A 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.

Toxicology studies performed with fampridine included acute and repeated-dose toxicology studies, reproductive toxicity studies, genotoxicity studies, and carcinogenicity studies. Clinical signs evident after large, single, oral doses or repeated, lower, oral doses (and continuous intrathecal infusion in the dog) were similar in all species studied and were indicative of central nervous system activation (including tremors, convulsions, ataxia, dyspnea, dilated pupils, prostration, abnormal vocalization, increased respiration, excess salivation, gait abnormalities, and hyper- and hypo-excitability). These clinical signs are considered to represent exaggerated pharmacology of fampridine. It would appear that limiting toxicities would rule out any concerns regarding potential mutagenicity, carcinogenicity, or teratogenicity of fampridine. During the Fampyra development program, more than 1900 subjects were exposed to fampridine in 57 clinical studies. The most frequent treatment-related adverse events (AEs) reported with fampridine in subjects with MS, as well as other populations, including subjects with spinal cord injury, may be broadly categorized as excitatory effects in the nervous system consistent with the K+ channel blocking activity of the compound in the nervous system. These AEs include dizziness, paresthesias, insomnia, balance disorders, anxiety, confusion, and seizure. In studies in MS patients, the following most frequent treatment-related AEs were also observed: urinary tract infection, asthenia, back pain, constipation, dyspepsia, and pharyngolaryngeal pain. At higher dose levels, more severe central nervous system AEs such as confusion and seizure have been seen. With the adoption of the 10 mg BID dose in extension studies, the rate of first seizure has been approximately 0.32 per 100 subject-years. This rate does not exceed the expected incidence of seizures in the MS population, particularly in the more advanced disease state with significant ambulatory disability18. However, patients were excluded from these studies if they had a history of seizure or evidence of epileptiform activity on a screening electroencephalogram. Seizures have been seen in the post marketing setting in the US although confounding factors such as seizure history and use of concomitant medications that have been associated with a seizure risk may have contributed to the occurrence of seizures in some patients. No new safety signal has been detected as of March 2011.

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.

Efficacy Assessment

A responder to study medication will be a subject who has a 20% improvement in the 9-HPT at both on treatment visits (assessment 4 & 5 or 7 & 8) compared with baseline visits.

A secondary measure of upper limb responsiveness will be defined as a 20% improvement in from baseline in the average time taken to complete all seven tasks on the JTT "on treatment" (assessments 4 & 5 or 7 & 8) compared with baseline assessments (assessments 1,2 & 3).

A mobility responder to fampridine will be defined as a patient with both of the two "on treatment" T25FW assessments (assessments 4 & 5 or 7 & 8) being better than the maximum of any of the four "off treatment" assessments (assessments 1, 2, 3, & 9). Otherwise the patient will be deemed a non-responder.

The responders to the 9-HPT and/or JTT will be compared to the non-responders in relation to their changes in the DASH and AMSQ on treatment and off treatment at the baseline assessment. The change in the DASH and AMSQ in responders at Assessment 5 or 8 (week 10 or 20) will be compared to non-responders at that time-point.

Upper limb response will be examined at the end of treatment phase 1 and repeated at the end of the trial by comparing patients receiving active drug with those receiving placebo to assess any placebo effect and allow assessment of any residual beneficial effect on those who receive fampridine in treatment phase 1 and then switch to placebo in treatment phase 2. Response will again be considered as a 20% improvement in the 9HPT in the active treatment group compared with placebo and a 20% improvement from baseline in the time taken to complete all seven tasks in the JTT. See earlier comment The responders to the T25FW will be compared to the non-responders in relation to their changes in the MSWS-12 on treatment and off treatment at the baseline assessment. The change in the MSWS-12 in responders at Assessment 5 or 8 (week 10 or 20) will be compared to non-responders at that time-point.

The patients' scores on the MSIS-29 (physical) and SF-36 will be examined in relation to the objective changes (responder/non-responder) in the 9-HPT, JTT and the T25FW

Safety Assessment

Adverse events will be monitored, through out the study. Subjects will be required to inform the study team of all new or worsening symptoms within 24 hours of onset. All adverse events will be recorded in the CRF.

Randomisation

Generation of Randomisation Codes

Subjects were randomised to each of two groups, A or B using the program:

http://www.graphpad.com/quickcalcs/randomize1.cfm

The randomisation sequence was generated on 07/03/2012.

Randomisation Groups

A = Initial treatment with Fampridine followed by placebo.

B = Initial treatment with placebo followed by Fampridine.

Security and Distribution of Randomisation Codes The randomisation codes will be kept on the Pharmacy Network Drive in St. Vincent's University Hospital. A hardcopy will be kept in the Pharmacy Department in the clinical trial folder.

The investigators and subjects will not have access to the randomisation codes (double blind).

A copy of the randomisation code and individual product codes will also be kept in a sealed envelope, with signature and date across the seal, which may be opened by the Principal Investigator if an emergency code-break is required. This will be stored in a secure location in the Neurology department but can be accessed by the Principle investigator if needed.

Handling Pharmacy staff will use the information when dispensing clinical trial medication to each subject to ensure the appropriate medication is dispensed (ie placebo or active).

Retention The study pharmacist will retain the randomisation codes until the database is locked at the end of the trial. Thereafter, the randomisation code will be made known to the investigators.

Code-Break Mechanisms In the case of emergency, when knowledge of the subject's study treatment assignment is essential for the clinical management of the subject. Any intentional or unintentional breaking of the blind will be recorded and reported to the sponsor as soon as possible.

After database is locked at the end of the trial.

Blinding

Procedure for blinding of Fampridine versus placebo.

1. Capsules look identical. Fampridine and placebo capsules look identical.

2. Identical packaging Fampridine and placebo are packaged in identical packaging.

3. Identical labeling The label instructions will be identical for both. See copy of label below

Use of numbers in random order for product codes Each product will be labeled with a product code. It was decided that 4-digit codes would be used.

Using Microsoft Excel, a sequence of 1400 numbers in numerical order was generated. The numbers range from 1,000 to 2,199. The numbers were then shuffled into random order for use as product codes.

The first 700 numbers in random order will be used as the Fampyra codes The last 700 numbers in random order will be used as the placebo codes.

Use of numbers in random order for the product codes means that the investigators and subjects will not be able to determine from the product codes whether the patient is on active or placebo treatment. The codes will used by the study pharmacist to ensure that patients are correctly dispensed active or placebo as required and to allow identification of active or placebo if unblinding required.

Who will be blinded?

The study will be conducted in a double-blind fashion. Study treatment assignment will be blinded for both the investigators and the subject.

The study pharmacist will retain the list of fampridine and placebo product codes.

Circumstances in which the blind would be broken

In the case of an emergency, when knowledge of the subject's study treatment assignment is essential for the clinical management of the subject, an investigator may unblind a subject. For example, the blind would be broken in the event of a serious adverse effect experienced by a subject. Any intentional or unintentional breaking of the blind will be recorded and reported to the sponsor as soon as possible.

Procedure for unblinding

The Principal Investigator should be contacted if emergency unblinding is required. He will be provided with a sealed envelope (with signature and date across the seal) containing the Randomisation Code, active product codes and placebo product codes. The envelope may be opened if emergency unblinding is required.

This will be stored in a locked safe in the Neurology Department offices in St. Vincent's University Hospital.

The list of active and placebo product codes will be shuffled back into numerical order and saved as a separate file before being printed to allow quick identification of a particular product code if emergency unblinding is required.

DEFINITION OF END-OF-TRIAL

The trial will end on the date of the last visit of the last subject. The Sponsors and/or the trial steering committee have the right at any time to terminate the study for clinical or administrative reasons.

The end of the study will be reported to the REC and Regulatory Authority within 90 days, or 15 days if the study is terminated prematurely. The investigators will inform subjects and ensure that the appropriate follow-up is arranged for all involved. A summary report of the study will be provided to the REC and Regulatory Authority within 1 year of the end of the study.

The end-of-trial is the date of the last visit of the last subject.

The end of study visit form will include:

- assessment 9-HPT, JTT, T25FW, MSIS-29, MSWS-12, DASH, AMSQ, EDSS.

- assessments of safety including general neurological examination and recording of adverse events.

- assessment of compliance with study treatment.

- recording of concomitant medication

Premature termination of the study

Health authorities and ethics committees must be notified of completion or termination of this study, and sent a copy of the study synopsis in accordance with the necessary timelines. This study will be terminated early if recruitment is slow. Recruitment should take 6 months. It recruitment targets are not met and recruitment has slowed to more than 12 months the trial will be terminated.

DISCONTINUATION/WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT

Subjects have the right to voluntarily discontinue study treatment or withdraw from the study at any time for any reason without any consequences. The investigator has the right to discontinue a subject from study treatment or withdraw a subject from the study at any time if it is in the best interest of the subject.

Subjects must discontinue the investigational medicinal product(s) and be withdrawn from the study for any of the following reasons:

- Withdrawal of consent by the subject

- Any medical condition that the investigator or sponsor determines may jeopardize the subject's safety if she or he continues receiving the study treatment

- Pregnancy

- Ineligibility (either arising during the study or retrospectively having been overlooked at screening)

- An adverse event which requires discontinuation of the study medication

- Treatment failure and disease progression

- Lack of compliance with the study and/or study procedures (e.g., dosing instructions, study visits).

- Lost to follow-up following at least 3 documented attempts to contact any subject before defining them as lost to follow-up.

All subjects who discontinue should comply with protocol specified follow-up procedures. The only exception to this requirement is when a subject withdraws consent for all study procedures.

If a subject is withdrawn before completing the study, the reason for withdrawal must be entered on the appropriate case report form (CRF) page.

If a subject is withdrawn due to an adverse event, the investigator will arrange for follow-up visits until the adverse event has resolved or stabilised.