Clinical Trial Results:
A Multicenter, Randomized, Double Blind, Placebo Controlled Study to Assess the Long-Term Efficacy and Safety of Prolonged-Release Fampridine (BIIB041) 10 mg, Administered Twice Daily in Subjects with Multiple Sclerosis (ENHANCE)
Summary
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EudraCT number |
2013-003600-40 |
Trial protocol |
GB LT CZ IT FI BG NL |
Global end of trial date |
11 Feb 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Feb 2017
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First version publication date |
23 Feb 2017
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
218MS305
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02219932 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Biogen
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Sponsor organisation address |
225 Binney Street, Cambridge, Massachusetts,, United States, 02142
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Public contact |
Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
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Scientific contact |
Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
11 Feb 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Feb 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective is to determine whether prolonged-release fampridine (10 mg twice daily) has a clinically meaningful effect on participant-reported walking ability over a 24-week study period.
The secondary objectives are: to determine whether prolonged-release fampridine 10 mg taken twice daily (BID) has a clinically meaningful effect on dynamic and static balance, physical impact of multiple sclerosis (MS), and upper extremity function over a 24-week study period; to evaluate criteria for early assessment of response to fampridine that can predict clinically meaningful benefits in walking ability and balance; to assess the safety and tolerability of prolonged-release fampridine 10 mg twice daily over a 24-week treatment period.
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Protection of trial subjects |
Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Sep 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 164
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Country: Number of subjects enrolled |
Bulgaria: 89
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Country: Number of subjects enrolled |
United Kingdom: 88
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Country: Number of subjects enrolled |
Czech Republic: 75
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Country: Number of subjects enrolled |
United States: 61
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Country: Number of subjects enrolled |
Russian Federation: 44
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Country: Number of subjects enrolled |
Serbia: 32
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Country: Number of subjects enrolled |
Finland: 23
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Country: Number of subjects enrolled |
Lithuania: 23
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Country: Number of subjects enrolled |
Netherlands: 22
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Country: Number of subjects enrolled |
Italy: 15
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Worldwide total number of subjects |
636
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EEA total number of subjects |
499
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
607
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From 65 to 84 years |
29
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 646 participants were enrolled. A single site in Poland was later closed due to serious Good Clinical Practice noncompliance issues observed during study conduct. There were 10 participants randomized at this site (6 to fampridine / 4 to placebo). Data from this site were excluded from all analyses (including the age and country tables). | |||||||||||||||||||||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
636 | |||||||||||||||||||||||||||||||||||||||
Number of subjects completed |
635 | |||||||||||||||||||||||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Randomized but not treated: 1 | |||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer | |||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Study treatment was prepackaged for supply to study sites so that no site personnel would be unblinded in the course of study drug dispensing. Study treatment was stored in a secure location, and accountability for study treatment was the responsibility of the Investigator. To maintain the study blind, treatment assignments were not shared with the subjects, their families, or any member of the study team, either at the study site or at the Sponsor.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||||||||||||||||||||
Arm description |
Placebo twice daily (BID) for up to 24 weeks | |||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo, given orally twice daily (approximately 12 hours apart) for 24 weeks.
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Arm title
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Fampridine 10 mg BID | |||||||||||||||||||||||||||||||||||||||
Arm description |
Prolonged-release fampridine 10 mg BID for up to 24 weeks | |||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fampridine
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Investigational medicinal product code |
BIIB041
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Other name |
dalfampridine, Ampyra, Fampyra, fampridine prolonged-release tablets
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Pharmaceutical forms |
Prolonged-release tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Prolonged-release fampridine (10 mg), given orally twice daily (approximately 12 hours apart) for 24 weeks.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: A total of 646 participants were enrolled. A single site in Poland was later closed due to serious Good Clinical Practice noncompliance issues observed during study conduct. There were 10 participants randomized at this site (6 to fampridine / 4 to placebo). Data from this site were excluded from all analyses (including the age and country tables and subject disposition). |
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo twice daily (BID) for up to 24 weeks | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fampridine 10 mg BID
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Reporting group description |
Prolonged-release fampridine 10 mg BID for up to 24 weeks | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo twice daily (BID) for up to 24 weeks | ||
Reporting group title |
Fampridine 10 mg BID
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Reporting group description |
Prolonged-release fampridine 10 mg BID for up to 24 weeks | ||
Subject analysis set title |
Intent-to-treat population: Placebo
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.
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Subject analysis set title |
Intent-to-treat population: Fampridine 10 mg BID
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.
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End point title |
Proportion of Participants Achieving a Mean Improvement of ≥ 8 Points From Baseline on the Multiple Sclerosis Walking Scale (MSWS-12) Over 24 Weeks | ||||||||||||
End point description |
MSWS-12 is a participant self-assessment of the walking limitations due to MS during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where higher scores indicate greater impact on walking. A responder is defined as a participant with a mean improvement of at least 8 points over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. If a participant has a mean MSWS-12 score of < 0.5 over the double-blind period, and a baseline MSWS-12 score of < 8 points, the participant is counted as a responder. A participant who indicates they cannot walk at all on MSWS-12 during any double-blind visit, and who shows severe disability and an inability to walk on other efficacy assessments is counted as a non-responder. Estimated proportion obtained from binomial proportions.
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End point type |
Primary
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End point timeframe |
Baseline to 24 weeks
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Based on logistic regression, adjusting for baseline MSWS-12 score, baseline TUG speed, age, screening Expanded Disability Status Scale (EDSS) score
and prior aminopyridine. Missing data handled by multiple imputation. Hypothesis testing was performed at the 2-sided 5% significance level overall, with adjustment for testing multiple secondary endpoints.
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Comparison groups |
Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
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Number of subjects included in analysis |
633
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.006 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.61
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.15 | ||||||||||||
upper limit |
2.26 | ||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||
Statistical analysis description |
Based on logistic regression, adjusting for baseline MSWS-12 score, baseline TUG speed, age, screening Expanded Disability Status Scale (EDSS) score
and prior aminopyridine. Missing data handled by multiple imputation. Hypothesis testing was performed at the 2-sided 5% significance level overall, with adjustment for testing multiple secondary endpoints.
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Comparison groups |
Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
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Number of subjects included in analysis |
633
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Risk Difference for Adjusted Proportions | ||||||||||||
Point estimate |
0.104
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.03 | ||||||||||||
upper limit |
0.178 | ||||||||||||
Statistical analysis title |
Statistical Analysis 3 | ||||||||||||
Statistical analysis description |
Based on logistic regression, adjusting for baseline MSWS-12 score, baseline TUG speed, age, screening Expanded Disability Status Scale (EDSS) score
and prior aminopyridine. Missing data handled by multiple imputation. Hypothesis testing was performed at the 2-sided 5% significance level overall, with adjustment for testing multiple secondary endpoints.
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Comparison groups |
Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
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Number of subjects included in analysis |
633
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Relative Risk | ||||||||||||
Point estimate |
1.38
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.06 | ||||||||||||
upper limit |
1.7 |
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End point title |
Proportion of Participants Achieving a Mean Improvement From Baseline of ≥ 15% in Time Up dand Go (TUG) Speed Over 24 Weeks | ||||||||||||
End point description |
TUG is a timed walking test designed to measure gait performance and balance. It measures in seconds the time taken by an individual to stand up from a standard arm chair (approximate seat height of 46 cm [18in], arm height 65 cm [25.6 in]), walk a distance of 3 meters (118 inches, approximately 10 feet), turn, walk back to the chair, and sit down.
A responder is defined as a participant with a mean improvement of at least 15% in TUG speed over 24 weeks compared to baseline. Baseline is defined as the mean of Screening and Day 1 visits. Estimated proportion obtained from binomial proportions. There are 2 TUG tests given, and the average across the 2 tests is used to calculate average speed. Healthy participants below the age of 79 are expected to complete this task in 7-10 seconds (American College of Rheumatology). Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 24
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.
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Comparison groups |
Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
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Number of subjects included in analysis |
633
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.03 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.46
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.04 | ||||||||||||
upper limit |
2.07 | ||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||
Statistical analysis description |
Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.
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Comparison groups |
Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
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Number of subjects included in analysis |
633
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Risk Difference for Adjusted Proportions | ||||||||||||
Point estimate |
0.092
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.009 | ||||||||||||
upper limit |
0.175 | ||||||||||||
Statistical analysis title |
Statistical Analysis 3 | ||||||||||||
Statistical analysis description |
Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.
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Comparison groups |
Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
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Number of subjects included in analysis |
633
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Relative Risk | ||||||||||||
Point estimate |
1.25
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.99 | ||||||||||||
upper limit |
1.51 |
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End point title |
Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Physical Score Over 24 Weeks | ||||||||||||
End point description |
The 29-item MSIS-29 is a participant-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a participant’s perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 (no impact of MS) to 100 (extreme impact of MS); a negative change indicates an improvement in function.
Data are based on a mixed model for repeated measures (MMRM) model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline MSIS-29 physical score and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 24
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
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Number of subjects included in analysis |
633
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
mixed model for repeated measures | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-3.31
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-5.13 | ||||||||||||
upper limit |
-1.5 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.925
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End point title |
Change From Baseline in Berg Balance Scale (BBS) Over 24 Weeks | ||||||||||||
End point description |
The BBS is a widely used assessment tool to identify balance impairment. Functional activities such as reaching, bending, transferring, and standing are evaluated on the test to evaluate balance. Participants are asked to complete 14 tasks that are rated from 0 (cannot perform) to 4 (normal performance) for a total of 56 points. BBS scores range from 0 (poor balance) to 56 (good balance); a positive change indicates improvement.
Data are based on a MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline BBS and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 24
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
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Number of subjects included in analysis |
633
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.141 | ||||||||||||
Method |
mixed model for repeated measures | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
0.41
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.13 | ||||||||||||
upper limit |
0.95 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.277
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End point title |
Change From Baseline in ABILHAND Score Over 24 Weeks | ||||||||||||
End point description |
The ABILHAND Questionnaire measures a participant’s perceived difficulty in performing everyday manual activities in the last 3 months. The participant completes a 56-item questionnaire by estimating their own difficulty or ease in performing each of 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 (poor manual ability) to 100 (good manual ability); a positive change indicates an improvement in manual ability.
Data are based on a MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline ABILHAND and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the Day 1 assessment.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 24
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Notes [1] - subjects evaluable for analysis [2] - subjects evaluable for analysis |
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
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Number of subjects included in analysis |
627
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.197 | ||||||||||||
Method |
mixed model for repeated measures | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
0.74
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.38 | ||||||||||||
upper limit |
1.86 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.573
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Adverse events information
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Timeframe for reporting adverse events |
Collected through follow-up (14 [±3] days following Week 24/Early Termination). Serious adverse events collected from signing of informed consent; adverse events collected from first dose of study treatment.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Fampridine 10mg BID
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Reporting group description |
Prolonged-release fampridine 10 mg BID for up to 24 weeks | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Placebo BID for up to 24 weeks | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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12 Dec 2014 |
- In response to questions by the Committee for Medicinal Products for Human Use about potential biases that might be introduced based on prior AP use, stratification at randomization was added for prior use (yes or no) of any AP (including
fampridine/4-AP and 3,4-DAP in any formulation) to help achieve balance in the numbers of subjects with prior use in each treatment group.
- Enrollment caps were added based on stratification factors, as follows:
- Enrollment of subjects with prior AP use was limited to approximately 10% of the overall study population. This cap was added to mitigate the risk of potential unblinding due to prior treatment.
- Enrollment of subjects with an EDSS score >6 was limited to approximately 35% of the overall study population. This cap was added to ensure that the study would generate data across the range of EDSS scores (4 to 7) and to allow a distribution of EDSS scores among enrolled subjects that is representative of the actual MS patient population treated with prolonged-release fampridine.
- A statement was added that TUG and BBS assessments could not be performed by the same study site personnel.
- The required sequence for multiple tests and assessments at a visit was updated to facilitate the capture of the endpoints in a hierarchical manner.
- Permissible and exclusionary prior and concomitant medications were clarified with respect to alemtuzumab, dimethyl fumarate, and botulinum toxin.
- Clarification was added to contraception requirements and the definitions of childbearing potential, effective contraception (for males and females), and abstinence. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |