A Randomized, Parallel-arm, Double Blind, Placebo-controlled Study to Assess the Efficacy of Fampridine for Patients With Spinocerebellar Ataxia SCA27B Caused by a GAA Expansion in the FGF14 Gene

Overview

Spinocerebellar ataxias 27B (SCA27B) is caused by an expansion of ≥ 250 GAA triplets in the FGF14 gene and accounts for 15% of cerebellar ataxias (around 500 patients in France). It is a late-onset form often presenting paroxysmal episodes of ataxia and/or diplopia. The disease progresses slowly, with an average increase of 0.10 points/year on the Friedreich's Ataxia Rating Scale (FARS) - Functional Staging and by 0.23 points/year on the Scale for the Assessment and Rating of Ataxia (SARA). To date, no treatment has been proven to be effective in these patients. Three open-label studies using 4-aminopyridine, have shown improvements in visual symptoms and gait in a total of 36 out of 44 patients, although these improvements were evaluated through diverse methodologies. In a subgroup of patients (n=7), administration of 4-aminopyridine resulted in a reduction in FARS - Functional Staging, ranging from 0.5 to 2 points. Notably, this beneficial effect rapidly disappearing in all patients stopping the drug. 4-aminopyridine, a potassium channel blocker, may involve restoration of cerebellar Purkinje cell rhythmic firing property, impaired with the loss of FGF14 function. Although these results appear very promising, the positive effect of 4-aminopyridine is reported only in restricted sample sizes and open-label experiences. Therefore, a robust clinical trial is necessary to provide the level of evidence required for a definitive conclusion on the benefit-risk of fampridine and before introducing the treatment into the regular patient clinical management. Hence, to confirm the beneficial effect of 4-aminopyridine treatment, this study will compare fampridine 10 mg bid (sustained-release form) to placebo during a 3-month treatment in a randomized, double-blind, multicenter, placebo-controlled study, on functional handicap in SCA27B cerebellar ataxia patients.

Interventions

• Drug Fampridine 10 mg prolonged-release tablet (per os)
  Patients randomized in the experimental arm will take 1 tablet twice a day, 12 hours apart, on an empty stomach, for 12 weeks.
• Drug Placebo (tablets per os)
  Patients randomized in the control arm will take 1 tablet twice a day, 12 hours apart, on an empty stomach, for 12 weeks.

Primary outcome measures

• Proportion of patients showing an improvement of at least 0.5 point on the Friedreich's Ataxia Rating Scale (FARS) -Functional Staging at week 12 [Time frame: At week 12]

Secondary outcome measures (12)

• Improvement of at least 0.5 point on the Friedreich's Ataxia Rating Scale (FARS) -Functional Staging at week 2 [Time frame: At week 2]
• Variation in cerebellar syndrome assessed by the Scale for the assessment and rating of ataxia (SARA) at week 2 and week 12 [Time frame: At week 2 and week 12]
• Variation in cerebellar syndrome assessed by the modified Friedreich Ataxia Rating Scale (mFARS) at week 2 and week 12 [Time frame: At week 2 and week 12]
• Variation in cerebellar syndrome assessed by the Composite Cerebellar Functional Severity Score (CCFS score) at week 2 and week 12 [Time frame: At week 2 and week 12]
• Variation in extracerebellar signs assessed by the Inventory of Non-Ataxia Signs (INAS) at week 12 [Time frame: At week 12]
• Variation on Timed 25-foot walk (T25FW) at week 2 and week 12 [Time frame: At week 2 and week 12]
• Variation in oculomotor signs assessed by the Scale for Ocular motor Disorders in Ataxia (SODA) at week 2 and week 12 [Time frame: At week 2 and week 12]
• Variation in oculomotor signs assessed by oculomotor recording (OMR) at week 2 and week 12 [Time frame: At week 2 and week 12]
• Variation in daily frequency of diplopia assessed on a Numerical Diplopia Rating Scale (NDRS) at week 2 and week 12 [Time frame: At week 2 and week 12]
• Variation in daily living activities evaluated by the FARS -Activities of Daily Living scale (FARS-ADL) at week 12 [Time frame: At week 12]
• Quality of life evaluated by the Patient Reported Outcome Measure of Ataxia (PROM-ATAXIA) questionnaire at week 12 [Time frame: At week 12]
• Quality of life evaluated by the 36-Item Short Form Health Survey (SF-36) questionnaire at week 12 [Time frame: At week 12]

Eligibility criteria

Inclusion criteria

• Genetic diagnosis of spinocerebellar ataxia SCA27B caused by an expansion ≥ 250 GAA repeats in the FGF14 gene
• At least 18 years of age
• SARA total score > 3 and score ≥ 1 on the "gait" item of the SARA scale.
• Physically able and expected to complete the trial as designed and having the ability to take oral medication
• Signature of informed consent
• Covered by social security

Exclusion criteria

• Hypersensitivity to fampridine
• Hypersensitivity to any excipients present in fampridine
• Serious systemic illnesses or conditions known for enhancing the side-effects of fampridine (i.e., creatinine clearance < 50 ml/min, hepatic insufficiency, medically significant heart conduction disorders such as occurrence of torsades de pointes or another severe ventricular arrhythmia, high-degree atrioventricular block (Mobitz II or complete), Brugada pattern, QTcF time of >480 msec in 3 consecutive ECG recordings taken at least 5 minutes apart, uncompensated cardiovascular disorder, epilepsy)
• Unstable, clinically significant neurologic (other than the disease being studied; eg, recurrent strokes), psychiatric, cardiovascular (eg, pulmonary arterial hypertension, cardiac valvulopathy, orthostatic hypotension/tachycardia), pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, or endocrine disease or other abnormality which may impact the ability of the participant to participate or potentially confound the study results.
• Patients with known recurrent, active, or chronic infections.
• Patients with prior history of seizure.
• Concurrent treatment with other medicinal products containing fampridine (4-aminopyridine).
• Concomitant use of Fampyra with medicinal products that are inhibitors or substrates of Organic Cation Transporter 2 (OCT2) for example, cimetidine.
• Participation in another clinical trial with an investigational drug or receipt of an investigational product within 12 weeks or 5 times the half-life of the product (whichever is longer) prior to Baseline visit
• Previous treatment with fampridine
• Patients considered at risk of suicidal behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS), defined as reporting suicidal ideation with intent to act (C-SSRS items 4 or 5) within the 6 months prior to randomization, or any suicidal behavior (including actual, aborted, or interrupted attempts) within the past 12 months.
• Pregnancy and breastfeeding (women in childbearing potential will have a urine pregnancy test at each visit)
• Sexual non abstinence or absence of effective contraception (for child-bearing aged women, contraception using highly effective methods (see section 6.2 of the protocol) for the duration of treatment and up to 7 days after the last dose of treatment)
• Inability to understand information about the protocol
• Legally incapacitated adults (e.g., individuals under legal protection such as guardianship or curatorship)
• Persons deprived of their liberty by judicial decision
• Other ataxic syndromes than SCA27B

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

France · 9 centers

• Neurology Department, CHU d'Angers — Angers
• Genetics Department, CHU de Bordeaux — Bordeaux
• Neurology and Gentics Department, CHU de Dijon — Dijon
• Neurology Department, Hôpital Pierre Wertheimer Hospital — Lyon
• Neurology Department, Gui De Chauliac Hospital — Montpellier
• Genetics Department, Pitié-Salpêtrière University Hospital — Paris
• Genetics Department, CHU de Rouen — Rouen
• Neurology Department, CHRU de Strasbourg — Strasbourg
• … and 1 more center

Identifiers

NCT: NCT07185347 · APHP240921 · 2024-520413-53-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗