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

BackgroundCerebellar 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/DesignAn 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.DiscussionThe 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.Trial registrationThe trial was prospectively registered at www.clinicaltrialsregister.eu (EudraCT no. 2015–000460–34) and at https://www.germanctr.de (DRKS-ID: DRKS00009733).

Efficacy of acetylleucine in vertigo and dizziness: a systematic review of randomised controlled trials

“…A significant improvement of SARA score and quality of life was also noted on 12 patients with Niemann-Pick disease class C after 1 month of acetylleucine administration [28]. A randomised and placebocontrolled clinical trial testing acetylleucine in cerebellar syndrome (ALCAT) is currently underway and could provide more evidence [29,30].…”

Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

“…Recently, N-acetyl-leucine has experienced a renaissance with renewed interest from both academia and industry as a promising treatment for several disorders with unmet medical needs including cerebellar ataxia [3,[6][7][8], cognition and mobility in the elderly [9], lysosomal storage disorders [10,11] migraine [12] and restless legs syndrome [13]. Given the broad therapeutic potential of N-acetyl-leucine, its pharmacodynamics and pharmacokinetics warrant further exploration.…”

N-acetyl-L-leucine treatment attenuates neuronal cell death and suppresses neuroinflammation after traumatic brain injury in mice

“…It has also been shown to reduce postural imbalance caused by the vestibular lesion following unilateral labyrinthectomy in rats 12 . In vitro electrophysiological studies indicated that such a beneficial role of NAL might be mediated through restoration of previously abnormal membrane potential to a normal state, as demonstrated in vestibular nuclei in guinea pig 8,11 . Promising outcome following NAL treatment in improving ataxic symptoms were also observed among Niemann Pick disease patients, a neurodegenerative lysosomal storage disorder caused by mutation in cholesterol transporting NPC 1 and 2 genes 13,14 .…”

“…Recently, N-acetyl-leucine (NAL), an acetylated derivative of leucine has been shown to improve neurological functions in cerebellar ataxia 8,9 . The racemic mixture, N-acetyl-DL-leucine (ADLL) has been used as a medication for the treatment of acute vertigo and vertiginous symptoms in France since 1957; it is orally available and has an excellent safety profile 10 .…”