Neuromodulation strategies to enhance the effects of gait rehabilitation in multiple sclerosis patients with cerebellar ataxia

INTERVENTION: Trade Name: FAMPYRA ‐ 10 MG ‐ COMPRESSA A RILASCIO PROLUNGATO ‐ USO ORALE ‐ FLACONE (HDPE) 56 COMPRESSE (4 FLACONI DA 14) Pharmaceutical Form: Tablet INN or Proposed INN: FAMPRIDINA CAS Number: 504‐24‐5 Current Sponsor code: 4‐AP Other descriptive name: 4‐aminopyridine Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 10‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use CONDITION: Multiple sclerosis with cerebellar ataxia ; MedDRA version: 20.1 Level: PT Classification code 10028245 Term: Multiple sclerosis System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: To evaluate the safety and clinical effectiveness of cerebellar TBS and 4‐aminopiridine for enhancing the effects of gait rehabilitation Primary end point(s): we expect to find a >21.43% difference between the treatment (baseline/end of treatment T25FT score ratio: mean 1.4, SD 0.17) and the placebo group (baseline/end of treatment T25FT score ratio: mean 1.1, SD 0.04). Secondary Objective: To describe the behavioural changes in motor control and learning induced by cerebellar iTBS and by 4‐AP, and to detect the associated changes in the cerebello‐cortical circuits in multiple sclerosis (MS) patients with CGA Timepoint(s) of evaluation of this end point: At the end of the two‐week experimental treatment period (day 14) with respect to baseline. SECONDARY OUTCOME: Secondary end point(s): changes of motor control and learning (saccades adaptation, gait analysis, ICARS, Ashworth score for spasticity, a lower extremity manual muscle test ‐LEMMT); Changes of fatigue (ocular motor fatigue task, Fatigue Severity Scale ‐ FSS); Changes of functional disability and quality of life (12‐item multiple sclerosis walking scale MSWS‐12, Activities of Daily Living ‐ ADL, Barthel index ‐ BI, Functional Independence Measure ‐ FIM, Multiple Sclerosis Quality of life inventory ‐ MSQoL‐54); Changes of cerebellar‐thalamo‐cortical inhibition (CBI), parieto‐motor functional connection (PPC‐M1) short intracortical inhibition (SICI) and intracortical facilitation (ICF), vestibular‐spinal tract function (soleus EMG response); Changes of cognitive function (Paced Auditory Serial Addition Task ‐ PASAT, Symbol Digit Modalities Test ‐SDMT, Controlled Oral Word Association Test, Nine‐hole pegboard task). Timepoint(s) of evaluation of this end point: The changes will be evaluated at the end of the two‐week experimental treatment period (day 14), and at the end of the standard rehabilitation (day 28) and after another four week period (day 56) as follow‐up. ; The changes will be evaluated at the end of the two‐week experimental treatment period (day 14), and at the end of the standard rehabilitation (day 28) and after another four week period (day 56) as follow‐up. ; The changes will be evaluated at the end of the two‐week experimental treatment period (day 14), and at the end of the standard rehabilitation (day 28) and after another four week period (day 56) as follow‐up. ; The changes will be evaluated at the end of the two‐week experimental treatment period (day 14), and at the end of the standard rehabilitation (day 28) and after a INCLUSION CRITERIA: Aged 18–70 years, With clinically defined multiple sclerosis (McDonald 2010), Able to complete two trials of the timed 25‐foot walk (T25FW) EDSS between 4 and 6, International Cooperative Ataxia Rating Scale (ICARS) walking capacities score =2, Pyramidal Functional System Score (FSS) =2. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 30 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 15