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

Glavna funkcija malog mozga je koordinacija pokreta i održavanje ravnoteže. Oštećenjem malog mozga i njegovih veza sa ostalim dijelovima živčanog sustava nastaje ataksija to jest poremećaj koordinacije voljnih pokreta udova i trupa. Simptomi se očituju kao poremećaj održavanja ravnoteže, stajanja, hodanja, sjedenja, koordinacije pokreta udova, poremećajem govora i okulomotoričkim poremećajem. Ataksije se mogu podijeliti s obzirom na uzrok na stečene i nasljedne. Stečene mogu biti uzrokovane infekcijama,mehaničkim,cirkulacijskim i strukturalnim oštećenjem malog mozga. Nasljedne su posljedica molekularnih promjena u više od 40 različitih gena, a dijelimo ih na autosomno – dominantne, autosomno –recesivne, spolno vezane i mitohondrijske. Relativno je mala učestalost u populaciji, uzročne mutacije i patogenetski mehanizmi još nisu u potpunosti istraženi. Zbog tih razloga učinkovitog lijeka još uvijek nema. Većina ataksija je progresivna i terapijski se pokušava djelovati na simptome i usporiti tijek bolesti. Sa ciljem stvaranja standardnog instrumenta za mjerenje uspjeha liječenja i mogućnosti provođenja kliničkih istraživanja od 1997.godine kad je napravljena prva semikvantitativna ljestvica/test za procjenu ataksija ICARS (International Cooperative Ataxia Rating Scale), stvoreni su brojni testovi pomoću kojih se boduju i mjere simptomi bolesti i prati se progresija ili regresija prilikom primjene različitih metoda liječenja. Možemo ih podijeliti na na semikvantitativne testove za cerebelarne simptome (ICARS, SARA, MICARS, BARS), semikvantitativne za cerebelarne i ekstracerebelarne simptome (UMSARS, FARS, NESSCA), semikvantitativni test za ekstracerebelarne simptome (INAS), kvantitativne testove (CATSYS 2000, AFCS, CCFS, CCFSw i SCAFI) te test u obliku upitnika (FAIS). Kod djece je sazrijevanje živčanog sustava povezano sa poboljšanjem koordinacije i razvojem fine motorike. Rast i razvoj malog mozga završavaju kasnije nego ostatka mozga. Do 12. godine rezultati skala/testova bi se trebali interpretirati ovisno o dobi. Da bi se mogli provoditi kvantitativni testovi potrebno je odrediti pedijatrijske norme. Daljnja istraživanja su potrebna., The main function of the cerebellum is to coordinate movement and maintain balance. Damage of the cerebellum and its connections with other parts of the nervous system results in ataxia; disorder of coordination of voluntary movements of the limbs and trunk. Symptoms can manifest as a disorder of maintaining balance, standing, walking, sitting, coordination of movements of the limbs, impaired speech and oculomotor disorder. Ataxia can be classified by the cause to the acquired and hereditary. Acquired can be caused by infection, mechanical, circulation and structural damage to the cerebellum. Hereditary are the result of molecular changes in more than 40 different genes, and they can be autosomal - dominant, autosomalrecessive, sex-related and mitohondrial. There is relatively low population frequency of ataxia and the causal mutations and pathogenic mechanisms have not yet been fully explored. For these reasons, an effective drug is still missing. Most ataxia are progressive and there are therapeutic attempts to act on the symptoms and to slow the progress of the disease. With the goal of creating a standard instrument for measuring the success of treatment and conducting clinical trials, since 1997 when the first semiquantitative scale/test to evaluate ataxia ICARS (International Cooperative Ataxia Rating Scale) was made, a number of tests were created to measure and score symptoms and monitor the progression or regression in applying various methods of treatment. We can divide them into the semi quantitative tests for ataxia (ICARS, SARA, MICARS, BARS), semiquantitative for ataxia and non-ataxia (UMSARS, Farsi, NESSCA), semiquantitative test for non-ataxia (INAS), quantitative tests (CATSYS 2000, AFCS, CCFS, CCFSw and Scafi) and the test in the form of a questionnaire (FAIS). In children, age-related maturation of the nervous system is associated with improved coordination and fine motor skills. The growth and development of the cerebellum end later than the rest of the brain. Up to 12 years of age the results of scale/tests should be interpreted depending on age. Further studies are needed.