Efficacy, Safety, and Tolerability of Dimethyl Fumarate in Patients with Friedreich's Ataxia: A Double-Blind, Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate the effect of **Dimethyl Fumarate** (DMF) on FXN transcription and frataxin protein levels in patients with **Friedreich's Ataxia**. This is clinically relevant as alterations in FXN transcription and frataxin protein are central to the pathophysiology of Friedreich's Ataxia, a progressive neurodegenerative disorder. Understanding the impact of DMF on these molecular targets could provide insights into potential therapeutic mechanisms and efficacy.

Secondary objectives include assessing the effect of DMF on the **nrf2 pathway**, mitochondrial biogenesis, safety, tolerability, and other clinical aspects of Friedreich's Ataxia. These objectives aim to provide a comprehensive evaluation of DMF's potential benefits and risks, contributing to a better understanding of its overall therapeutic profile in this patient population.

The clinical trial involves participants diagnosed with **Friedreich's Ataxia**, characterized by a homozygous GAA expansion. The study population includes both male and female subjects aged 12 years and older, with a minimum body weight of 30 kg. Participants are required to have the ability to read and sign informed consent. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection process for the trial population considers individuals who meet the molecular diagnosis criteria and are capable of providing informed consent. The study includes a vulnerable population, indicating a need for careful ethical considerations. Lifestyle factors such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is designed as a **double-blind**, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of **dimethyl fumarate** in patients with **Friedreich's Ataxia**. The trial will involve the administration of Skilarence 120 mg gastro-resistant tablets or a placebo, with the primary objective being to assess the effect of dimethyl fumarate on FXN gene expression and frataxin protein levels. The study is expected to run from June 2023 to June 2024, with a core phase duration of 12 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a molecular diagnosis of Friedreich's Ataxia, age of at least 12 years, and a body weight of at least 30 kg. Following the screening, participants will be randomized to receive either the active treatment or placebo. The core phase will include regular follow-up visits to monitor safety and efficacy endpoints, including cardiopulmonary exercise outputs, echocardiographic measures, and changes in FXN and frataxin protein levels. The end-of-study visit will conclude the trial, assessing the overall impact of the treatment.

The expected length of participant involvement is approximately 12 weeks for the core phase, with potential extension based on study outcomes. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or non-compliance with study protocols. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results, contributing valuable insights into the treatment of Friedreich's Ataxia.

The clinical trial involves the administration of **Skilarence 120 mg gastro-resistant tablets**, which contain the active substance **dimethyl fumarate**. This medication is provided in the form of gastro-resistant tablets, designed to prevent the release of the active ingredient until it reaches the intestines, thereby minimizing gastric irritation. The tablets are administered orally, with a maximum daily dose of 480 mg. The treatment period extends up to 24 weeks. Dimethyl fumarate is a chemical compound, also known by its synonyms BG00012 and FP 187, and is classified under the ATC code L04AX07. The medication is manufactured by ALMIRALL, S.A., and is not a paediatric formulation. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a **placebo** group, receiving a placebo of dimethyl fumarate 120 mg gastro-resistant tablets. The placebo is designed to mimic the appearance of the active medication but does not contain any active substance. This allows for a double-blind, randomized, placebo-controlled trial design, ensuring that neither the participants nor the investigators know which treatment is being administered, thereby reducing bias. The placebo is administered in the same manner as the active medication, with the same dosing schedule and monitoring for compliance.

The efficacy of Dimethyl Fumarate (DMF) in the treatment of **Friedreich Ataxia** will be assessed through a double-blind, randomized, placebo-controlled trial. The primary endpoints for evaluating efficacy include the effect of DMF compared to placebo on FXN gene expression and frataxin protein levels. These will be measured by assessing the change from baseline to 12 weeks during the core phase of the study. Secondary endpoints will further evaluate the effect of DMF on various parameters, including cardiopulmonary exercise outputs (VO2max, anaerobic threshold, peak workload), echocardiographic measures, and FXN and frataxin protein levels from pooled data from both the core and extension phases. Additional secondary endpoints include the effect on Nrf2 pathway genes, mitochondrial biogenesis genes, and mtDNA/nDNA, as well as the number and distribution of adverse events. Differences in clinical scales such as the Scale for the Rating and Assessment of Ataxia (SARA), modified Friedreich Ataxia Rating Scale (mFARS), 9-hole pegboard test (9HPT), EQ-5D, and ADL/IADL between DMF and placebo will also be assessed. The efficacy parameters will be collected and analyzed at specified timepoints, including week 4 and week 12, using validated scales and laboratory tests to ensure accurate and reliable data collection.