Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43881   clinical trials with a EudraCT protocol, of which   7295   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Estudio multicéntrico de fase 3 de retirada aleatorizada, doble ciego y controlado con placebo, seguido de un periodo abierto de extensión para evaluar la eficacia y la seguridad del fosfato de amifampridina (fosfato de 3,4-diaminopiridina) en pacientes con el síndrome miasténico de Lambert-Eaton (LEMS) A Phase 3, Multicenter, Double-blind, Placebo-controlled Randomized Discontinuation Study Followed by an Open-label Extension Period to Evaluate the Efficacy and Safety of Amifampridine Phosphate (3,4-Diaminopyridine Phosphate) in Patients with Lambert-Eaton Myasthenic Syndrome (LEMS)

    Summary
    EudraCT number
    		 2010-021850-20
    Trial protocol
    		 DE   ES   IT   HU   CZ   BG  
    Global end of trial date
    08 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Oct 2017
    First version publication date
    21 Oct 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    LMS-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01377922
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Catalyst Pharmaceuticals, Inc.
    Sponsor organisation address
    335 Alhambra Circle, Suite 1250, Coral Gables, United States, 33134
    Public contact
    Head of Regulatory, Catalyst Pharmaceuticals, Inc., 1 305.420.3200, gingenito@catalystpharma.com
    Scientific contact
    Head of Regulatory, Catalyst Pharmaceuticals, Inc., 1 305.420.3200, gingenito@catalystpharma.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
    10 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study (LMS-002) was to evaluate the efficacy and safety, including the long-term efficacy (at least 91 days of previous amifampridine treatment) and safety (2-year, Open-label Long-term Safety), of amifampridine as a symptomatic treatment for patients with LEMS. This study was the first, randomized, placebo-controlled clinical efficacy study with amifampridine phosphate in patients with LEMS.
    Protection of trial subjects
    Rescue treatment was provided to patients who experienced treatment failure as defined by meeting at least 1 of the following criteria: became non-ambulatory (after having been ambulatory at Screening), demonstrated an increase (worsening) in QMG score by >5 points, developed respiratory failure. Rescue Visit 1 and the confirmatory Rescue Visit 2 were performed as soon as a patient was identified as potentially requiring open-label amifampridine rescue treatment. Rescue treatment could include open-label amifampridine at a dose level determined by the investigator. Anti-tumor, immunologic, or symptomatic treatment for LEMS could be administered as determined by the investigator; however, immunosuppressives that lowered the seizure threshold (eg, cyclosporine, tacrolimus) or other aminopyridines were not permitted in combination with amifampridine.
    Background therapy
    		 In addition to amifampridine, patients received best supportive care (BSC) treatment as determined by the investigator using concomitant medications permitted by protocol, which were as follows: (1) selected oral immunosuppressants (eg, prednisone or other corticosteroids; azathioprine, mycophenolate) and (2) peripherally acting cholinesterase inhibitors (eg, pyridostigmine).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Spain: 2
    Worldwide total number of subjects
    54
    EEA total number of subjects
    15
    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)
    39
    From 65 to 84 years
    14
    85 years and over
    1

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 15 sites in 10 countries, including Argentina (1 site), Czech Republic (1 site), France (1 site), Germany (1 site), Hungary (1 site), Poland (1 site), Russia (1 site), Serbia (1 site), Spain (1 site), and the United States (6 sites).

    Pre-assignment
    Screening details
    		 After providing informed consent, patients underwent a screening evaluation to determine study eligibility. Efficacy and safety assessments were performed for all patients during screening. A total of 74 patients were screened and had data on the database. Twenty did not meet all eligibility criteria and were excluded from the study.

    Pre-assignment period milestones
    Number of subjects started
    		 54
    Intermediate milestone: Number of subjects
    Amifampridine phosphate titration: 54
    Intermediate milestone: Number of subjects
    Minimum 91 days of amifampridine: 54
    Number of subjects completed
    		 38

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Directly go to Long-term Safety phase: 2
    Reason: Number of subjects
    		 Adverse event, non-fatal: 5
    Reason: Number of subjects
    		 Personal decision: 3
    Reason: Number of subjects
    		 Lack of efficacy: 2
    Reason: Number of subjects
    		 Physician decision: 1
    Reason: Number of subjects
    		 Intermittent heart block: 1
    Reason: Number of subjects
    		 Did not meet QMG criterion: 1
    Reason: Number of subjects
    		 Abnormal ECG: 1
    Period 1
    Period 1 title
    Discontinuation-Treatment Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    A centralized randomization method (interactive voice/web response system [IXRS]) was used to assgin one of the blinded treatments. For patients randomized to treatment discontinuation, blinding was maintained by providing patients with daily dose packets containing a constant number of tablets, which were a combination of placebo and amifampridine phosphate. The same investigator did not perform both the CMAP and QMG tests on an individual patient.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Continuation of Treatment
    Arm description
    		 Amifampridine phosphate at a dose established during the open-label pre-assignment phase was continued for a total of 14 days (7 day of the "discontinuation phase" plus 7 days of the "treatment phase").
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amifampridine phosphate
    Investigational medicinal product code
    Other name
    3,4-diaminopyridine phosphate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All patients were required to be on a minimum of 30 mg/day of amifampridine to start the "discontinuation-treatment phase"; they had to continue the amifampridine treatment at least for 91 consecutive and have at least 7 consecutive days of stable open-label amifampridine dosing (ie, the same total daily dose and dose regimen) immediately before entering into "discontinuation-treatment phase". After randomization, amifampridine phosphate was continued for 7 days (at a dose established during Open-label pre-assignment period). All doses of study treatment were taken at home and with food.

    Arm title
    		 Discontinuation of Treatment
    Arm description
    		 The discontinuation of treatment involved downward titration of amifampridine phosphate dose to 0 mg beginning on Day 2 of the "discontinuation phase" by substituting an increasing proportion of matching placebo tablets. On Day 7 (end of the "discontinuation phase"), all tablets were placebo. Patients for whom the dose was titrated downward to placebo in the "discontinuation phase" remained on placebo for 7 days (Treatment phase).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Amifampridine phosphate
    Investigational medicinal product code
    Other name
    3,4-diaminopyridine phosphate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All patients were required to be on a minimum of 30 mg/day of amifampridine to start the "discontinuation-treatment phase"; they had to continue the amifampridine treatment at least for 91 consecutive and have at least 7 consecutive days of stable open-label amifampridine dosing (ie, the same total daily dose and dose regimen) immediately before entering into "discontinuation-treatment phase". After randomization, amifampridine phosphate was continued for 7 days (at a dose established during Open-label pre-assignment period). All doses of study treatment were taken at home and with food.

    Number of subjects in period 1 [1]
    		Continuation of Treatment Discontinuation of Treatment
    Started
    16
    22
    Entry in the "Treatment phase"
    16
    21
    Completed
    16
    21
    Not completed
    0
    1
         Rescue treatment required
    -
    1
    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: Sixteen patients did not succefully complete the pre-assignment period and were excluded from study prior to randomization.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Continuation of Treatment
    Reporting group description
    		 Amifampridine phosphate at a dose established during the open-label pre-assignment phase was continued for a total of 14 days (7 day of the "discontinuation phase" plus 7 days of the "treatment phase").

    Reporting group title
    Discontinuation of Treatment
    Reporting group description
    		 The discontinuation of treatment involved downward titration of amifampridine phosphate dose to 0 mg beginning on Day 2 of the "discontinuation phase" by substituting an increasing proportion of matching placebo tablets. On Day 7 (end of the "discontinuation phase"), all tablets were placebo. Patients for whom the dose was titrated downward to placebo in the "discontinuation phase" remained on placebo for 7 days (Treatment phase).

    Reporting group values
    		 Continuation of Treatment Discontinuation of Treatment Total
    Number of subjects
    		 16 22 38
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 13 18 31
        From 65-84 years
    		 3 3 6
        85 years and over
    		 0 1 1
        Not recorded
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 53 (25 to 67) 56.5 (21 to 88) -
    Gender categorical
    Units: Subjects
        Female
    		 9 14 23
        Male
    		 7 8 15
        Not recorded
    		 0 0 0
    Number of patients taking amifampridine immediately prior to enrollment
    Units: Subjects
        Yes
    		 3 7 10
        No
    		 13 15 28
    Number of continuous days of amifampridine exposure prior to enrollment
    Units: days
        median (full range (min-max))
    		 365 (365 to 5700) 630 (166 to 4457) -
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set consisted of all randomized patients who received at least 1 dose of IP (amifampridine phosphate or placebo) in Part 2-discontinuation phase and who had at least one post baseline efficacy assessment. Patients were analyzed as randomized.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled patients (ie, entered in the open-label pre-assignment phase) who received at least 1 dose of study drug, and had any posttreatment safety information collected, were included in the safety analyses. Patients were analyzed as treated.

    Subject analysis set title
    Safety analysis Extension set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients who had completed the pre-assignment period, discontinuation phase, and treatment phase; patients who had received rescue treatment with amifampridine phosphate during discontinuation and treatment phase; and patients participating in the pre-assignment period who had not had the opportunity to establish 7 days of stable amifampridine phosphate dosing could participate in the open-label, long term safety study. A total of 40 patients were enrolled into the open-label, long term safety study. This included all 38 patients, who participated in the discontinuation and treatment phases, and 2 patients who rolled over directly from the pre-assigment period.

    Subject analysis sets values
    		 Full analysis set Safety analysis set Safety analysis Extension set
    Number of subjects
    38
    53
    40
    Age categorical
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
        85 years and over
        Not recorded
    Age continuous
    Units: years
        median (full range (min-max))
    54.0 (21 to 88)
    55 (20 to 88)
    54.0 (21 to 88)
    Gender categorical
    Units: Subjects
        Female
    23
    35
    24
        Male
    15
    18
    16
        Not recorded
    0
    0
    0
    Number of patients taking amifampridine immediately prior to enrollment
    Units: Subjects
        Yes
        No
    Number of continuous days of amifampridine exposure prior to enrollment
    Units: days
        median (full range (min-max))

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Continuation of Treatment
    Reporting group description
    		 Amifampridine phosphate at a dose established during the open-label pre-assignment phase was continued for a total of 14 days (7 day of the "discontinuation phase" plus 7 days of the "treatment phase").

    Reporting group title
    Discontinuation of Treatment
    Reporting group description
    		 The discontinuation of treatment involved downward titration of amifampridine phosphate dose to 0 mg beginning on Day 2 of the "discontinuation phase" by substituting an increasing proportion of matching placebo tablets. On Day 7 (end of the "discontinuation phase"), all tablets were placebo. Patients for whom the dose was titrated downward to placebo in the "discontinuation phase" remained on placebo for 7 days (Treatment phase).

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set consisted of all randomized patients who received at least 1 dose of IP (amifampridine phosphate or placebo) in Part 2-discontinuation phase and who had at least one post baseline efficacy assessment. Patients were analyzed as randomized.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled patients (ie, entered in the open-label pre-assignment phase) who received at least 1 dose of study drug, and had any posttreatment safety information collected, were included in the safety analyses. Patients were analyzed as treated.

    Subject analysis set title
    Safety analysis Extension set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients who had completed the pre-assignment period, discontinuation phase, and treatment phase; patients who had received rescue treatment with amifampridine phosphate during discontinuation and treatment phase; and patients participating in the pre-assignment period who had not had the opportunity to establish 7 days of stable amifampridine phosphate dosing could participate in the open-label, long term safety study. A total of 40 patients were enrolled into the open-label, long term safety study. This included all 38 patients, who participated in the discontinuation and treatment phases, and 2 patients who rolled over directly from the pre-assigment period.

    Primary: Change in QMG score from baseline to Day 14

    		 Close Top of page
    End point title
    		 Change in QMG score from baseline to Day 14
    End point description
    The QMG is a physician-rated test including 13 assessments such as facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. The FDA accepted this endpoint along with SGI as coprimary endpoints, as part of its acceptance of the statistical analysis plan (SAP) for this study. A mixed-effect model repeated measures (MMRM) was used to analyze each component of the coprimary endpoint. The primary contrast was a comparison of the change from baseline in the QMG scores and SGI scores of those assigned to amifampridine phosphate to those assigned to placebo at Day 14. The treatment groups were compared at Day 14 using both QMG score and SGI score.
    End point type
    Primary
    End point timeframe
    From day 1 to day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: QMC score
        arithmetic mean (standard deviation)
    0.3 ± 2.6
    2.2 ± 2.93
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline QMG score as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Discontinuation of Treatment v Continuation of Treatment
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0452 [1]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 0
    Notes
    [1] - The p-values was determined using a permutation test to estimate the effect of treatment on the mean differences in the primary efficacy endpoints (QMG and SGI scores) on Day 14 under strong test conditions. Significant at 5% level.

    Primary: Change in SGI score from baseline to Day 14

    		 Close Top of page
    End point title
    		 Change in SGI score from baseline to Day 14
    End point description
    The SGI is a 7-point scale on which the patients rated their global impression of the effects of the study treatment (1 = Terrible; 2 = Mostly Dissatisfied; 3 = Mixed; 4 = Partially Satisfied; 5 = Mostly Satisfied; 6 = Pleased; 7 = Delighted). The FDA accepted this endpoint along with QMG as coprimary endpoints, as part of its acceptance of the statistical analysis plan (SAP) for this study. A mixed-effect model repeated measures (MMRM) was used to analyze each component of the coprimary endpoint. The primary contrast was a comparison of the change from baseline in the QMG scores and SGI scores of those assigned to amifampridine phosphate to those assigned to placebo at Day 14. The treatment groups were compared at Day 14 using both QMG score and SGI score.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: Score
        arithmetic mean (standard deviation)
    -0.7 ± 1.82
    -2.7 ± 2.29
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    Ls was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline QMG score as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0028 [2]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 3
    Notes
    [2] - The p-values was determined using a permutation test to estimate the effect of treatment on the mean differences in the primary efficacy endpoints (QMG and SGI scores) on Day 14 under strong test conditions. Significant at 1% level.

    Secondary: CGI-I Score at Day 14

    		 Close Top of page
    End point title
    		 CGI-I Score at Day 14
    End point description
    The CGI-I captured the investigator’s global impression of improvement or worsening from baseline status. The 7-point scale was scored by the investigator (1 = Very much improved; 2 = Much improved; 3 = Minimally Improved; 4 = No Change; 5 = Minimally Worse; 6 = Much Worse; 7 = Very Much Worse) based on changes in symptoms, behavior, and functional abilities. The CGI-I scale measurement on Day 14 was considered. CGI-I scale was analyzed by using a near identical mixed-model effects as used for the coprimary endpoints; however, there was no covariate for baseline value in the model.
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: score
        arithmetic mean (standard deviation)
    3.6 ± 1.5
    4.8 ± 1.45
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0267 [3]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 -0.1
    Notes
    [3] - Pairwise contrast at Day 14 from MMRM model. Significant at 5%

    Secondary: Change in T25FW walking speed from baseline to Day 14

    		 Close Top of page
    End point title
    		 Change in T25FW walking speed from baseline to Day 14
    End point description
    The T25FW test, a component of the Multiple Sclerosis Functional Composite, was a quantitative mobility and leg function performance test based on a timed 25-foot walk. The changes in the T25FW walking speed (feet/minute) from double-blind baseline (Part 2, Day 1) to Day 14 (end of Part 3) were analyzed using the same mixed-effects model used for the coprimary efficacy endpoints, but with double-blind baseline T25FW walking speed as the covariate.
    End point type
    Secondary
    End point timeframe
    From day 1 to day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: feet/minute
        arithmetic mean (standard deviation)
    -1.46 ± 52.5
    -10.4 ± 53.1
    Statistical analysis title
    		 Difference in LS means (amifampridine-placeo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline T25FW walking speed as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6274 [4]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    8.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.77
         upper limit
    		 43.79
    Notes
    [4] - Pairwise contrast at Day 14 from MMRM model.

    Other pre-specified: Change in QMG Scores from baseline to Day 8

    		 Close Top of page
    End point title
    		 Change in QMG Scores from baseline to Day 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: score
        arithmetic mean (standard deviation)
    0.1 ± 1.24
    3.6 ± 3.06
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline QMG score as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Discontinuation of Treatment v Continuation of Treatment
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.9
         upper limit
    		 -1.9
    Notes
    [5] - Significant at 0.1% level

    Other pre-specified: Change in QMG Scores for the Arms Subdomain from baseline to Day 8

    		 Close Top of page
    End point title
    		 Change in QMG Scores for the Arms Subdomain from baseline to Day 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: score
        arithmetic mean (standard deviation)
    0 ± 0
    1.2 ± 1.15
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline QMG Subdomains Arms score as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 -0.6
    Notes
    [6] - Pairwise contrast from MMRM model. Significant at 0.1% level.

    Other pre-specified: Change in QMG Subdomain Arms Scores from Baseline to Day 14

    		 Close Top of page
    End point title
    		 Change in QMG Subdomain Arms Scores from Baseline to Day 14
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: score
        arithmetic mean (standard deviation)
    0.3 ± 0.93
    0.9 ± 1.09
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0486 [7]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0
    Notes
    [7] - Pairwise contrast from MMRM model. Significant at 5% level.

    Other pre-specified: Change in QMG Subdomain Legs Scores from Baseline to Day 8

    		 Close Top of page
    End point title
    		 Change in QMG Subdomain Legs Scores from Baseline to Day 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: score
        arithmetic mean (standard deviation)
    0.3 ± 0.68
    0.7 ± 1.35
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1508 [8]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 0.2
    Notes
    [8] - Pairwise contrast from MMRM model

    Other pre-specified: Change in QMG Subdomain Legs Scores from Baseline to Day 14

    		 Close Top of page
    End point title
    		 Change in QMG Subdomain Legs Scores from Baseline to Day 14
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: score
        arithmetic mean (standard deviation)
    -0.1 ± 0.93
    0.6 ± 1.16
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0554 [9]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0
    Notes
    [9] - Pairwise contrast from MMRM model

    Other pre-specified: Change in CMAP Amplitude from Baseline to Day 8

    		 Close Top of page
    End point title
    		 Change in CMAP Amplitude from Baseline to Day 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: mV
        arithmetic mean (standard deviation)
    0 ± 1.2
    -1.6 ± 1.82
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline value as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0065 [10]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 2.6
    Notes
    [10] - Pairwise contrast from MMRM model

    Other pre-specified: Change in CMAP Amplitude from Baseline to Day 14

    		 Close Top of page
    End point title
    		 Change in CMAP Amplitude from Baseline to Day 14
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: mV
        arithmetic mean (standard deviation)
    -0.7 ± 1.75
    -1 ± 2.2
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline value as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6398 [11]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1.6
    Notes
    [11] - Pairwise contrast from MMRM model

    Other pre-specified: Percentage Change in CMAP Amplitude between First and Fifth CMAP in the First Series of 3 Hz Stimuli at Day 8

    		 Close Top of page
    End point title
    		 Percentage Change in CMAP Amplitude between First and Fifth CMAP in the First Series of 3 Hz Stimuli at Day 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: mV
        arithmetic mean (standard deviation)
    -0.1 ± 6.53
    -4.5 ± 11.06
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline value as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1131 [12]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 11.1
    Notes
    [12] - Pairwise contrast from MMRM model

    Other pre-specified: Percentage Change in CMAP Amplitude between First and Fifth CMAP in the First Series of 3 Hz Stimuli at Day 14

    		 Close Top of page
    End point title
    		 Percentage Change in CMAP Amplitude between First and Fifth CMAP in the First Series of 3 Hz Stimuli at Day 14
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: mV
        arithmetic mean (standard deviation)
    0.3 ± 10.43
    0.7 ± 52.42
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline value as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9928 [13]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.6
         upper limit
    		 26.8
    Notes
    [13] - Pairwise contrast from MMRM model

    Other pre-specified: Percentage Change in Amplitude Between First CMAP in the First Series of 3 Hz Stimuli and the Single CMAP Following Maximum Voluntary Contraction at Day 8

    		 Close Top of page
    End point title
    		 Percentage Change in Amplitude Between First CMAP in the First Series of 3 Hz Stimuli and the Single CMAP Following Maximum Voluntary Contraction at Day 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: mV
        arithmetic mean (standard deviation)
    -4.3 ± 338.81
    82.4 ± 112.82
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline value as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7117 [14]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -29.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -187.5
         upper limit
    		 129.3
    Notes
    [14] - Pairwise contrast from MMRM model

    Other pre-specified: Percentage Change in Amplitude Between First CMAP in the First Series of 3 Hz Stimuli and the Single CMAP Following Maximum Voluntary Contraction at Day 14

    		 Close Top of page
    End point title
    		 Percentage Change in Amplitude Between First CMAP in the First Series of 3 Hz Stimuli and the Single CMAP Following Maximum Voluntary Contraction at Day 14
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: mV
        arithmetic mean (standard deviation)
    -30.3 ± 402.2
    152.7 ± 377.05
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline value as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2923 [15]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -127.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -369.5
         upper limit
    		 114.5
    Notes
    [15] - Pairwise contrast from MMRM model

    Other pre-specified: CGI-I Scores at Day 8

    		 Close Top of page
    End point title
    		 CGI-I Scores at Day 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: score
        arithmetic mean (standard deviation)
    3.5 ± 0.97
    4.6 ± 1.53
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction as fixed effects and patient as a random effect. The model assumed time effect to be random between patients
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017 [16]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 -0.2
    Notes
    [16] - Pairwise contrast at Day 8 from MMRM model

    Other pre-specified: Change in SGI Scores from Baseline to Day 8

    		 Close Top of page
    End point title
    		 Change in SGI Scores from Baseline to Day 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: score
        arithmetic mean (standard deviation)
    -0.3 ± 0.68
    -2.4 ± 2.24
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction and double-blind baseline SGI score as fixed effects and patient as a random effect. The model assumed time effect to be random between patients
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [17]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 3.1
    Notes
    [17] - Pairwise contrast at Day 8 from MMRM model

    Other pre-specified: Change in CGI-S Scores from Baseline to Day 8

    		 Close Top of page
    End point title
    		 Change in CGI-S Scores from Baseline to Day 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: score
        arithmetic mean (standard deviation)
    -0.1 ± 0.25
    0.7 ± 1.32
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline CGI-S score as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0537 [18]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 0
    Notes
    [18] - Pairwise contrast from MMRM model

    Other pre-specified: Change in CGI-S Scores from Baseline to Day 14

    		 Close Top of page
    End point title
    		 Change in CGI-S Scores from Baseline to Day 14
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: score
        arithmetic mean (standard deviation)
    0.2 ± 0.54
    1 ± 1.3
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline CGI-S score as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.075 [19]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 0.1
    Notes
    [19] - Pairwise contrast from MMRM model

    Other pre-specified: Change in T25FW walking speed from Baseline to Day 8

    		 Close Top of page
    End point title
    		 Change in T25FW walking speed from Baseline to Day 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: feet/minute
        arithmetic mean (standard deviation)
    7.96 ± 53.59
    -38.33 ± 72.55
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline T25FW Walking Speed as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0302 [20]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    47.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.8
         upper limit
    		 89.92
    Notes
    [20] - Pairwise contrast at Day 8 from MMRM model.

    Other pre-specified: Change in CGI-I Scores from Baseline to Day 14

    		 Close Top of page
    End point title
    		 Change in CGI-I Scores from Baseline to Day 14
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From day 1 to day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: score
        arithmetic mean (standard deviation)
    1.1 ± 1.53
    2.2 ± 2.02
    Statistical analysis title
    		 Difference in LS means (amifampridine-placebo)
    Statistical analysis description
    LS was estimated via a MMRM with the scores at Day 8 and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline CGI-I score as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
    Comparison groups
    Continuation of Treatment v Discontinuation of Treatment
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0252 [21]
    Method
    		 mixed-effects model repeated measures
    Parameter type
    		 Difference in LS means
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 -0.1
    Notes
    [21] - Pairwise contrast at Day 14 from MMRM model.

    Other pre-specified: CGI-I Scale ratings of 1,2,3, and 4 at Day 8

    		 Close Top of page
    End point title
    		 CGI-I Scale ratings of 1,2,3, and 4 at Day 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: Subject
    16
    10
    No statistical analyses for this end point

    Other pre-specified: CGI-I Scale ratings of 1,2,3, and 4 at Day 14

    		 Close Top of page
    End point title
    		 CGI-I Scale ratings of 1,2,3, and 4 at Day 14
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: Subject
    13
    14
    No statistical analyses for this end point

    Other pre-specified: SGI Scale Ratings of 4,5,6, or 7 at Day 8

    		 Close Top of page
    End point title
    		 SGI Scale Ratings of 4,5,6, or 7 at Day 8
    End point description
    The number reporting these high scores indicates patient happiness with treatment.
    End point type
    Other pre-specified
    End point timeframe
    Day 8
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    22
    Units: Subject
    15
    10
    No statistical analyses for this end point

    Other pre-specified: SGI Scale Ratings of 4,5,6, or 7 at Day 14

    		 Close Top of page
    End point title
    		 SGI Scale Ratings of 4,5,6, or 7 at Day 14
    End point description
    The number reporting these high scores indicates patient happiness with treatment.
    End point type
    Other pre-specified
    End point timeframe
    Day 14
    End point values
    		 Continuation of Treatment Discontinuation of Treatment
    Number of subjects analysed
    16
    21
    Units: Subject
    12
    9
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From the pre-assignment period to the end of the "discontinuation-treatment phase" - from 12/09/2011 to 09/07/2014. 2-year Open-label extension phase lasted from 26/10/2011 to 08/07//2016
    Adverse event reporting additional description
    Only treatment-emergent AEs (TEAEs) were included in the safety analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Pre-assignment period
    Reporting group description
    		 All enrolled patients entered in the open-label pre-assignment phase who received at least 1 dose of study drug, and had any posttreatment safety information collected, were included in the safety analyses.

    Reporting group title
    Discontinuation phase
    Reporting group description
    		 All patients randomized to continue amifampridine at the dosing established in the pre-assignment phase for 7 days or to downtitrate it to 0 mg in 7 days.

    Reporting group title
    Treatment phase
    Reporting group description
    		 Patients who continued amifampridine for 7 days and patients who had downtitrated amifampridine to 0 mg and received placebo for 7 days.

    Reporting group title
    Extension phase
    Reporting group description
    		 Patients who had completed the pre-assignment period, discontinuation phase, and treatment phase; patients who had received rescue treatment with amifampridine phosphate during discontinuation and treatment phase; and patients participating in the pre-assignment period who had not had the opportunity to establish 7 days of stable amifampridine phosphate dosing.

    Serious adverse events
    		 Pre-assignment period Discontinuation phase Treatment phase Extension phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    10 / 40 (25.00%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Liver enzymes elevation
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
    Additional description: Microcellular pulmonic carcinoma
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Sick sinus syndrome
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered mental status
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Macular degeneration
    Additional description: Worsening
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
    Additional description: Left eye
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract operation
    Additional description: Right and left eye
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
    Additional description: Acute
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture
    Additional description: Fractured hip due to fall
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weakness
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LEMS
    Additional description: Worsening of LEMS
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Viral infection
    Additional description: Acute
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pre-assignment period Discontinuation phase Treatment phase Extension phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 53 (66.04%)
    9 / 38 (23.68%)
    9 / 38 (23.68%)
    25 / 40 (62.50%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Edema peripheral
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    0
    3
    Pain
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    2
    Pyrexia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Chest pain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 38 (2.63%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 38 (2.63%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 38 (2.63%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chronic sinusitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 38 (2.63%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dyspnea
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Creatinine Phosphokinase increased
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    5 / 53 (9.43%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Fall
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    0
    0
    7
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    23 / 53 (43.40%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    56
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    18 / 53 (33.96%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    36
    0
    0
    0
    Headache
         subjects affected / exposed
    5 / 53 (9.43%)
    1 / 38 (2.63%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    5
    2
    0
    0
    Dizziness
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 38 (2.63%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Depression
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    5 / 40 (12.50%)
         occurrences all number
    0
    0
    0
    9
    Ear and labyrinth disorders
    Otitis externa
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    2
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    30 / 53 (56.60%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    62
    0
    0
    0
    Paraesthesia oral
         subjects affected / exposed
    21 / 53 (39.62%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    23
    0
    0
    0
    diarrhoea
         subjects affected / exposed
    5 / 53 (9.43%)
    1 / 38 (2.63%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    6
    1
    0
    0
    Nausea
         subjects affected / exposed
    5 / 53 (9.43%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Constipation
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 38 (5.26%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 38 (2.63%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Periodontitis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pulpitis dental
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    2
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    0
    0
    4
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    8 / 53 (15.09%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    13
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 38 (2.63%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 38 (2.63%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    2 / 38 (5.26%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Sensation of heaviness
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    2 / 38 (5.26%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Infections and infestations
    Infection
         subjects affected / exposed
    11 / 53 (20.75%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    14
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 38 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 38 (2.63%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 38 (0.00%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    2

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Sun May 19 03:06:41 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA