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Trial registered on ANZCTR


Registration number
ACTRN12613000439741
Ethics application status
Not yet submitted
Date submitted
11/04/2013
Date registered
17/04/2013
Date last updated
17/04/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
A clinical and electrophysiological study of the effects of
4-aminopyridine on upper limb impairment in Multiple Sclerosis
Scientific title
A clinical and electrophysiological study of the effects of
4-aminopyridine on upper limb impairment in Multiple Sclerosis
Secondary ID [1] 282315 0
Nil
Universal Trial Number (UTN)
U1111-1141-7984
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Sclerosis 288857 0
Condition category
Condition code
Neurological 289199 289199 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Temporary withdrawal of modified-release oral fampridine (4-aminopyridine) 10mg twice daily (bd) in patients who are taking the drug, in order for clinical and electrophysiological testing of upper limb function to be carried out and compared on and off the drug. The drug does not require to be weaned prior to withdrawal. Adherence will be monitored by participant self-report.
Intervention code [1] 286929 0
Treatment: Drugs
Comparator / control treatment
Comparison will be made within patients on and off drug. Patients will require to be off drug for a minimum of 10 days prior to "off drug" measurements being made, and "on drug" for a minimum of 10 days. Most patients will then continue on drug indefinitely, depending on response.
Control group
Active

Outcomes
Primary outcome [1] 289310 0
Correlation between clinical (9-hole PEG test, fatigue impact score, manual muscle strength assessment, strength measured using hand-held dynamometer) and electrophysiological findings (i.e. change in motor threshold, motor evoked potential recruitment curves, paired-pulse transcranial magnetic stimulation, central motor conduction time, somatosensory and visual evoked potentials) in patients on compared to off drug.
Timepoint [1] 289310 0
On treatment (patients currently taking treatment prior to enrolement and will restart again once "off treatment" measurements hav been taken) compared to off treatment for a minimum duration of 10 days.

NB Patients will be enrolled into the trial at a screening visit. They will attend for three additional visits over the course of the study, and the examiner will not know whether patients are currently on or off medication. This will be managed by the study co-ordinator in conjunction with the patient. Therefore some patients will be studied initially "ON" drug and subsequently come off drug, be re-studied again after being off drug for at least 10 days; subsequently patients will resume drug and be studied again (after a minumum of 10 days). Thus the order of testing (ON, OFF, ON; OFF, ON, ON; ON, ON, OFF) will vary between patients without the examiner's knowledge.
Secondary outcome [1] 302205 0
Change in upper extremity manual muscle strength assessed by an examining neurologist and measured using a hand-held dynamometer.
Timepoint [1] 302205 0
On treatment (patients currently taking treatment prior to enrolement and will restart again once "off treatment" measurements hav been taken) compared to off treatment for a minimum duration of 10 days.

NB Patients will be enrolled into the trial at a screening visit. They will attend for three additional visits over the course of the study, and the examiner will not know whether patients are currently on or off medication. This will be managed by the study co-ordinator in conjunction with the patient. Therefore some patients will be studied initially "ON" drug and subsequently come off drug, be re-studied again after being off drug for at least 10 days; subsequently patients will resume drug and be studied again (after a minumum of 10 days). Thus the order of testing (ON, OFF, ON; OFF, ON, ON; ON, ON, OFF) will vary between patients without the examiner's knowledge.
Secondary outcome [2] 302206 0
Change in sensory discrimination capacity. Objective clinical measurement of sensory impairment will be obtained using standard indices of texture discrimination (Fabric Matching Test), limb position sense (Wrist Position Sense Test) and tactile object recognition (functional Tactile Object Recognition Test).
Timepoint [2] 302206 0
On treatment (patients currently taking treatment prior to enrolement and will restart again once "off treatment" measurements hav been taken) compared to off treatment for a minimum duration of 10 days.

NB Patients will be enrolled into the trial at a screening visit. They will attend for three additional visits over the course of the study, and the examiner will not know whether patients are currently on or off medication. This will be managed by the study co-ordinator in conjunction with the patient. Therefore some patients will be studied initially "ON" drug and subsequently come off drug, be re-studied again after being off drug for at least 10 days; subsequently patients will resume drug and be studied again (after a minumum of 10 days). Thus the order of testing (ON, OFF, ON; OFF, ON, ON; ON, ON, OFF) will vary between patients without the examiner's knowledge.
Secondary outcome [3] 302207 0
Change in modified fatigue impact scale score
Timepoint [3] 302207 0
On treatment (patients currently taking treatment prior to enrolement and will restart again once "off treatment" measurements hav been taken) compared to off treatment for a minimum duration of 10 days.

NB Patients will be enrolled into the trial at a screening visit. They will attend for three additional visits over the course of the study, and the examiner will not know whether patients are currently on or off medication. This will be managed by the study co-ordinator in conjunction with the patient. Therefore some patients will be studied initially "ON" drug and subsequently come off drug, be re-studied again after being off drug for at least 10 days; subsequently patients will resume drug and be studied again (after a minumum of 10 days). Thus the order of testing (ON, OFF, ON; OFF, ON, ON; ON, ON, OFF) will vary between patients without the examiner's knowledge.
Secondary outcome [4] 302208 0
Change in visual acuity assessed using a Snellen Chart
Timepoint [4] 302208 0
On treatment (patients currently taking treatment prior to enrolement and will restart again once "off treatment" measurements hav been taken) compared to off treatment for a minimum duration of 10 days.

NB Patients will be enrolled into the trial at a screening visit. They will attend for three additional visits over the course of the study, and the examiner will not know whether patients are currently on or off medication. This will be managed by the study co-ordinator in conjunction with the patient. Therefore some patients will be studied initially "ON" drug and subsequently come off drug, be re-studied again after being off drug for at least 10 days; subsequently patients will resume drug and be studied again (after a minumum of 10 days). Thus the order of testing (ON, OFF, ON; OFF, ON, ON; ON, ON, OFF) will vary between patients without the examiner's knowledge.

Eligibility
Key inclusion criteria
Patients with multiple sclerosis who are currently taking modified release fampridine 10mg bd and who are willing to stop the drug for at least 10 days in order to permit measurements to be taken and compared on and off drug; preserved cognitive function permitting informed consent for participation.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
The following are contraindications to fampridine therapy: history of seizures or epilepsy; hypersensitivity to fampridine; moderate/severe renal impairment; pregnancy; current or recent (60 days) MS relapse; alternative likely cause for upper limb impairment (e.g. peripheral neuropathy, injury); current or recent (60 days) therapy with corticosteroids; current therapy with benzodiazepines; recent (within 60 days) addition of new therapy for multiple sclerosis including disease-modifying therapies and symptomatic therapies.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients will already be taking fampridine and will be asked to cease treatment for at least 10 days. Three sets of measurements will be made, two while on treatment and one while off treatment. Measurements will include clinical tests of upper limb function (including 9-hole PEG test, sensory discrimination testing) and electrical tests of nerve function including evoked potentials and transcranial magnetic stimulation. The patient will know whether they are taking the drug or not but the tester will be blinded.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
The electrophysiological studies and clinical assessments will be assessed using repeated measures ANOVA. Correlations between changes in electrophysiology parameters and performance on the 9-hole peg test will be examined using Pearson correlation coefficients. One-way ANOVA will be used to compare the measures at baseline between fampridine responders and non-responders. This will be repeated after medication. Post hoc analysis with pairwise paired t test and Bonferroni correction will be used to compare all significant interactions. This study is designed as an adjunct to a placebo-controlled clinical trial of fampridine in upper limb function (ACTRN12613000331730) for which a sample size calculation has been included (40 patients). The magnitude of effects of fampridine on upper limb function (clinically or electrophysiologically) has not previously been systematically studied. Therefore the data in the current study may augment those of the associated study. In addition, the patient pool of the current study is limited to patients already taking fampridine, of whom there are around 40-50 in our service, hence the target number of 30 patients which has been chosen.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
13/05/2013
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 871 0
Austin Health - Austin Hospital - Heidelberg

Funding & Sponsors
Funding source category [1] 287076 0
Government body
Name [1] 287076 0
National Health and Medical Research Council - funding the study doctor via a postgraduate scholarship.
Country [1] 287076 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road
Heidelberg
VIC 3084
Country
Australia
Secondary sponsor category [1] 285851 0
None
Name [1] 285851 0
Address [1] 285851 0
Country [1] 285851 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 289091 0
Austin Health Ethics Committee
Ethics committee address [1] 289091 0
145 Studley Road
Heidelberg
VIC 3084
Ethics committee country [1] 289091 0
Australia
Date submitted for ethics approval [1] 289091 0
29/01/2013
Approval date [1] 289091 0
Ethics approval number [1] 289091 0

Summary
Brief summary
Modified-release fampridine is licensed in Australia for the symptomatic treatment of walking disability in multiple sclerosis (MS). However, many patients with MS have reported beneficial effects on other areas such as fatigue, vision and upper limb function. These benefits have not been formally studied in a trial. In addition, it is not known how modified-release fampridine works and why it seems to work better in some people than others.
Electrophysiological techniques such as nerve conduction studies, evoked potentials and transcranial magnetic stimulation can be used to study the nervous system and the effects of drugs on it. These techniques can be used to identify where particular drugs might exert their effect and help to uncover more information about how the drugs work, with the eventual aim of developing new symptomatic treatments for MS. The aim of this study is to use these techniques to examine the nervous system in study participants on and off fampridine and to compare the findings between responders and non-responders to the drug.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 39206 0
Prof Richard Macdonell
Address 39206 0
Austin Health
145 Studley Road
Heidelberg
VIC 3084
Country 39206 0
Australia
Phone 39206 0
+61 3 94965529
Fax 39206 0
Email 39206 0
richard.macdonell@austin.org.au
Contact person for public queries
Name 39207 0
Dr Marion Simpson
Address 39207 0
Austin Health
145 Studley Road
Heidelberg
VIC 3084
Country 39207 0
Australia
Phone 39207 0
+61 3 94965529
Fax 39207 0
Email 39207 0
marion.simpson@austin.org.au
Contact person for scientific queries
Name 39208 0
Dr Marion Simpson
Address 39208 0
Austin Health
145 Studley Road
Heidelberg
VIC 3084
Country 39208 0
Australia
Phone 39208 0
+61 3 94965529
Fax 39208 0
Email 39208 0
marion.simpson@austin.org.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
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Documents added automatically
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