Spinocerebellar Ataxia 27B (SCA27B)
Conditions
Keywords
SCA27B, Fampridine, Ataxia, Diplopia, FARS-Functional Staging
Brief summary
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
DRUGFampridine 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.
DRUGPlacebo (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.
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 | At week 12 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Variation in cerebellar syndrome assessed by the Composite Cerebellar Functional Severity Score (CCFS score) at week 2 and week 12 | At week 2 and week 12 | — |
| Variation in extracerebellar signs assessed by the Inventory of Non-Ataxia Signs (INAS) at week 12 | At week 12 | — |
| Variation on Timed 25-foot walk (T25FW) at week 2 and week 12 | 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 | At week 2 and week 12 | — |
| Improvement of at least 0.5 point on the Friedreich's Ataxia Rating Scale (FARS) -Functional Staging at week 2 | 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 | 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 | 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 | 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 | At week 12 | — |
| Quality of life evaluated by the Patient Reported Outcome Measure of Ataxia (PROM-ATAXIA) questionnaire at week 12 | At week 12 | — |
| Quality of life evaluated by the 36-Item Short Form Health Survey (SF-36) questionnaire at week 12 | At week 12 | — |
| Patient's impression evaluated by the Patient Global Impression of change (PGI-C) at week 2 and week 12 | At week 2 and week 12 | — |
| Clinician's impression evaluated by the Clinician Global Impression of Change (CGI-C) at week 2 and week 12 | At week 2 and week 12 | — |
| Tolerance to the investigational drug | At week 2 and week 12 | Tolerance will be evaluated through clinical examination, blood analysis, and electrocardiogram (ECG) performed at Week 2 and Week 12. In addition, adverse events will be systematically recorded throughout the study period. |
| Variation in oculomotor signs assessed by oculomotor recording (OMR) at week 2 and week 12 | At week 2 and week 12 | — |
| Variation in cerebellar syndrome assessed by the FARS-Functional Staging at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Variation in cerebellar syndrome assessed by the SARA scale at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Variation in cerebellar syndrome assessed by the mFARS scale at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Variation in cerebellar syndrome assessed by the CCFS score at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Variation in extracerebellar signs assessed by the Inventory of Non-Ataxia Signs (INAS) at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Variation on Timed 25-foot walk (T25FW) at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Variation in oculomotor signs assessed by the Scale for Ocular motor Disorders in Ataxia (SODA) at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Variation in oculomotor signs assessed by oculomotor recording (OMR) at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Variation in daily frequency of diplopia assessed on a Numerical Diplopia Rating Scale (NDRS) at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Variation in daily living activities evaluated by the FARS -Activities of Daily Living scale at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Quality of life evaluated by the PROM-ATAXIA questionnaire at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Quality of life evaluated by the 36-Item Short Form Health Survey (SF-36) questionnaire at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Patient's impression evaluated by the Patient Global Impression of change (PGI-C) at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Clinician's impression evaluated by the Clinician Global Impression of Change (CGI-C) at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
| Clinical assessments at week 16, i.e. 4 weeks after treatment interruption | At week 16 | — |
Countries
France
Contacts
Primary ContactGiulia COARELLI
Backup ContactAlexandra DURR
Outcome results
None listed