A Study of the Effectiveness of Fampridine in Improving Upper Limb Function in MS
Condition: Secondary Progressive Multiple Sclerosis; Primary Progressive Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to examine the effect of treatment with fampridine in patients
      with secondary progressive MS (SPMS) or primary progressive MS (PPMS) with upper limb
      dysfunction (as defined by a 9-HPT time of between 15-90 seconds) and Kurtzke EDSS scores in
      the range 4.0-7.0 on upper limb function assessed by the nine-hole peg test (9-HPT) and the
      Jebson Taylor Hand Function Test (JTT).

      Fampridine has been shown to be effective in improving motor function, specifically walking
      ability in prior studies in this patient population and is currently licensed for this use in
      Europe and the United States. Upper limb dysfunction is common in SPMS and PPMS and often
      underestimated. Fampridine effects action potential conduction in demyelinated nerve fibres
      and we would hypothesise that the improvement previously reported in walking ability would be
      similar to that on upper limb dysfunction. Our study aims to address this question using both
      independent and patient reported outcomes in the context of a randomised placebo controlled
      crossover trial.
    

Detailed description: 
      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

      The objective of this study is to assess the affect of PR-fampridine medication compared to
      placebo for upper limb function in patients with progressive multiple sclerosis

      TRIAL DESIGN

      This will be a single centre, phase IV, double blind, randomized, placebo controlled,
      crossover study on the effectiveness of oral Fampridine-PR 10mg tablets BID on upper limb
      function for patients with progressive multiple sclerosis.

      The trial will consist of a two week run in period followed by an eight week treatment period
      were enrolled subjects will be randomised to receive either study drug or placebo in a double
      blinded manner. This will be followed by a two-week wash out period followed by a further
      eight-week study period using active drug or placebo. There will be a two-week washout period
      at the end of the study. The total period of the study will be 22 weeks.

      Each subject will attend for a screening visit and 8 assessment visits (total number of
      visits, 9).

      STUDY ASSESSMENTS AND PROCEDURES

      Patients likely to fulfill the inclusion criteria and not meet any exclusion criteria will be
      provided with information on the study and invited to attend a subsequent screening visit.
      Only patients who have signed the informed consent form will participate in any study related
      procedures including blood testing and ECG.

      At screening visit (Assessment 1) subjects will have a physical examination and an expanded
      disability status scale (EDSS) score rated. Blood samples will be taken for renal and liver
      function and a baseline ECG performed. Patients will complete a nine-hole peg test (9-HPT)
      and a Jebsen Taylor Hand Function Test (JTT). Timed 25 foot walk (T25FW) will be recorded and
      the patients invited to complete the Multiple Sclerosis Impact Scale (MSIS-29), Multiple
      Sclerosis Walking Scale (MSWS-12), Disabilities of the Arm, Shoulder and Hand (DASH) score,
      Arm Function in Multiple Sclerosis Questionnaire (AMSQ) and SF-36 (quality of life)
      questionnaire. Patients with any abnormalities on ECG, blood tests will not be invited to a
      baseline visit and considered a screening failure.

      Following screening visit subjects fulfilling the inclusion / exclusion criteria will have
      two baseline visits (Assessments 2 and 3) at the end of week one and end of week two. The
      9-HPT, JTT and T25FW will be repeated to allow for training effects. Patients will be
      randomised to group A or group B and receive study medication or placebo at baseline visit
      based on their blinded randomisation (Assessment 3).

      The first treatment period will be from the start of week 3 until the end of week 10.
      Patients will have an assessment at the end of week 6 (Assessment 4) and the end of week 10
      (Assessment 5). At both assessments patients will have the 9-HPT, JTT, T25FW, MSIs-29,
      MSWS-12, DASH, AMSQ and SF-36 recorded. Weeks 11 and 12 will be a washout period (no
      drug/placebo). Assessment 6 will occur at the end of week 12 and will include recording of
      9-HPT, JTT, T25FW, MSIs-29, MSWS-12, DASH, AMSQ and SF-36. Any adverse events will be
      recorded at each visit as will the use of concomitant medications.

      The second treatment period will begin at the start of week thirteen with groups A and B
      switching study drug / placebo in a blinded manner. The second treatment period will continue
      for a further 8 weeks with two more assessments ant week 16 (Assessment 7) and week 20
      (Assessment 8). At both of these assessments subjects will complete the 9-HPT, JTT, T25FW,
      MSIs-29, MSWS-12, DASH, AMSQ and SF-36. At the end of week 20 and EDSS score will be
      recorded. Any adverse events will be recorded at each visit as will the use of concomitant
      medications.

      There will be a final washout period (weeks 21 and 22) after which a final visit (assessment
      9) will occur and subjects once again completing 9-HPT, JTT, T25FW, MSIS-29, MSWS-12, DASH,
      AMSQ and SF-36 and having n EDSS score recorded. Once again adverse events will be recorded.

      Description of Study Assessments

      Medical and Surgical History will be recorded with particular attention on the diagnosis of
      MS, duration of MS and MS subtype.

      Demographics The date of birth, gender and race will be recorded. Physical Examination The
      complete physical examination will include the evaluation of the neurological system and a
      recording of the EDSS score and T25FW.

      ECG Test One ECG including a 12-lead examination will be performed at Screening (assessment
      1).

      Abnormal findings will be noted for clinical significance. The report will be signed by the
      investigator.

      Clinical Laboratory Tests

        1. Haematology: haemoglobin, WBC, RBC, platelet count

        2. Biochemistry: creatinine or creatinine-clearance, sodium, potassium, liver function
           tests

        3. All laboratory results will be reviewed and the reports signed by the investigator who
           will record in the CRF whether they are normal, abnormal but not clinically significant,
           or abnormal and clinically significant.

      Pregnancy Tests Serum pregnancy test and urine pregnancy test in women of childbearing
      potential will be performed.

      Concomitant Medication In addition to Fampyra, any other treatments or procedures that are
      considered necessary for the patient's welfare may be given at the discretion of the
      Investigator. Administration of continuous concomitant procedures and medications (including
      herbals and nutraceuticals) must be reported in the appropriate section of the CRF along with
      reasons for use. Continuous concomitant procedures and medications are defined as a treatment
      administered regularly for 2 weeks or more. The generic names for concomitant medications
      should be recorded, if possible. The total daily dose should be recorded in the CRF whenever
      possible. Concomitant use of medicinal products that are inhibitors of OCT2 for example,
      cimetidine will be noted and will be deemed exclusion criteria. Concomitant use medicinal
      products that are substrates of OCT2 for example, carvedilol, propanolol and metformin will
      also be noted and the investigator will decide if the subject should successfully complete
      screening.
    

Intervention name(s): Fampridine; Placebo
Intervention type(s): Drug; Drug
Other intervention name(s): Fampyra
Intervention MeSH terms: 4-Aminopyridine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Secondary Progressive Multiple Sclerosis; Primary Progressive Multiple Sclerosis; Multiple Sclerosis; Upper limb function; Mobility; Fampridine; DASH; AMSQ; MSWS-12; MSIS-29; SF-36; 9HPT; 25FTW; JTT