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    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
    EudraCT number
    2013-003600-40
    Trial protocol
    GB   LT   CZ   IT   FI   BG   NL  
    Global end of trial date
    11 Feb 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Feb 2017
    First version publication date
    23 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    218MS305
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02219932
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, Massachusetts,, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    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.
    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.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Sep 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 164
    Country: Number of subjects enrolled
    Bulgaria: 89
    Country: Number of subjects enrolled
    United Kingdom: 88
    Country: Number of subjects enrolled
    Czech Republic: 75
    Country: Number of subjects enrolled
    United States: 61
    Country: Number of subjects enrolled
    Russian Federation: 44
    Country: Number of subjects enrolled
    Serbia: 32
    Country: Number of subjects enrolled
    Finland: 23
    Country: Number of subjects enrolled
    Lithuania: 23
    Country: Number of subjects enrolled
    Netherlands: 22
    Country: Number of subjects enrolled
    Italy: 15
    Worldwide total number of subjects
    636
    EEA total number of subjects
    499
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    607
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    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
    Number of subjects started
    636
    Number of subjects completed
    635

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Randomized but not treated: 1
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    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.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo twice daily (BID) for up to 24 weeks
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, given orally twice daily (approximately 12 hours apart) for 24 weeks.

    Arm title
    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
    Investigational medicinal product code
    BIIB041
    Other name
    dalfampridine, Ampyra, Fampyra, fampridine prolonged-release tablets
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prolonged-release fampridine (10 mg), given orally twice daily (approximately 12 hours apart) for 24 weeks.

    Number of subjects in period 1 [1]
    Placebo Fampridine 10 mg BID
    Started
    319
    316
    Completed
    254
    266
    Not completed
    65
    50
         Protocol deviation
    10
    6
         Consent Withdrawn
    11
    6
         Pregnancy
    1
    -
         NotSpecified
    5
    11
         Investigator Decision
    -
    1
         Adverse event, serious fatal
    1
    1
         Adverse event, non-fatal
    23
    21
         Lack of Efficacy (Participant Perception)
    10
    2
         Lost to follow-up
    4
    2
    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).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo twice daily (BID) for up to 24 weeks

    Reporting group title
    Fampridine 10 mg BID
    Reporting group description
    Prolonged-release fampridine 10 mg BID for up to 24 weeks

    Reporting group values
    Placebo Fampridine 10 mg BID Total
    Number of subjects
    319 316 635
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    48.8 ± 10.5 49 ± 9.82 -
    Gender, Male/Female
    Units: Subjects
        Female
    181 187 368
        Male
    138 129 267

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo twice daily (BID) for up to 24 weeks

    Reporting group title
    Fampridine 10 mg BID
    Reporting group description
    Prolonged-release fampridine 10 mg BID for up to 24 weeks

    Subject analysis set title
    Intent-to-treat population: Placebo
    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.

    Subject analysis set title
    Intent-to-treat population: Fampridine 10 mg BID
    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.

    Primary: Proportion of Participants Achieving a Mean Improvement of ≥ 8 Points From Baseline on the Multiple Sclerosis Walking Scale (MSWS-12) Over 24 Weeks

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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.
    End point type
    Primary
    End point timeframe
    Baseline to 24 weeks
    End point values
    Intent-to-treat population: Placebo Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects analysed
    318
    315
    Units: proportion of participants
        number (not applicable)
    0.336
    0.432
    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.
    Comparison groups
    Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.61
    Confidence interval
         level
    95%
         sides
    2-sided
         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.
    Comparison groups
    Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk Difference for Adjusted Proportions
    Point estimate
    0.104
    Confidence interval
         level
    95%
         sides
    2-sided
         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.
    Comparison groups
    Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Relative Risk
    Point estimate
    1.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.06
         upper limit
    1.7

    Secondary: Proportion of Participants Achieving a Mean Improvement From Baseline of ≥ 15% in Time Up dand Go (TUG) Speed Over 24 Weeks

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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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Intent-to-treat population: Placebo Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects analysed
    318
    315
    Units: proportion of participants
        number (not applicable)
    0.347
    0.434
    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.
    Comparison groups
    Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.46
    Confidence interval
         level
    95%
         sides
    2-sided
         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.
    Comparison groups
    Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk Difference for Adjusted Proportions
    Point estimate
    0.092
    Confidence interval
         level
    95%
         sides
    2-sided
         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.
    Comparison groups
    Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Relative Risk
    Point estimate
    1.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.99
         upper limit
    1.51

    Secondary: Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Physical Score Over 24 Weeks

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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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Intent-to-treat population: Placebo Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects analysed
    318
    315
    Units: units on a scale
        least squares mean (standard error)
    -4.68 ± 0.936
    -8 ± 0.911
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    mixed model for repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    -3.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.13
         upper limit
    -1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.925

    Secondary: Change From Baseline in Berg Balance Scale (BBS) Over 24 Weeks

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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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Intent-to-treat population: Placebo Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects analysed
    318
    315
    Units: units on a scale
        least squares mean (standard error)
    1.34 ± 0.284
    1.75 ± 0.278
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.141
    Method
    mixed model for repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.13
         upper limit
    0.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.277

    Secondary: Change From Baseline in ABILHAND Score Over 24 Weeks

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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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Intent-to-treat population: Placebo Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects analysed
    315 [1]
    312 [2]
    Units: units on a scale
        least squares mean (standard error)
    0.75 ± 0.593
    1.49 ± 0.574
    Notes
    [1] - subjects evaluable for analysis
    [2] - subjects evaluable for analysis
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Intent-to-treat population: Placebo v Intent-to-treat population: Fampridine 10 mg BID
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.197
    Method
    mixed model for repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.38
         upper limit
    1.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.573

    Adverse events

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    Adverse events information
    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.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Fampridine 10mg BID
    Reporting group description
    Prolonged-release fampridine 10 mg BID for up to 24 weeks

    Reporting group title
    Placebo
    Reporting group description
    Placebo BID for up to 24 weeks

    Serious adverse events
    Fampridine 10mg BID Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 316 (7.91%)
    21 / 319 (6.58%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 316 (0.63%)
    2 / 319 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian endometrioid carcinoma
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    14 / 316 (4.43%)
    10 / 319 (3.13%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial atrophy
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder empyema
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site infection
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 316 (0.63%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Fampridine 10mg BID Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    100 / 316 (31.65%)
    93 / 319 (29.15%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    22 / 316 (6.96%)
    17 / 319 (5.33%)
         occurrences all number
    39
    26
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    31 / 316 (9.81%)
    31 / 319 (9.72%)
         occurrences all number
    34
    35
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    16 / 316 (5.06%)
    11 / 319 (3.45%)
         occurrences all number
    16
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    15 / 316 (4.75%)
    18 / 319 (5.64%)
         occurrences all number
    15
    19
    Urinary tract infection
         subjects affected / exposed
    40 / 316 (12.66%)
    29 / 319 (9.09%)
         occurrences all number
    53
    32

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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