A randomised, placebo-controlled trial investigating the role of Fampridine in cognitive performance of patients with multiple sclerosis.

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1 A randomised, placebo-controlled trial investigating the role of Fampridine in cognitive performance of patients with multiple sclerosis. PRINCIPAL INVESTIGATOR: Name: Carlo Pozzilli Institution/Organization: Department of Neurology and Psychiatry, La Sapienza University Address: Viale dell Università 30 City/State/Zip: Rome 00185, Italy Phone: Fax: CONTACTS: Contact person Name: Rossella Pichi Phone: / Study Coordinator Name: Laura De Giglio Institution/Organization: Department of Neurology and Psychiatry, La Sapienza University Address: Viale dell Università 30 City/State/Zip: Rome, Italy Phone: Background and Rationale MS affects young people, causing progressive disability. Over recent years there have been several advances in the pharmacological management of MS. Disease modifying treatments, however, have little or no impact on existing impairments. Therefore, the management of the person with MS is focused on optimizing function and symptom control. The 3,4-diaminopyridine or 4-diaminopyridine have been used on a named patient basis in Europe for many years to improve motor function and fatigue in MS patients. In 2009 a randomisedcontrolled trial showed that the oral sustained-release Fampridina (AMPYRA ) given at the dosage 10 mg twice daily is more effective than placebo in ameliorating the walking speed as measured by the timed 25-foot walking test (1) and demonstrated the potential of the drug to improve motor disability in MS [1]. In March of 2010 the Fampridina was approved by the Food and Drug Administration for the

2 symptomatic treatment of walking difficulty in individuals with MS. Fampridina is a broad spectrum potassium (K+) channel blocking agent, with the capacity to improve conduction across demyelinated internodes in axons of the central nervous system. Fampridina prolongs the duration of the Na++ action current at the internode; this increases the safety factor for conduction (ie, the ratio of action current generated by an impulse to the minimum amount of action current needed to maintain conduction) and thus can reverse conduction block due to focal demyelination [2-4]. K+ channel blocking compounds also enhance neuronal and neuromuscular transmission by increasing pre-synaptic and end-terminal calcium (Ca++) influx [5]. Collectively these properties are thought to underlie the restored axonal conduction and neurological function reported in patients with MS and other demyelinating disorders. In vivo, cortical effects have been reported. An FMRI study conducted from our group reported that 3,4-DAP induce a grater motor-evoked brain activation in sensory-motor cortex and supplementary motor area compared to placebo. In the same study authors showed a decreased intra-cortical inhibition (ICI) and enhanced intra-cortical facilitation (ICF) after paired-pulse Transcranial Magnetic Stimulation (TMS) in patients treated with 3,4-DAP compared to placebo [6]. Cognitive dysfunction is a common and disabling symptom in MS. Different cognitive domains are involved but the most common deficit is speed of processing, typically associated with working memory impairment. The heterogeneity in neuropsychological presentation among patients with MS reflects the influence of many factors, including genetics, sex, intelligence, disease course, co-morbid neuropsychiatric illness, and health behaviours. Neuropsychological deficits are also robustly correlated with brain MRI metrics reflecting demyelination process and axonal loss [7]. To date no effective treatment has yet been established for this cognitive impairment in MS. The strongest evidence for symptomatic treatment of cognitive dysfunction in MS came from studies of AChEIs. Unfortunately, more recent studies did not confirm previous ones [8]. Studies on the role of 4-aminopyridine in ameliorating cognitive deficits in MS patients are unsatisfactory. In a pilot study Smits et al [9] demonstrated a trend for improved performance with 4-AP in two tests assessing long term memory and speed of processing/working memory but could not demonstrate significant effects of 4-AP on cognitive function. The negative results of this study can be explained by the small sample size and by methodological aspects induced by the study design. Although Rossini et al didn't report a significant effect of 4-aminopyridine on cognitive function in

3 progressive MS patients, they didn't assess the effect on speed of processing and working memory impairment, focusing on sustained attention, memory, executive function and general intelligence [10]. We hypothesize that improvement of axonal conduction and synaptic facilitation induced by Fampridina can improve efficiency of cerebral circuits related to cognitive function in MS patients. The aim of the study is to evaluate the effect of Fampridina in ameliorating cognitive impairment in Multiple Sclerosis patients with particular interest on speed of processing. Objectives Primary objectives Improvement in speed processing assessed with Symbol Digit Modalities Test (SDMT) scores. Secondary objectives Improvement in other cognitive domains measured with: Paced Auditory Serial Addition Test (PASAT), STROOP and Tower of London (TOW) scores, the Selective Reminding Test (SRT), the 10/36 Spatial Recall Test, Word List Generation (WLG) Tertiary objectives Improvement in the Multiple Sclerosis Impact Scale (MSIS-29) and in the Fatigue Scale for Motor and Cognitive Functions (FSMC) Design In this randomised, double-blind, placebo-controlled trial patients, after a screening period of 2 week will be randomly assigned to receive dalfampridine 10 mg or placebo twice daily for 12 consecutive weeks with a 2:1 ratio. Clinical evaluations with calculation of Expanded Disability Status Scale (EDSS) will be performed at screening, neuropsychological evaluations and MSFC will be performed at screening, after 12 weeks of treatment and at 4 week of follow-up Figure 1 shows study design

4 Population Inclusion criteria: In order to be eligible for this study, patients will be required to have: a diagnosis of MS according to revised McDonald criteria 2011 [16]; age from 18 to 65 years (inclusive); a cognitive impairment as defined as SDMT score below the 10 percentile of normative values of Italian Population [17]. Exclusion criteria: Clinical relapse occurred in the previous 60 days; history of major depression or psychosis, according on Beck Depression Inventory-IA [18]; history of seizures; any condition that would interfere with study conduction; Introduction or modification of any medication for mood, fatigue or cognition in the previous month. Methods Clinical and neuropsychological evaluation Clinical evaluation at screening will include EDSS and MSFC, MSFC will be repeated after treatment and after a 4-weeks follow-up. Neuropsychological evaluations will be performed at screening and repeated after 12 weeks of treatment and at 4 weeks of follow-up. The cognitive evaluation will include the Italian version of the BRBNT (including Symbol Digit Modalities Test (SDMT) and the Stroop test (ST)) [11-12]; the Tower of London (TOW) will be administrated to assess executive functions [13].To reduce learning effects different versions of the Rao Brief Repeatable Neuropsychological Battery (BRBNT ) will be administered at screening, after the treatment period and after the four weeks follow-up. Two questionnaires will be also administrated: the MSIS-29 to assess the physical and psychological impact of the disease on daily living [14], the FSMC for the assessment of physical,

5 cognitive and psychosocial fatigue [15] Statistical analysis All statistical test will be two-sided with a type-i error of 0.05, without adjustment for multiplicity. The null hypothesis (H0) to be tested is as follows: there are no differences in proportions of patients with a relevant improvement in SDMT scores. The alternative hypothesis (H1) to be tested is as follows: there are significant differences in proportions of patients with a relevant improvement in SDMT scores. Similar hypotheses will be tested for the secondary and tertiary efficacy parameters. Sample size calculation. Assuming a 20% difference between the two groups in de SDMT score at the end of study period with respect to baseline a total sample size of 105 patients (70 on active group, 35 on placebo) is required to ensure a power of about 80% (two-sided alpha level of 5%).Considering a drop-out rate of 15%, a total number of 123 subjects will be enrolled. This calculation is based upon results of previous study showing that a progression of at least one MSFC component by 20% is a sensitive measure of disability progression [19-20]. Expected outcomes We expect an improvement in the primary endpoint (SDMT) as well as in the secondary endpoints (PASAT, Stroop and TOW scores) and in tertiary endpoint (MSIS29 and FSMC) References 1. Goodman AD, Brown TR, Krupp LB, et al. Fampridine MS-F203 Investigators. Sustainedrelease oral fampridine in multiple sclerosis: a randomized, double-blind, controlled trial. Lancet 2009; 373: Bostock H, Sherratt RM, Sears TA. Overcoming conduction failure in demyelinated nerve fibres by prolonging action potentials. Nature 1978; 274: Targ EF, Kocsis JD. 4-aminopyridine leads to restoration of conduction in demyelinated rat sciatic nerve. Brain Res. 1985; 328: Leung G, Sun W, Brookes S, et al. Potassium channel blocker, 4-aminopyridine-3-methanol, restores axonal conduction in spinal cord of an animal model of multiple sclerosis. Exp Neurol. 2011; 227: Wu ZZ, Li DP, Chen SR, Pan HL. Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel beta subunit. J Biol Chem.

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7 20. Drake AS, Weinstock-Guttman B, Morrow SA et al. Psychometrics and normative datat for the Multiple Sclerosis Functional Composite: replacing the PASAT with the Symbol Digit Modalities Test. Mult Scler 2010;16(2)