title: Effects of acetyl-DL-leucine on cerebellar ataxia (ALCAT trial): study protocol for a multicenter, multinational, randomized, double-blind, placebo-controlled, crossover phase III trial.
abstract: BACKGROUND
  Cerebellar ataxia (CA) is a frequent and often disabling condition that impairs motor functioning and impacts on quality of life (QoL). No medication has yet been proven effective for the symptomatic or even causative treatment of hereditary or non-hereditary, non-acquired CA. So far, the only treatment recommendation is physiotherapy. Therefore, new therapeutic options are needed. Based on three observational studies, the primary objective of the acetyl-DL-leucine on ataxia (ALCAT) trial is to examine the efficacy and tolerability of a symptomatic therapy with acetyl-DL-leucine compared to placebo on motor function measured by the Scale for the Assessment and Rating of Ataxia (SARA) in patients with CA.
  
  
  METHODS
  An investigator-initiated, multicenter, European, randomized, double-blind, placebo-controlled, 2-treatment 2-period crossover phase III trial will be carried out. In total, 108 adult patients who meet the clinical criteria of CA of different etiologies (hereditary or non-hereditary, non-acquired) presenting with a SARA total score of at least 3 points will be randomly assigned in a 1:1 ratio to one of two different treatment sequences, either acetyl-DL-leucine (up to 5 g per day) followed by placebo or vice versa. Each sequence consists of two 6-week treatment periods, separated by a 4-week wash-out period. A follow-up examination is scheduled 4 weeks after the end of treatment. The primary efficacy outcome is the absolute change in the SARA total score. Secondary objectives are to demonstrate that acetyl-DL-leucine is effective in improving (1) motor function measured by the Spinocerebellar Ataxia Functional Index (SCAFI) and SARA subscore items and (2) QoL (EuroQoL 5 dimensions and 5 level version, EQ-5D-5 L), depression (Beck Depression Inventory, BDI-II) and fatigue (Fatigue Severity Score, FSS). Furthermore, the incidence of adverse events will be investigated.
  
  
  CONCLUSIONS
  The results of this trial will inform whether symptomatic treatment with the modified amino-acid acetyl-DL-leucine is a worthy candidate for a new drug therapy to relieve ataxia symptoms and to improve patient care. If superiority of the experimental drug to placebo can be established it will also be re-purposing of an agent that has been previously used for the symptomatic treatment of dizziness.
  
  
  BACKGROUND
  The trial was prospectively registered at www.clinicaltrialsregister.eu (EudraCT no. 2015-000460-34) and at https://www.germanctr.de (DRKS-ID: DRKS00009733 ).
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, University Hospital, Munich, Germany. katharina.feil@med.uni-muenchen.de.|German Center for Vertigo and Balance Disorders (DSGZ), University Hospital, Munich, Germany. katharina.feil@med.uni-muenchen.de.|Department of Neurology and German Center for Vertigo and Balance Disorders, University Hospital, Campus Grosshadern, Marchioninistrasse 15, Munich, 81377, Germany. katharina.feil@med.uni-muenchen.de.
authors.forename: Katharina
authors.identifier: http://orcid.org/0000-0002-4566-712X
authors.initials: K
authors.lastname: Feil
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology (IBE), University Hospital, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Adrion
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, University Hospital, Munich, Germany.|German Center for Vertigo and Balance Disorders (DSGZ), University Hospital, Munich, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Teufel
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Bösch
authors.affiliation: Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Claassen
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Center for Clinical Research, Bonn, Germany.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Giordano
authors.affiliation: Department of Neurology and Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Hengel
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Center for Clinical Research, Bonn, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Jacobi
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Center for Clinical Research, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, University Hospital, Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, 80336, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, 80336, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Nachbauer
authors.affiliation: Department of Neurology and Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, University Hospital, Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, 80336, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stendel
authors.affiliation: Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Uslar
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Warrenburg
authors.affiliation: German Center for Vertigo and Balance Disorders (DSGZ), University Hospital, Munich, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Berger
authors.affiliation: German Center for Vertigo and Balance Disorders (DSGZ), University Hospital, Munich, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Naumann
authors.affiliation: German Center for Vertigo and Balance Disorders (DSGZ), University Hospital, Munich, Germany.
authors.forename: Otmar
authors.initials: O
authors.lastname: Bayer
authors.affiliation: Institute for Medical Biometry and Epidemiology, Philipps University Marburg, Marburg, Germany.
authors.forename: Hans-Helge
authors.initials: HH
authors.lastname: Müller
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology (IBE), University Hospital, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mansmann
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, University Hospital, Munich, Germany.|German Center for Vertigo and Balance Disorders (DSGZ), University Hospital, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Strupp
mesh_terms: D000328:Adult; D002524:Cerebellar Ataxia / Q000188:drug therapy*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011569:Psychiatric Status Rating Scales; D011788:Quality of Life; D020754:Spinocerebellar Ataxias / Q000188:drug therapy
chemical_list: D007930:Leucine; C088117:acetylleucine
keywords: Acetyl-DL-leucine; Amino acids; Ataxia rating scales; Cerebellar ataxia; Crossover design; Patient questionnaires; Quality of life; Randomized controlled trial; Symptomatic therapy