Study to evaluate the effects of fampridine in patients with multiple sclerosis and eye movement abnormality

INTERVENTION: Trade Name: Fampyra 10 mg prolonged‐release tablets Pharmaceutical Form: Tablet INN or Proposed INN: FAMPRIDINE CAS Number: 504‐24‐5 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 20‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use CONDITION: Multiple sclerosis (MS) and a unilateral or bilateral internuclear ophthalmoplegia (INO) Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: To evaluate the effects of fampridine on eye movements in patients with multiple sclerosis (MS) and a unilateral or bilateral internuclear ophthalmoplegia (INO) Primary end point(s): Primary endpoints; Eye movements at each day and time point. Variables will include (but not limited to):; ‐ Eye position and velocity and the abducting/adducting eye; ‐ Peak velocity ratio for each saccade; ‐ Saccadic pulse in the 2 eyes; ‐ VDI (versional disconjugacy index) ; ‐ FPA (first‐pass amplitude) Secondary Objective: To evaluate the effects of fampridine on nerve conduction speed as determined through eye movement measurements and MRI scanning of the medial longitudinal fasciculus (MLF) in MS patients with a unilateral or bilateral INO; To determine whether there is an association between MRI signal of the MLF and the nerve conduction velocity in MS patients with an INO; To evaluate the pharmacodynamics effects of fampridine using the NeuroCart test battery; To evaluate the pharmacokinetic (PK)‐pharmacodynamic (PD) relationship for the effect of fampridine on nerve conduction in MS patients with an INO; Timepoint(s) of evaluation of this end point: Eye movements at each day and time point: pre‐dose (‐1 h), 1.5 h, 2.5 h, 3.75 h and 5.5 h post‐dose. SECONDARY OUTCOME: Secondary end point(s): Secondary endpoints; MRI brain:; ‐ Signal intensity MLF; ‐ Length of MLF; Nerve conduction speed as determined by lag time of the adducting eye divided by the length of the MLF; Cognitive function and neurophysiological test items from NeuroCart:; ‐ Adaptive tracking (motor‐coordination); ‐ Body sway (postural stability); ‐ Rapid visual information processing (RVIP); ‐ Simple reaction time task; ‐ Symbol Digit Substitution Test (SDST, cognitive processing speed); ‐ Pharmaco‐EEG; ; Pharmacokinetic endpoints; Plasma pharmacokinetic parameters of fampridine: Tmax, Cmax, AUCinf, t1/2, Vd/F, CL/F Timepoint(s) of evaluation of this end point: Brain MRI: screening; Cognitive function test items from NeuroCart: pre‐dose (‐1 h), 3 h and 4.25 h post‐dose.; PK sampling will be performed at pre‐dose (‐1 h), 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 5.5 h and 24 h post‐dose. INCLUSION CRITERIA: 1. Male and female patients 18 years or more of age; 2. Diagnosis of multiple sclerosis according to the revised McDonald criteria (Appendix A); 3. A disease duration > 1 year as defined by a diagnosis of MS at least one year prior to inclusion in the study; 4. Clinically stable disease > 30 days; 5. Subject shows evidence of INO for at least 30 days by quantitative neuro‐ophthalmological criteria; 6. Subject is able to understand the demands of the protocol, has had any questions answered and has voluntarily signed the informed consent prior to any study procedures; and 7. Subject is otherwise in good health, based on complete medical history and physical examination, including blood pressure and pulse rate measurement, 12‐lead ECG, and clinical laboratory tests. 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 20 F.1.3 Eld