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
Phase: PHASE4
Conditions: Secondary Progressive Multiple Sclerosis, Primary Progressive Multiple Sclerosis
Sponsor: University College Dublin

 
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Title page:  
 
 
PROTOCOL NUMBER: SVUHneuro002 
 
  
 
PHASE OF DEVELOPMENT: 4 
 
 
 
PROTOCOL TITLE:  
A double blind, randomized, placebo controlled, crossover study of the effectiveness of oral 
fampridine in improving upper limb function in progressive multiple sclerosis. 
 
 
 
VERSION: 2.1 
 
 
 
DATE: 3rd February 2013 
 
 
 
Department of Neurology, 
St. Vincent’s University Hospital, 
Elm Park, 
Dublin 4, 
Ireland 

 
2/33 
 
 
 
 
 
 
 
 
 
2.0 APPLICATION DETAILS 
2.1 STUDY TITLE 
A double blind, randomized, placebo controlled, crossover study of the effectiveness of oral fampridine in 
improving upper limb function in progressive multiple sclerosis. 
2.2 REFERENCE NUMBERS 
Protocol identification (code or reference number): SVUHneuro002 
 
EudraCT number: 2011-002561-38 
 
 
 
 
 
Date and version number: Version2.1/Feb2013  
 
 
 
2.3 APPLICANT DETAILS 
Chief investigator/ Co-ordinating investigator 
Name/title:  Christopher McGuigan  (Dr) 
Contact details:   
Department of Neurology, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland 
Tel: 012214179, Fax: 012213842, Email: c.mcguigan@st-vincents.ie 
 
Principal Investigators Name(s)/ titles:  
Michael Hutchinson (Prof) & Tubridy Niall (Prof) 
Contact details: Department of Neurology, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. 
Tel: 012214179. Email: mhutchin@iol.ie; n.tubridy@st-vincents.ie 
Sponsor 
Name: St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland 
Contact details: Dr. P. Doran, Scientific Director, Clinical Research Centre, University College Dublin. 
Telephone 017164587 
Funder: 
Name: Department of Neurology, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland 
Contact details: Tel: 012214179 email:k.kinsella@svuh.ie 
2.4 SIGNATURES 
  
Sponsor’s Signature…………………………………………………………….Date…………… 
Sponsor:  Dr Peter Doran, Scientific Director, Clinical Research Centre, University College Dublin 
 
Principle Investigator……………………………………………………..Date………………… 
Principle Investigator: Christopher McGuigan, St. Vincent’s University Hospital, Dublin 
 
 
 
2.5 OTHER RELEVANT INFORMATION  
 
 
 
 
3.0 CONFIDENTIALITY STATEMENT 
 
This document contains confidential information that must not be disclosed to anyone other than the 
sponsor, the investigative team, regulatory authorities, and members of the Research Ethics 
Committee. 

 
3/33 
 
 
 
 
 
 
 
 
 
4.0 TABLE OF CONTENTS 
 
2.0 APPLICATION DETAILS 
2 
2.1 STUDY TITLE 
2 
2.2 REFERENCE NUMBERS 
2 
2.3 APPLICANT DETAILS 
2 
2.4 SIGNATURES 
2 
2.5 OTHER RELEVANT INFORMATION 
2 
4.0 TABLE OF CONTENTS 
3 
5.0 DOCUMENT HISTORY 
5 
6.0 SYNOPSIS 
5 
7.0 ABBREVIATIONS 
7 
8.0  INTRODUCTION 
8 
8.1 BACKGROUND INFORMATION 
8 
8.2 RATIONALE FOR THE STUDY 
8 
9.0 STUDY OBJECTIVE 
9 
9.1 PRIMARY OBJECTIVE 
9 
9.2 SECONDARY OBJECTIVE 
9 
9.3 EXPLORATORY OBJECTIVES 
10 
9.4 PRIMARY AND SECONDARY/ EXPLORATORY ENDPOINTS/OUTCOME MEASURES 
10 
10.0 TRIAL DESIGN 
11 
10.1 GENERAL CONSIDERATIONS 
11 
10.2 SELECTION OF STUDY POPULATION 
12 
10.3 STUDY ASSESSMENTS AND PROCEDURES 
13 
10.4 DEFINITION OF END-OF-TRIAL 
19 
10.5 DISCONTINUATION/WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
19 
11.0 TREATMENT OF TRIAL SUBJECTS 
20 
11.1 DESCRIPTION OF STUDY TREATMENT(S) 
20 
11.2 FORMULATION, PACKAGING, AND HANDLING 
20 
11.3 STORAGE AND DISPOSITION OF STUDY TREATMENTS(S) 
21 
11.4 ACCOUNTABILITY OF THE STUDY TREATMENT(S) 
22 
10.5 ASSESSMENT OF COMPLIANCE 
22 
10.6 OVERDOSE OF STUDY TREATMENT 
22 
10.7 PRIOR AND CONCOMITANT THERAPY 
22 
12.0 SAFETY REPORTING 
23 
12.1 DEFINITIONS 
23 
12.2 EVALUATIONS OF AES AND SAES 
24 
12.3 REPORTING PROCEDURES FOR ALL ADVERSE EVENTS 
25 
12.4 REPORTING PROCEDURES FOR SERIOUS ADVERSE EVENTS 
26 

 
4/33 
 
 
 
 
 
 
 
 
 
12.5 DATA SAFETY MONITORING BOARD (DSMB) 
27 
12.6 PREGNANCY 
27 
13.0 STATISTICS 
27 
13.1 DESCRIPTION OF STATISTICAL METHODS 
27 
13.2 DETERMINATION OF SAMPLE SIZE SUBJECTS 
27 
13.3 ANALYSIS SETS 
27 
13.4 DEMOGRAPHIC AND BASELINE DISEASE CHARACTERISTICS 
27 
13.5 EFFICACY ANALYSIS 
27 
13.6 SAFETY ANALYSIS 
28 
13.7 THE LEVEL OF STATISTICAL SIGNIFICANCE 
28 
13.8 CRITERIA FOR THE TERMINATION OF THE TRIAL 
28 
13.9 PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED AND SPURIOUS DATA 
28 
13.10 PROCEDURE FOR REPORTING ANY DEVIATION(S) FROM THE ORIGINAL STATISTICAL PLAN 
29 
14.0 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
29 
15.0 DATA HANDLING AND RECORD KEEPING 
29 
15.1 DATA COLLECTION, SOURCE DOCUMENTS AND CASE REPORT FORMS (CRF): 
29 
15.2 DATA REPORTING 
29 
16.0 RETENTION OF ESSENTIAL DOCUMENTS 
29 
17.0 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
30 
18.0 AUDITS AND INSPECTIONS 
30 
19.0 ETHICS 
30 
19.1 DECLARATION OF HELSINKI 
30 
19.2 GOOD CLINICAL PRACTICE 
30 
19.3 APPROVALS 
31 
19. 4 INFORMED CONSENT 
31 
19.5 BENEFITS AND RISKS ASSESSMENT 
31 
19.6 SUBJECT CONFIDENTIALITY 
31 
20.0 FINANCING AND INSURANCE/INDEMNITY 
31 
21.0 CLINICAL STUDY REPORT AND PUBLICATION POLICY 
31 
22.0 REFERENCES 
32 
 
 

 
5/33 
 
 
 
 
 
 
 
 
 
5.0 DOCUMENT HISTORY 
 
Document 
Date of Issue 
Summary of Change 
Protocol Version 2.1 
03.02.2013 
1.Defined 
walking 
speed 
removed from inclusion criteria 
2. Additional questionnaire on 
upper 
limb 
function added 
(AMSQ).  
Protocol Version 2.0 
28.03.2012 
Formatted IMB specification 
Original Protocol 
02.01.2012 
Not applicable 
 
 
6.0 SYNOPSIS 
 
Title of study 
A double blind, randomized, placebo controlled, crossover study of the 
effectiveness of oral fampridine in improving upper limb function in 
progressive multiple sclerosis. 
Name of sponsor/company 
St. Vincent’s University Hospital, Dublin 
Phase of development 
IV 
Objectives 
Primary Aims: To assess 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). 
Secondary aims: To assess the effect of treatment with fampridine on 
walking mobility assessed by the Timed 25 foot Walk (T25FW) and the 
Multiple Sclerosis Walking Scale (MSWS-12). To determine whether 
response or non-response to fampridine by the T25FW can be easily 
determined using self reported changes in the MSWS-12 alone within 4 
weeks in the course of active therapy. To determine whether response 
or non-response to fampridine by the 9HPT or JTT can be easily 
determined using self reported changes in the DASH and AMSQ alone 
within 4 weeks on the course of active therapy. To determine whether 
any relation exists between improvement / lack of improvement on the 
T25FW and improvement/ lack of improvement on the 9-HPT or JTT. 
To examine the safety of fampridine in this patient population. To 
assess the impact of fampridine on health related quality of life in 
patients with multiple sclerosis (HRQOL) as measured by the SF-36 
questionnaire. 
Trial design 
Crossover, randomized, double blind, placebo-controlled trial. 
Key inclusion criteria 
Patients with SPMS or PPMS, male and female, aged 18-70, who have 
Kurtzke EDSS scores in the range 4.0 to 7.0 inclusive and evidence of 
significant upper limb dysfunction as defined by a 9HPT of 15 – 90 
seconds (dominant or non-dominant hand), will be recruited. Women in 
reproductive years will be required to use barrier or hormonal methods 
of contraception. 

 
6/33 
 
 
 
 
 
 
 
 
 
Key exclusion criteria 
Patients with a history of seizures, significant liver dysfunction, renal 
dysfunction, significant upper or lower limb arthritis or any other 
disorder including cognitive dysfunction which would affect the ability 
to accurately complete questionnaires and give full informed consent.  
Patients with clinically significant upper limb ataxia or upper limb 
proprioceptive sensory loss, which in the opinion of the Clinician affect 
upper limb functional assessment. Patients concomitantly using 
medicinal products that are inhibitors of Organic Cation Transporter 2 
(OCT2). 
Patients on concurrent treatment with other medicinal products 
containing fampridine (4-aminopyridine). Pregnant or breast-feeding 
patients. 
Number of subjects 
80 
Test product, dose and 
mode of administration 
Oral PR-Fampridine 10mg b.d 
Oral Placebo one tablet b.d. 
Duration of treatment 
Two 8 week treatment periods 
Statistical methods 
Participants will be classified as to whether they are “responders” or 
“non-responders” by the 9-HPT and the T25FW according to defined 
criteria. Change in the MSWS-12, the MSIS-29 (physical) and the 
DASH and AMSQ in responders and non-responders will be examined 
by the Wilcoxin Signed Rank test to assess the significance of the mean 
differences between groups. 
Sample size 
80 
 

 
7/33 
 
 
 
 
 
 
 
 
 
 
7.0 ABBREVIATIONS 
 
 
AE 
 
Adverse event 
AR 
 
Adverse reaction 
CA 
 
Competent authority 
CI 
 
Chief investigator/Co-ordinating investigator 
CRF 
 
Case report form 
CRO 
 
Contract research organisation 
CT 
 
Clinical trial 
CTA 
 
Clinical trial authorization 
DASH  
Disabilities arm, shoulder, hand questionnaire 
ECG   
Electrocardiogram 
EDSS  
Expanded Disability Status Scale 
EU  
 
European Union 
e-CRF  
Electronic case report form 
GCP 
 
Good Clinical Practice 
GP 
 
General Practitioner 
9-HPT  
Hole Peg test 
IB 
 
Investigators brochure 
ICF 
 
Informed consent form 
ICH 
 
International Conference on Harmonisation 
IEC 
 
Independent Ethics Committee 
IMB 
 
Irish Medicines Board 
IMP 
 
Investigational medicinal products 
IMPD  
Investigational medicinal product dossier 
HSE 
 
Health Service Executive 
JTT 
 
Jebson Taylor Hand Function Test 
MS 
 
Multiple Sclerosis 
MSIS-29 
Multiple Sclerosis Impact Scale 29 
MSWS-12 
Multiple Sclerosis Walking Scale 
OCT-2  
Organic Cation Transporter 2 
PI 
 
Principal investigator 
PIL 
 
Patient/subject information leaflet 
PPMS  
Primary Progressive MS 
REC 
 
Research ethics committee 
ROI 
 
Republic of Ireland 
SAE 
 
Serious adverse event 
SAR 
 
Serious adverse reaction 
SmPC  
Summary of product characteristics 
SOP 
 
Standard operating procedure 
SPMS  
Secondary Progressive MS 
SVUH  
St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland 
SUSAR 
Suspected unexpected serious adverse reaction 
T25FW  
Twenty-five foot timed walk 
 

 
8/33 
 
 
 
 
 
 
 
 
 
8.0  INTRODUCTION 
 
8.1 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®. 
 
 
8.2 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 

 
9/33 
 
 
 
 
 
 
 
 
 
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. 
 
 
9.0 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 
 
9.1 PRIMARY OBJECTIVE 
 
The primary objective is to assess the effect of treatment with oral PR-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 EDSS14 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). Scores of the MSIS-29 (physical), MSWS-12 and the Disabilities of the Arm, 
Shoulder and Hand Score (DASH)10 and the Arm Function in Multiple Sclerosis Questionnaire  
(AMSQ)19. 
 
 
9.2 SECONDARY OBJECTIVE 
 
Secondary objectives are: 
 
To assess the effect of treatment with fampridine on walking mobility assessed by the Timed 25 foot 
Walk (T25FW) and the Multiple Sclerosis Walking Scale (MSWS-12)6,7 

 
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To determine whether response or non-response to fampridine by the T25FW can be easily 
determined using self reported changes in the MSWS-12 alone within 4 weeks in the course of active 
therapy  
To determine whether response or non-response to fampridine by the 9HPT or JTT can be easily 
determined using self reported changes in the DASH and AMSQ alone within 4 weeks on the course 
of active therapy  
To determine whether any relation exists between improvement / lack of improvement on the T25FW 
and improvement/ lack of improvement on the 9-HPT or JTT. 
To examine the safety of fampridine in this patient population  
To assess the impact of fampridine on health related quality of life in patients with multiple sclerosis 
(HRQOL) as measured by the SF-36 questionnaire. 
 
9.3 EXPLORATORY OBJECTIVES 
None 
 
 
9.4 PRIMARY AND SECONDARY/ EXPLORATORY ENDPOINTS/OUTCOME MEASURES 
 
Primary endpoint: 
The primary end point will be identifying an upper limb responder to fampridine defined as a patient 
with both of the two “on treatment” 9-HPT assessments (assessments 4 & 5 or 7 & 8) improving 20% 
from the average of the baseline assessments (1, 2 & 3). 
 
Secondary endpoints:  
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. 

 
11/33 
 
 
 
 
 
 
 
 
 
 
 
10.0 TRIAL DESIGN 
 
10.1 GENERAL CONSIDERATIONS 
 
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). 
 
 
Figure 1: Study Schema 
 
 

 
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10.2 SELECTION OF STUDY POPULATION 
 
Overall description of trial subjects 
 
The study will recruit male and female patients between the ages of 18 – 70 years with clinically 
definite primary or secondary progressive multiple sclerosis. Patients will be identified in and 
recruited from the multiple sclerosis clinics in St. Vincent’s University Hospital, Dublin, Ireland. 
 
Inclusion criteria 
 
To be eligible for inclusion, each subject must meet each of the following criteria at Screening (Visit 
and must continue to fulfill these criteria at Baseline (Visit 2).  
 
 
Subjects must be able and willing to give written informed consent and to comply with the 
requirements of this study protocol  
Subjects must be diagnosed with clinically definite SPMS or PPMS and be judged to be in generally 
good health by the investigator based upon the results of the medical history, laboratory tests (liver 
and renal function), physical examination, 12-lead electrocardiogram performed during Screening 
Subjects must be Male or female aged 18-70 at baseline 
Kurtzke EDSS scores in the range 4.0 to 7.0 inclusive 
Evidence of significant upper limb dysfunction as defined by a 9HPT of 15 – 90 seconds (dominant or 
non-dominant hand) 
Female subjects with reproductive capabilities must have a negative serum pregnancy test at baseline 
and agree to using an acceptable form of contraception for the duration of the study (barrier, coil or 
oral contraceptives only). 
 
 
Exclusion criteria 
 
Subjects are excluded from the study if any of the following criteria are met at Screening (Visit 1) or 
at Baseline (Visit 2): 
 
• 
Allergy/sensitivity to study medications or their ingredients 
• 
Female subjects who are pregnant or breast-feeding or considering becoming pregnant during 
the study.  
• 
Subjects unable to provide written informed consent  
• 
Subjects with a history of epilepsy or previous seizures (including provoked seizures). 
• 
Subjects who have a history of drug or alcohol use that, in the opinion of the investigator, 
would interfere with adherence to study requirements. 
• 
Subjects with an AST or ALT ≥ 3 x ULN on liver function tests 
• 
Subjects have clinically significant ECG findings as judged by the investigator, in particular 
evidence of a cardiac conduction defect. 
• 
Significant upper or lower limb arthritis as considered by the investigator to interfere with 
study assessments. 
• 
Significant cognitive impairment as considered by the investigator to interfere with study 
assessments 

 
13/33 
 
 
 
 
 
 
 
 
 
• 
Subjects with clinically significant upper limb ataxia considered by the investigator to 
interfere with ability to complete study outcome measures. 
• 
Patients with mild, moderate or severe renal impairment (creatinine clearance<80ml/min) 
measured by 24-hour urine collection or estimated by the Cockcroft and Gault formula 
• 
Subjects concomitantly using medicinal products that are inhibitors of Organic Cation 
Transporter 2 (OCT2) for example cimetidine 
• 
Concurrent treatment with other medicinal products containing fampridine (4- aminopyridine) 
 
10.3 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 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 and a JTT. T25FW will be recorded and the patients invited to complete 
the MSIS-29, MSWS-12, DASH, AMSQ and SF-36 questionnaires. 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. 
 
 
(See Schedule of Events, page 15) 
 
 
 
Figure 2: Schedule of events 
 

 
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Assessment 
1 
Screenin
g Visit 
2 
Baseline 
Visit 
3 
Base
- 
line 
Visit 
 
4 
Rx 
Phase 1 
 
5 
End 
of 
Rx 
Phase 1 
 
6 
End 
Wash- 
out 
phase 
7 
Rx 
Phase 2 
 
8 
End of 
Rx 
Phase 2 
 
 
9 
End of 2 
week 
washout 
Time 
(start/end week) 
week  1 
(start) 
week 1 
(end) 
week 
2 
(end) 
 
week 6 
(end) 
 
week 10 
(end) 
 
week 
12 
(end) 
 
week 16 
(end) 
week 
20 
(end) 
 
week 22 
(end 
of 
trial) 
Informed consent X 
 
 
 
 
 
 
 
 
Serum pregnancy 
test  
(female subjects) 
X 
 
 
 
 
 
 
 
 
EDSS 
x 
 
 
 
 
 
 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
Receiving 
Medication 
 
No 
No 
Start 
drug 
 
Continu
e drug 
 
Stop 
drug 
Start 
drug 
Continu
e drug 
Stop 
drug 
 
Wash out 
9- HPT 
x 
x 
x 
x 
x 
x 
x 
x 
X 
JTT 
x 
x 
x 
x 
x 
x 
x 
x 
X 
T25FW 
x 
x 
x 
x 
x 
x 
x 
x 
X 
MSIS-29 
x 
 
x 
x 
x 
x 
x 
x 
X 
MSWS-12 
x 
 
x 
x 
x 
x 
x 
x 
X 
DASH 
x 
 
x 
x 
x 
x 
x 
x 
X 
AMSQ 
x 
 
x 
x 
x 
x 
x 
x 
x 
SF-36 
X 
 
X 
X 
X 
X 
X 
X 
X 
Adverse 
event 
recording 
 
 
 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
recording 
X 
 
X 
X 
X 
X 
X 
X 
X 
Study 
Drugs 
dispensed 
 
 
X 
 
 
X 
 
 
 

 
15/33 
 
 
 
 
 
 
 
 
 
 
 
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.  
 
 
10.3.1 Endpoints assessments 
Endpoint assessment will include the 9-HPT; JTT and T25FW test 
 
 

 
16/33 
 
 
 
 
 
 
 
 
 
 
 
10.3.2 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. 
 
 
10.3.3 Method of assigning Subjects to treatment groups  
 
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 

 
17/33 
 
 
 
 
 
 
 
 
 
 
The randomisation sequence was generated on 07/03/2012.  
 
Table 1. Randomisation Groups 
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 

 
18/33 
 
 
 
 
 
 
 
 
 
 
 
Figure 3. Study drug label. 
 
 
FAMPYRA® 10MG TABLETS OR PLACEBO                                
Fampridine 10mg tablets or  placebo 
  
Take ONE tablet TWICE daily                                            
To be taken orally. For clinical trial use only. 
  
Patient 
Name/ID 
No. 
_________________________ 
Date__________ 
  
Product 
Code 
No. 
_________________  
Expiry 
Date 
______________ 
  
Principal Investigator: Dr. C. McGuigan. Trial Sponsor: SVUH 
Site: St. Vincent’s University Hospital. Trial Ref. No. SVUHneur002 
  
  
14 tablets 
  
  
Keep out 
of reach of 
children. 
Store 
at 
room 
temperature 
in 
original 
container. 
  
 
4. 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 

 
19/33 
 
 
 
 
 
 
 
 
 
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. 
 
 
10.4 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.  
 
10.4.1 End of study visits: procedures and assessments:  
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. 
 
 
10.5 DISCONTINUATION/WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
 

 
20/33 
 
 
 
 
 
 
 
 
 
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. 
 
11.0 TREATMENT OF TRIAL SUBJECTS 
 
11.1 DESCRIPTION OF STUDY TREATMENT(S) 
 
Active therapy – Fampyra (fampridine) oral capsules 10 mg BID. (Supplied by Biogen Idec Ltd.) 
Placebo – an identical placebo capsule administered BID will also be used (supplied by Biogen Idec) 
 
11.2 FORMULATION, PACKAGING, AND HANDLING 
 
Fampyra and Fampyra identical placebo are produced in tablet form for twice daily oral use. They 
will be supplied in a box of 14 tablets (one weeks supply). There is no secondary packaging. 
 
 
 
 
 
 
 
 

 
21/33 
 
 
 
 
 
 
 
 
 
 
 
The product label will look as follows: 
 
FAMPYRA® 10MG TABLETS OR PLACEBO                                
Fampridine 10mg tablets or placebo 
  
Take ONE tablet TWICE daily                                            
To be taken orally. For clinical trial use only. 
  
Patient 
Name/ID 
No. 
_________________________ 
Date__________ 
  
Product 
Code 
No. 
_________________  
Expiry 
Date 
______________ 
  
Principal Investigator: Dr. C. McGuigan. Trial Sponsor: SVUH 
Site: St. Vincent’s University Hospital. Trial Ref. No. SVUHneur002 
  
  
14 tablets 
  
  
Keep out 
of reach of 
children. 
Store 
at 
room 
temperature 
in 
original 
container. 
 
 
 
Name and address of supplier of Fampyra and Placebo medication: 
Biogen Idec Ltd. United Drug House,  
Magna Drive,  
Magna Business Park,  
Citywest Road,  
Dublin 24,  
Ireland 
 
Name and Address of Pharmacy who will label the study treatment: 
Pharmacy Department 
St. Vincent’s University Hospital, 
Elm Park, 
Dublin 4, 
Ireland 
 
 
11.3 STORAGE AND DISPOSITION OF STUDY TREATMENTS(S) 
 
The Fampyra and Placebo tablets will be stored on separate shelves of a locked press at room 
temperature in the Pharmacy Department of St. Vincent’s University Hospital until dispensed to 
subjects. Returns will be stored by the study nurse in a secure location in the Neurology department 
until authorised for destruction. 
 
The temperature of study medications will be monitored during shipment to SVUH. On arrival to 
SVUH, temperature will be monitored and recorded daily on a temperature log. Subjects will be 
advised to store the study drug at room temperature. 

 
22/33 
 
 
 
 
 
 
 
 
 
 
The study treatments are for investigational use only and are only to be used within the context of this 
trial. 
 
11.4 ACCOUNTABILITY OF THE STUDY TREATMENT(S) 
 
The investigator is responsible for the control of the treatment under investigation. Adequate records 
for receipt and disposition of the IMP will be maintained. 
The study medication will be supplied to pharmacy by Biogen Idec Ltd. and retrieved at the end of the 
study.  
The investigator will use a standard prescription form and the investigator/research nurse will collect 
the medication from the pharmacy on the day of dosing. 
Maintaining dispensing and return records will assess accountability and subject compliance with 
study treatments.  A master accountability investigational product log will be maintained for each 
product. This will record the total quantity received and dispensed to each subject. Two single subject 
investigational product accountability logs will also be maintained for each subject, one for 
medication dispensed and one for medication returned. 
The study nurse will monitor compliance at each return visit. 
 
Prior consent will be obtained from the study sponsor to allow destruction of returns and unused 
excess stock provided by Biogen Idec Ltd. It will destroyed according to the SVUH Whole Hospital 
Waste Disposal and Management Policy, SVUH HS POL 01, May 2011 and a receipt of destruction 
will be provided to the sponsor. 
 
  
10.5 ASSESSMENT OF COMPLIANCE 
 
The investigator is responsible for ensuring that the study treatment is administered in compliance 
with the protocol. Maintaining dispensing records will assess subject compliance. 
 
 
10.6 OVERDOSE OF STUDY TREATMENT 
 
Patients who overdose will be admitted to SVUH and provided with supportive care. Repeated seizure 
activity will be treated with benzodiazepine, phenytoin, or other appropriate acute anti-seizure 
therapy. 
 
10.7 PRIOR AND CONCOMITANT THERAPY 
 
Any medication, other than the study medication taken during the study will be recorded in the CRF 
from the second baseline visit to the last visit. 
 
Permitted medications/non- investigational medicinal products will include treatments of acute MS 
exacerbations including corticosteroids (high dose IV or short course of oral steroids) and symptom 
therapies such as baclofen. Antibiotics will be permitted for intercurrent infections. 

 
23/33 
 
 
 
 
 
 
 
 
 
 
Prohibited medications: 
Concomitant use of medicinal products that are inhibitors of Organic Cation Transporter 2(OCT2) for 
example cimetidine are prohibited for the duration of the study. Concurrent treatment with other 
medicinal products containing fampridine (4- aminopyridine) is also prohibited. 
 
12.0 SAFETY REPORTING 
 
The safety and tolerability of the IMP will be evaluated throughout the study e.g. by AEs and 
neurological examination. 
 
12.1 DEFINITIONS 
 
12.1.1Adverse event (AE) 
 
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product 
and which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product  
 
12.1.2 Adverse reaction (AR) 
 
All untoward and unintended responses to a medicinal product related to any dose. 
The phrase ‘responses to a medicinal product’ means that a causal relationship between a study 
medication and an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the sponsor as having a 
reasonable suspected causal relationship to the study medication qualify as adverse reactions.   
 
12.1.3 Serious adverse event  
 
Any untoward medical occurrence or affect that at any dose:  
• 
Results in death  
• 
Is life-threatening*  
• 
Requires hospitalisation or prolongation of existing hospitalisation  
• 
Results in persistent or significant disability or incapacity  
• 
Is a congenital anomaly or birth defect 
• 
Important medical events** 
 
 
*Regarding a life-threatening event, this refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event, which hypothetically might have caused death if it 
were more severe.  
 
**Some medical events may jeopardise the subject or may require an intervention to prevent one of the 
above characteristics/consequences. Such events (hereinafter referred to as ‘important medical events’) 
should also be considered as ‘serious’ in accordance with the definition  

 
24/33 
 
 
 
 
 
 
 
 
 
 
12.1.4 Severe adverse events 
 
The term ‘severity’ is used here to describe the intensity of a specific event. This has to be 
distinguished from the term ‘serious.  
 
 
12.1.5 Suspected unexpected serious adverse reactions 
 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. investigator’s brochure for an unauthorised investigational medicinal product or 
summary of product characteristics for an authorised medicinal product. 
 
 
12.2 EVALUATIONS OF AES AND SAES 
 
Seriousness, causality, severity and expectedness will be evaluated. 
 
12.2.1 Assessment of seriousness 
The investigator will make an assessment of seriousness as defined in section 12.1.4. 
 
12.2.2 Assessment of casualty 
All adverse events judged by either the investigator or the sponsor as having a reasonable 
suspected causal relationship to an investigational medicinal product qualifies as adverse 
reactions. 
The sponsor should not downgrade the causality assessment given by the investigator. 
The investigator/sponsor must make an assessment of whether the AE/SAE is likely to be 
related to treatment according to the following definitions: 
Unrelated 
Where an event is not considered to be related to the study medication. 
Possibly 
Although a relationship to the study medication cannot be completely ruled out, the nature of 
the event, the underlying disease, concomitant medication or temporal relationship makes 
other explanations possible. 
Probably 
The temporal relationship and absence of a more likely explanation suggest the event could 
be related to the study medication. 
 
All AEs/SAEs judged as having a reasonable suspected causal relationship (e.g. possibly, 
probably) to the study medication will be considered as ARs/SARs. 
 
All AEs/SAEs judged as being related (e.g. possibly, probably) to an interaction between the 
study medication and another medication will also be considered to be ARs/SAR. 
 
Alternative causes such as natural history of the underlying disease, concomitant therapy, 
other risk factors and the temporal relationship of the event to the treatment should be 
considered. 
 

 
25/33 
 
 
 
 
 
 
 
 
 
12.2.3 Assessment of severity 
 
The investigator will make an assessment of severity for each AE/SAE and record this on the CRF 
according to one of the following categories: 
 
Mild 
An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with every day activities. 
 
Moderate 
An event that is sufficiently discomforting to interfere with normal everyday activities. 
 
Severe 
An event that prevents normal everyday activities. 
  
12.2.4 Assessment of expectedness 
The expectedness of an adverse reaction will be determined by the sponsor according to the 
reference document e.g. the investigator's brochure for a non-authorised investigational 
medicinal product, or the summary of product characteristics for an authorised medicinal 
product, which is used according to the terms and conditions of the marketing authorisation. 
 
12.2.5 Emergency unblinding procedures 
 
The principle investigator should be contacted if emergency unblinding is required. They will be 
provided with a sealed envelope (with a signature and date across the seal) containing the 
randomization code, active product codes and placebo product codes. The envelope may be opened if 
emergency unblinding is required. 
 
12.3 REPORTING PROCEDURES FOR ALL ADVERSE EVENTS 
 
All AEs occurring during the study observed by the investigator or reported by the subject, whether or 
not attributed to the study medication, will be recorded on the CRF. 
 
The following information will be recorded: description, date of onset and end date, severity, and 
assessment of relatedness to the study medication, other suspect medication or device and action 
taken. Follow-up information should be provided as necessary. 
 
AEs considered related to the study medication as judged by an investigator or the sponsor will be 
followed until resolution or until the event is considered stable. All related AEs that result in a 
subject’s withdrawal from the study or are present at the end of the study, should be followed up until 
a satisfactory resolution occurs. 
 
It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient severity to 
require the subject’s removal from treatment. A subject may also voluntarily withdraw from treatment 
due to what he or she perceives as an intolerable AE. If either of these occurs, the subject must 
undergo an end-of-study assessment and be given appropriate care under medical supervision until 
symptoms cease or the condition becomes stable. 
 

 
26/33 
 
 
 
 
 
 
 
 
 
The severity of events will be assessed on the following scale: mild, moderate, and severe. 
 
The investigator will assess the relationship of AEs to the study medication. 
 
Any pregnancy occurring during the clinical study and the outcome of the pregnancy should be 
recorded and followed-up for congenital abnormality or birth defect. 
 
12.4 REPORTING PROCEDURES FOR SERIOUS ADVERSE EVENTS 
 
The investigator will report all serious adverse events immediately to the sponsor except for those that 
the protocol or investigator’s brochure identifies as not requiring immediate reporting. The immediate 
report will be followed by detailed, written reports. The immediate and follow-up reports will identify 
subjects by unique code numbers assigned to the latter. 
 
The investigator will make the immediate report within a very short period of time and under no 
circumstances should this exceed 24 hours following knowledge of the serious adverse event. 
 
All SAE information must be recorded on an SAE forms and sent expeditiously to the sponsor. 
Additional information received for a case (follow-up or corrections to the original case) need to be 
detailed on a new SAE form and sent expeditiously to the sponsor. 
 
The sponsor will keep detailed records of all adverse events, which are reported to him by the 
investigator or investigators. 
 
In cases where reporting is not required immediately the investigator will report within the 
appropriate time frame, taking account of the specificities of the trial and of the serious adverse event, 
as well as possible guidance in the protocol or the IB. 
 
The sponsor will report all SUSARs to the competent authorities (the IMB in Ireland) and the ethics 
committees concerned. Fatal or life-threatening SUSARs must be reported within 7 days.  SUSARs 
which are not fatal and not life threatening are to be reported within 15 days. The sponsor will also 
inform all investigators concerned of relevant information about SUSARs that could adversely affect 
the safety of subjects. 
 
If the initial report is incomplete, e.g. if the sponsor has not provided all the information/assessment 
within seven days, the sponsor will submit a completed report based on the initial information within 
an additional eight days. 
 
If the sponsor receives significant new information on an already reported case, the clock starts again 
at day zero, i.e. the date of receipt of new information. This information will be reported as a follow-
up report within 15 days. 
 
In addition to the expedited reporting above, the sponsor shall submit once a year throughout the 
clinical trial or on request, a safety report to the competent authority (the IMB in Ireland) and ethics 
committees. The annual safety report will be presented in the DSUR format as per ICH guideline E2F 
- Note for guidance on development safety update reports. This is a legal requirement 
 
 

 
27/33 
 
 
 
 
 
 
 
 
 
12.5 DATA SAFETY MONITORING BOARD (DSMB)   
 
Due to the short duration of this study the Trial Steering Committee has determined that a DSMB is 
not needed. 
 
12.6 PREGNANCY 
 
Pregnancy is not considered an AE or SAE however the investigator will collect pregnancy 
information for female trial subjects or female partners of male trial subjects who become pregnant 
while participating in a study. 
 
The investigator will record the information on a Pregnancy Notification Form and submit this to the 
sponsor. 
 
Any pregnancy that occurs in a trial subject or a trial subject’s partner during a trial will be followed 
to outcome.  
 
 
13.0 STATISTICS 
 
 
13.1 DESCRIPTION OF STATISTICAL METHODS 
 
Outcome will be assessed using the Wilcoxon Signed Rank test to establish whether there is a 
difference between the paired ‘on treatment’ outcome measures for each individual. 
 
13.2 DETERMINATION OF SAMPLE SIZE SUBJECTS 
 
Given the previous reports, one would anticipate in this observational study that approximately 30+ % 
of patients would experience a significant (25%) improvement in indices of upper limb and walking 
mobility.  Using a crossover design and treating the observations as paired within individuals, and 
allowing for loss to follow up during the trial, a sample size of 80 (40 in each arm) will be used. 
 
13.3 ANALYSIS SETS 
 
The primary analysis will be an intention to treat analysis. A secondary per protocol analysis will be 
carried out should this differ. 
 
13.4 DEMOGRAPHIC AND BASELINE DISEASE CHARACTERISTICS 
 
Demographic and baseline disease characteristic data will be summarized for each treatment group by 
presenting frequency distributions and descriptive statistics. 
 
13.5 EFFICACY ANALYSIS 
 
Primary efficacy endpoint: 
An upper limb responder to fampridine will be defined as a patient with both of the two “on 
treatment” 9-HPT assessments (assessments 4 & 5 or 7 & 8) improving 20% from the average of the 
baseline assessments (1, 2 & 3). 

 
28/33 
 
 
 
 
 
 
 
 
 
 
Secondary efficacy endpoints: 
a) 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). 
b) A mobility responder to dalfampridine 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. 
c) 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 
d) 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. 
 
13.6 SAFETY ANALYSIS 
 
All AEs occurring in the trial will be recorded and compared across the two groups. Comparison of 
prevalence of SEs between study groups will be expressed as a percentage. 
 
13.7 THE LEVEL OF STATISTICAL SIGNIFICANCE 
 
A significance level of 0.05 will be used for all analyses. 
 
13.8 CRITERIA FOR THE TERMINATION OF THE TRIAL 
 
The trial will be terminated after the last visit of the last participant. 
 
13.9 PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED AND SPURIOUS DATA 
Data will be analysed as is, with the primary analysis being based on complete case data. The amount 
and nature of missing data, together with demographic and baseline summaries of these cases will be 
documented. 
 
 

 
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13.10 PROCEDURE FOR REPORTING ANY DEVIATION(S) FROM THE ORIGINAL STATISTICAL 
PLAN 
 
Any deviations from the statistical plan, and additional analyses will be documented and noted in the 
final report. 
 
14.0 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
Direct access will be granted to authorised representatives from the sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 
 
 
15.0 DATA HANDLING AND RECORD KEEPING 
 
Source documents will be kept in the hospital charts of all participants. Data on CRFs and all other 
hard copies will be locked in filing cabinets in the Department of Neurology, SVUH. Electronic data 
will be held coded on a password-protected database on the H-Drive of the Department of Neurology, 
SVUH accessible only to members of the study group. Pharmacy records will be kept in the Pharmacy 
Department SVUH. Electronic files will be kept on the Pharmacy network drive. 
 
 
15.1 DATA COLLECTION, SOURCE DOCUMENTS AND CASE REPORT FORMS (CRF):  
 
Source documents for this study will include hospital records and procedure reports and data 
collection forms. These documents will be used to enter data on the CRFs. All data entered on CRFs 
must be entered legibly. If an error is made, the error will be crossed through with a single line in such 
a way that the original entry can still be read. The correct entry will then be clearly inserted, and the 
alterations will be initialed and dated by the investigator.  
Data reported on the CRF that are derived from source documents must be consistent with the source 
documents or the discrepancies must be explained. 
All documents will be stored safely in confidential conditions. On all study-specific documents other 
than the signed consent, the subject will be referred to by the study subject identification 
number/code.  
 
15.2 DATA REPORTING  
 
Data will be entered in hospital notes and these will act as source data. In addition a number of CRFs 
will be generated for each study participant. Summary data coded for each participant will be entered 
in a database stored in a coded password protected excel datasheet accessible only to the study 
personnel listed above. A study specific number and / or code in the database will identify subjects. 
The name of any subject or other identifiable information will not be included in any study data 
electronic file. 
 
 
16.0 RETENTION OF ESSENTIAL DOCUMENTS 
 
Essential documents will be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in 

 
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an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer period 
however if required by the applicable regulatory requirements or by an agreement with the sponsor.  
The investigator/institution should agree to retain the trial-related essential documents as required by 
the applicable regulatory requirements and until the sponsor informs the investigator/institution these 
documents are no longer necessary. 
All records and documents will be maintained by the investigator for a period of at least 5 years after 
FDA/European Medicines Agency (EMA) approval of the medicinal product or at least 5 years have 
elapsed since the formal discontinuation of clinical development of the investigational medicinal 
product, whichever is longer. 
 
 
17.0 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
 
This study will be conducted in accordance with the current approved protocol, ICH GCP, relevant 
regulations and standard operating procedures. All study participants hold up-to-date GCP training 
certification. The internal monitor shall ensure excellent quality of data collection and recording is 
maintained. 
 
18.0 AUDITS AND INSPECTIONS 
 
This trial may be subject to internal or external auditing or inspections procedure to ensure adherence 
to GCP. Access to all trial-related documents will be given at that time. 
 
 
19.0 ETHICS 
 
The investigator will have obtained ethics committee approval for the study protocol, PIL and other 
required study documents prior to starting the study. 
Any changes to the protocol will be submitted to the ethics committee. The principle investigator will 
ensure that all aspects of institutional review are conducted in accordance with current governmental 
regulations. Protocol amendments will be subject to the same requirements as the original protocol. A 
progress report will be submitted to the ethics committee at the study end. At the completion or 
termination of the study, the investigational site will submit a closeout letter to the ethics committee. 
 
19.1 DECLARATION OF HELSINKI 
 
The sponsor will ensure that this study is conducted in accordance with the ethical principles that have 
their origins in the Declaration of Helsinki. 
 
19.2 GOOD CLINICAL PRACTICE 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and 2005/28/EC. 
 

 
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19.3 APPROVALS 
 
Required documents including the protocol, informed consent form, subject information leaflet, 
investigational medicinal product dossier, investigators brochure and any other required documents 
will be submitted to a recognized research ethics committee and the competent authority for written 
approval.  
The sponsor will submit and obtain approval from the above parties for substantial amendments to the 
original approved documents. 
 
19. 4 INFORMED CONSENT 
 
The investigator or his/her representative will explain the nature of the study to the subject, and 
answer all questions regarding this study. Prior to any study-related screening procedures being 
performed on the subject, the informed consent statement will be reviewed and signed and dated by 
the subject, the person who administered the informed consent form. 
 
19.5 BENEFITS AND RISKS ASSESSMENT  
 
Fampyra medication has been shown to be safe and effective for improving mobility in patients with 
progressive multiple sclerosis. This study aims to assess whether subjects with upper limb dysfunction 
due to MS also derive a benefit from the medication. The medication already has been shown to have 
a favorable side effect profile and the benefits may significantly improve patients quality of life and 
ability to perform their activities of daily living. 
 
19.6 SUBJECT CONFIDENTIALITY 
 
The trial staff will ensure that the subjects’ anonymity is maintained. Only initials and a subject’s 
identification number on the CRF and any database will identify the subjects. All documents will be 
stored securely. The study will comply with the Data Protection Act. 
 
20.0 FINANCING AND INSURANCE/INDEMNITY 
 
St. Vincent’s University Hospital holds Public Liability (‘negligent harm’) and Clinical Trial (‘non-
negligent harm’) insurance policies, which apply to this trial. 
The Department of Neurology, St. Vincent’s University Hospital, Dublin 4, Ireland will fund the 
study.  
Study medication and placebo will be supplied free of charge by Biogen Idec Ltd. 
 
21.0 CLINICAL STUDY REPORT AND PUBLICATION POLICY 
 
Dr C McGuigan, Prof N Tubridy and Prof M Hutchinson will sign the study report. Papers resulting 
from the study will be published under the authorship of all the personnel listed. 
 
 
 

 
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22.0 REFERENCES 
 
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and muscle tension. Brain 2000;123:171-84. 
 
2. Sheean GL, Murray NM, Rothwell JC, Miller DH, Thompson AJ. An open-labeled clinical 
and electrophysiological study of 3,4 diaminopyridine in the treatment of fatigue in multiple 
sclerosis. Brain 1998;121:967-75.  
 
3. Schwid SR, Petrie MD, McDermott MP, Tierney DS, Mason DH, Goodman AD. Quantitative 
assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple 
sclerosis. Neurology 1997;48:817-21.  
 
4. Goodman AD, Brown TR, Cohen JA, Krupp LB, Schapiro R, Schwid SR, Cohen R, 
Marinucci LN, Blight AR; fampridine MS-F202 Study Group. Dose comparison trial of 
sustained-release fampridine in multiple sclerosis. Neurology 2008;71:1134-41.  
 
5. Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, Marinucci LN, 
Blight AR; fampridine MS-F203 Investigators. Sustained-release oral fampridine in multiple 
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6. Hobart J, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ. Measuring the impact of 
multiple sclerosis on walking ability: the 12-item Multiple Sclerosis Walking Scale  (MSWS-
12). Neurology 2003;60:31-36 
 
7. McGuigan C, Hutchinson M. Confirming the validity and responsiveness of the Multiple 
Sclerosis Walking Scale-12 (MSWS-12). Neurology 2004;62:2103-5.  
 
8. FDA Approval. http://www.accessdata.fda_docs/label/2010/022250s000REMS.pdf. Accessed 
July 2010. 
 
9. Jebsen RH, Taylor N, Trieschmann RB, Trotter MJ, Howard LA. An objective and 
standardized test of hand function. Arch Phys Med Rehabil 1969;50:311-319. 
 
10. Hudak PL, Amadio PC, Bombardier C, & the Upper Limb Collaborative Group (UECG). 
Development of an Upper Extremity Outcome Measure: The DASH (Disabilities of the Arm, 
Shoulder, and the Head). Am J Ind Med 1996; 29:602-608. [Published erratum appears in Am 
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11. Cano SJ, Barrett LE, Zajicek JP, Hobart JC. Beyond the reach of traditional Rasch to evaluate 
the DASH in people with multiple sclerosis. Mult Scler 2011;17:214-222. 
 
12. Hobart J, Lamping D, Fitzpatrick R, Riazi A, Thompson A. The Multiple Sclerosis Impact 
Scale (MSIS-29): a new patient based outcome measure. Brain 2001;124:962-973. 
 

 
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13. McGuigan C, Hutchinson M. The multiple sclerosis impact scale (MSIS-29) is a reliable and 
sensitive measure. J Neurol Neurosurg Psychiatry. 2004;75:266-9. 
 
14. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status 
scale (EDSS). Neurology 1983;33:1444-1452. 
 
15. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an 
international survey. Neurology 1996; 46:907-911. 
 
16. Brazier JE, Harper R, Jones NM et al. Validating the SF-36 health status questionnaire: a new 
outcome measure for primary care. BMJ 1992;305:160-164. 
 
17. Fampyra (Fampridine): summary of opinion - EMA/CHMP/396600/2011. 
www.ema.europa.eu  
 
18. Eriksson M, Ben-Menachem E, Andersen O. Epileptic seizures, cranial neuralgias and 
paroxysmal symptoms in remitting and progressive multiple sclerosis. Mult Scler. 
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19. Mokkink LB, Knol JM, Sonder FA et al. The Arm Function in Multiple Sclerosis 
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