultant for Abbott, Actelion, AurisMedical, Heel, IntraBio, and Sensorion; he is an investor and shareholder of IntraBio; and he is the distributor of M glasses and the Positional Vertigo App; and he has reported receiving grants for research for Decibel, Heel Pharma, and Hennig Pharma. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flowchart Diagram
Flow of patients through the trial and inclusion in the primary analysis. (Dropped out means study dropout with last contact, and no further data or visits documented.) A-P indicates treatment sequence acetyl-DL-leucine followed by placebo; AE, adverse event; FAS, full analysis set; P-A, treatment sequence placebo followed by acetyl-DL-leucine; PP, per protocol; SARA, Scale for the Assessment and Rating of Ataxia; SUSAR, suspected unexpected serious adverse reaction.
Figure 2.
Figure 2.. Principal Model-Based Analysis for the Primary Efficacy Outcome Scale for the Assessment and Rating of Ataxia (SARA) Total Score
Interaction plot for estimated marginal means (with 95% CI) on acetyl-DL-leucine vs on placebo, at prerandomization or period-dependent baseline, after 2 weeks, and at the end of the 6-week treatment period. The fitted values are derived from a mixed model for repeated measures with treatment, time and period, and treatment-by-time interaction as fixed effects (all considered as factor variables), and patient-individual random intercepts.
See this image and copyright information in PMC

Comment in

  • Clinical trials for cerebellar ataxia.
    Schroeder BE, Robertson NP. Schroeder BE, et al. J Neurol. 2022 May;269(5):2819-2821. doi: 10.1007/s00415-022-11088-w. Epub 2022 Apr 15. J Neurol. 2022. PMID: 35426533 Free PMC article. No abstract available.

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