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

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/DESIGN: 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. DISCUSSION: 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. TRIAL REGISTRATION: The trial was prospectively registered at www.clinicaltrialsregister.eu (EudraCT no. 2015-000460-34) and at https://www.germanctr.de (DRKS-ID: DRKS00009733 )

Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation

Background & Aims Aceruloplasminemia is a rare autosomal recessive neurodegenerative disease associated with brain and liver iron accumulation which typically presents with movement disorders retinal degeneration and diabetes mellitus Ceruloplasmin is a multi-copper ferroxidase that is secreted into plasma and facilitates cellular iron export and Iron binding to transferrin Results A novel homozygous ceruloplasmin gene mutation c 2554+1G<T was identified as the cause of aceruloplasminemia in three affected siblings Two siblings presented with movement disorders and diabetes Complementary DNA sequencing showed that this mutation causes skipping of exon 14 and deletion of amino acids 809-852 while preserving the open reading frame Western blotting of liver extracts and sera of affected patients showed retention of the abnormal protein in the liver Aceruloplasminemia was associated with severe brain and liver iron overload where hepatic mRNA expression of the iron hormone hepcidin was increased corresponding to the degree of iron overload Hepatic iron concentration normalized after 3 and 5 months of iron chelation therapy with deferasirox which was also associated with reduced insulin demands During short term treatment there was no clinical or imaging evidence for significant effects on brain iron overload Conclusions Aceruloplasminemia can show an incomplete clinical penetrance but is invariably associated with iron accumulation in the liver and in the brain Iron accumulation in aceruloplasminemia is a result of defective cellular Iron export where hepcidin regulation is appropriate for the degree of iron overload Iron chelation with deferasirox was effective in mobilizing hepatic iron but has no effect on brain iron (C) 2010 European Association for the Study of the Liver Published by Elsevier B V All rights reserve