Efficacy of Fampridine in Spinocerebellar Ataxia SCA27B with FGF14 Gene GAA Expansion: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this randomized, double-blind, placebo-controlled clinical trial is to demonstrate the efficacy of a 12-week treatment with **fampridine** 10 mg bid in patients with spinocerebellar ataxia (SCA27B). This objective is clinically relevant as it aims to establish the therapeutic potential of fampridine in managing symptoms associated with SCA27B, a condition characterized by progressive cerebellar ataxia due to a GAA expansion in the FGF14 gene.

Secondary objectives include evaluating the efficacy of fampridine sustained-release 10 mg bid on various clinical parameters in SCA27B patients: - Functional staging at week 2 - Cerebellar syndrome progression at weeks 2 and 12 - Extracerebellar signs progression at week 12 - Walking ability progression at weeks 2 and 12 - Oculomotor disorders and diplopia progression at weeks 2 and 12 - Daily living activities at week 12 - Quality of life at week 12 - Patient's and clinician's impressions of efficacy at weeks 2 and 12 - Clinical safety and biological tolerance over 12 weeks - Persistence of fampridine effects after a 4-week treatment interruption.

The clinical trial involves participants diagnosed with **spinocerebellar ataxia** SCA27B, characterized by an expansion of ≥ 250 GAA repeats in the FGF14 gene. The study population includes both male and female subjects, aged 18 years and older, who are physically able and expected to complete the trial as designed. Participants must have a SARA total score greater than 3 and a score of at least 1 on the "gait" item of the SARA scale. The trial does not include a vulnerable population. Participants are required to be covered by social security and capable of taking oral medication. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

This clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy of **fampridine** in patients with **spinocerebellar ataxia** SCA27B, caused by a GAA expansion in the FGF14 gene. The trial will involve a 12-week treatment period with fampridine 10 mg administered twice daily. The primary endpoint is the proportion of patients showing an improvement of at least 0.5 point on the FARS-Functional Staging at week 12 compared to baseline. Secondary endpoints include various assessments of cerebellar syndrome, walking ability, oculomotor signs, and quality of life at weeks 2 and 12.

The trial will commence with a screening visit to confirm eligibility, which includes a genetic diagnosis of cerebellar ataxia SCA27B, age of at least 18 years, and specific scores on the SARA scale. Participants must provide informed consent and be physically able to complete the trial. Following the screening, participants will be randomly assigned to receive either fampridine or a placebo. Study visits will occur at baseline, week 2, week 12, and a follow-up visit at week 16, which is 4 weeks after treatment interruption. These visits will include clinical, neurological, and quality of life assessments, as well as safety evaluations through clinical exams, blood analysis, and ECGs.

The expected duration of participant involvement is approximately 16 weeks, including the follow-up period. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any condition that, in the investigator's opinion, would make continued participation detrimental to the participant's health. The trial is estimated to conclude by February 2027, with recruitment starting in June 2025. The study is not classified as low intervention and is categorized as a Phase III trial.

The clinical trial involves the administration of **fampridine**, an experimental medication, to assess its efficacy in patients with spinocerebellar ataxia SCA27B. Fampridine is provided in the form of a **prolonged-release tablet**. The active substance, fampridine, is of chemical origin. The dosage regimen for this trial is 10 mg administered twice daily (bid) via the **oral** route. The maximum daily dose is 20 mg, and the treatment period extends up to 12 weeks. The total maximum dose over the treatment period is 168 mg. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

In addition to fampridine, a **placebo** is used as a comparator treatment in this double-blind, placebo-controlled study. The placebo, referred to as Placebo 515, is designed to match the experimental medication in appearance but contains no active substance. The placebo is administered in the same manner as fampridine, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thus maintaining the study's blinding integrity.

The efficacy of fampridine in patients with **spinocerebellar ataxia SCA27B** will be assessed through a randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the proportion of patients demonstrating an improvement of at least 0.5 points on the FARS-Functional Staging at week 12 compared to baseline. Secondary endpoints include various measures of cerebellar syndrome, oculomotor signs, walking ability, and quality of life, assessed at multiple timepoints including week 2 and week 12.

Specific scales and tools will be utilized to measure these endpoints, such as the SARA, mFARS, CCFS, INAS, T25FW, SODA, OMR, and the Numerical Diplopia Rating Scale (NDRS). Quality of life will be evaluated using the PROM-ATAXIA and the 36-Item Short Form Health Survey (SF-36). Patient and clinician impressions will be assessed using the Patient Global Impression of Change (PGI-C) and the Clinician Global Impression of Change (CGI-C), respectively. Tolerance will be monitored through clinical exams, blood analysis, ECG, and adverse event recordings at specified intervals.