A Phase IV Double Blind, Randomized, Placebo Controlled, Crossover Study of the Effectiveness of Oral Fampridine in Improving Upper Limb Function in Progressive Multiple Sclerosis

BACKGROUND INFORMATION Patients with secondary progressive MS (SPMS) and primary progressive MS (PPMS) have significant walking disability and impaired upper limb function due to repeated demyelination and axonal injury affecting the corticospinal pathways. In some patients this motor deficit may be predominantly due to demyelination resulting in motor conduction slowing and/or block which is potentially reversible by blocking potassium channels of demyelinated axons. Fampyra® (fampridine-PR) is a prolonged-release formulation of the active drug substance 4-aminopyridine {4-AP; fampridine [International Nonproprietary Name (INN)]. Fampridine is able to block certain voltage-gated K+ channels in neurons, particularly in demyelinated nerves. Blockade of repolarising K+ currents can increase synaptic transmission throughout the nervous system by increasing the duration of the presynaptic action potential. Demyelinated nerves lose their ability to effectively conduct action potentials and fampridine can help reverse this. This effect was demonstrated clinically in a proportion of multiple sclerosis (MS) patients who showed a significant improvement in motor function, specifically walking ability, with Fampyra treatment. Fampridine-PR 10 mg every 12 hours or twice daily (BID) was approved in Europe (20 July 2011) for this indication under the brand name of Fampyra®.

RATIONALE FOR THE STUDY Treatment with fampridine (4-aminopyridine), a potassium channel blocker,1,2 has been shown to cause significant improvement in walking speed in one third of MS patients with motor disability.3-5 In those patients who respond, approximately a 25% improvement in walking speed was obtained with a self-reported 7 point improvement in the Multiple Sclerosis Walking Scale (MSWS-12), a patient-rated measure of walking quality and ability, 6,7 in comparison to non-responding patients and placebo control subjects.

Pharmacologically, the K+ channel blocking properties of fampridine and its effects on action potential conduction in demyelinated nerve fiber preparations have been extensively characterized. At low concentrations that are relevant to clinical experience (in the range of 0.2 to 2 μM [18 to 180 ng/mL]), fampridine is able to block certain voltage-dependent K+ channels in neurons. It is this characteristic that appears to explain the ability of the drug to restore conduction of action potentials in some critically demyelinated nerve fibers. At higher (millimolar) concentrations, fampridine affects other types of K+ channels in both neural and non-neural tissues. Blockade of repolarising K+ currents may increase synaptic transmission throughout the nervous system by increasing the duration of the presynaptic action potential. A range of neurological effects consistent with increased excitability of nerve cells occurs with clinically relevant doses of fampridine.

The FDA has recently approved Fampridine, a slow release preparation, for use in the MS patient population.8 It has also recently been approved in Europe (20th July 2011).17 Most studies of fampridine assessed timed walking over twenty-five feet and the Multiple Sclerosis Walking Scale-12 (MSWS-12).3-5 Deficits in arm and hand function are commonly found in patients with SPMS and PPMS and can have an impact in performing many activities of daily living. We propose to examine the efficacy of fampridine in upper limb function and in overall disease impact in a single centre, double blind, randomized, placebo-controlled, crossover study of patients attending St Vincent's University Hospital with significant walking and upper limb disability due to SPMS and PPMS.

STUDY OBJECTIVE