Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety, and tolerability of dimethyl fumarate in Friedreich Ataxia (DMF-FA-201).

Introduction: Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that causes gait and limb ataxia, dysarthria, and impaired vibratory sense, with cardiomyopathy being the predominant cause of death. There is no approved therapy, which results in the use of symptomatic treatments and the chronic support of physiotherapy. Dimethyl fumarate (DMF) is a fumaric acid ester used for the treatment of psoriasis and Multiple Sclerosis (MS). It induces Nrf2 and , and it increases frataxin in FRDA patient lymphoblasts, in mouse models, and in MS treated patients.

Methods: The aim of our study is to investigate if DMF can increase the expression of the gene and frataxin protein and ameliorate detectable measures of mitochondrial dysfunction in FRDA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. EudraCT number 2021-006274-23.

Endpoints: The primary endpoint will be a change in gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level, ardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales.

Conclusions: This is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration .