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    Clinical Trial Results:
    A phase 3, multicenter, double-blind, placebo-controlled, randomized, outpatient two-period two-treatment crossover study to evaluate the efficacy and safety of amifampridine phosphate (3,4 diaminopyridine phosphate) in patients with Congenital Myasthenic Syndromes (CMS)

    Summary
    EudraCT number
    		 2018-000358-23
    Trial protocol
    		 IT  
    Global end of trial date
    24 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 May 2021
    First version publication date
    03 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CMS-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02562066
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 106263
    Sponsors
    Sponsor organisation name
    Catalyst Pharmaceuticals Inc.
    Sponsor organisation address
    355 Alhambra Circle, Coral Gables, United States, 33134
    Public contact
    Gary Ingenito, Catalyst Pharmaceuticals Inc., 001 (305) 420-3200, gingenito@catalystpharma.com
    Scientific contact
    Gary Ingenito, Catalyst Pharmaceuticals Inc., 001 (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
    13 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jan 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    - To characterize the overall safety and tolerability of amifampridine phosphate compared with placebo in patients with CMS; - To assess the clinical efficacy of amifampridine phosphate compared with placebo in patients with CMS, based on improvement in subject global impression (SGI) and motor function measure (MFM 20 or 32) scores
    Protection of trial subjects
    The investigator could prescribe additional medications during the study, as long as the prescribed medication was not prohibited by the protocol. In the event of an emergency, any needed medications could be prescribed without prior approval, but it was required that the Medical Monitor be notified of the use of any contraindicated medications immediately thereafter.
    Background therapy
    		 None
    Evidence for comparator
    		 The diagnosis and management of children with congenital myasthenic syndromes (CMS) are challenging and the response to treatment in CMS depends on the type of defect (pre-synaptic, synaptic, post-synaptic) and the kinetics of the channel affected (fast versus slow). Most patients are eligible and respond to pharmacologic intervention, including acetylcholinesterase inhibitors, 3,4-diaminopyridine (3,4-DAP), ephedrine, fluoxetine or quinidine, and albuterol. The particular therapy is dictated by the diagnosed CMS subtype, as drugs beneficial in one subtype can be detrimental in another subtype.
    Actual start date of recruitment
    30 Jan 2016
    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
    Canada: 2
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    16
    EEA total number of subjects
    0
    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)
    9
    Adolescents (12-17 years)
    3
    Adults (18-64 years)
    3
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 08 February 2016 to 24 January 2019, at 6 sites in the US and one site in Canada, patients were recruited and, after screening, were randomized on the last day of the open-label run-in period (Day 0) to either Treatment Sequence 1 or 2, in a 1:1 ratio.

    Pre-assignment
    Screening details
    		 Patients who completed screening proceeded to the run-in period. Patients who were previously naïve to amifampridine or amifampridine phosphate treatment began up-titration of medication, with frequent clinic evaluation for up to 4 weeks, until reaching a stable dose and frequency for 7 days. The patient must improve by 20% on MFM20 or 32.

    Pre-assignment period milestones
    Number of subjects started
    		 27 [1]
    Number of subjects completed
    		 16

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening failure: 11
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Some patients who had started the pre-assignment period were screen failures and were not enrolled in the trial.
    Period 1
    Period 1 title
    Period 1 Days 1-8
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    The placebo was provided as tablets indistinguishable from amifampridine phosphate.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Amifampridine phosphate
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amifampridine phosphate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The amifampridine phosphate total daily dose of 10 mg to 80 mg, given in 2 to 4 divided doses, with no single dose >15 mg in patients up to 16 years of age or >20 mg in patients >16 years of age was chosen based on completed animal and in vitro pharmacology, pharmacokinetic, and toxicology studies. The dose of amifampridine phosphate was individually determined by the investigator, within the bounds of a total daily dose of 10 mg to 80 mg, divided into doses taken 2 to 4 times per day. Doses of amifampridine phosphate were taken with food (e.g., breakfast, lunch, dinner, and snack before bed) as prescribed by the investigator, based on optimal neuromuscular benefit.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A placebo equivalent was provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo was administered consistent with the dosing regimen of amifampridine phosphate. The dose of amifampridine phosphate was individually determined by the investigator, within the bounds of a total daily dose of 10 mg to 80 mg, divided into doses taken 2 to 4 times per day. Doses of amifampridine phosphate were taken with food (e.g., breakfast, lunch, dinner, and snack before bed) as prescribed by the investigator, based on optimal neuromuscular benefit.

    Number of subjects in period 1
    		Amifampridine phosphate Placebo
    Started
    8
    8
    Completed
    8
    7
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1
    Period 2
    Period 2 title
    Period 2 Days 21-29
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Amifampridine phosphate
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amifampridine phosphate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The amifampridine phosphate total daily dose of 10 mg to 80 mg, given in 2 to 4 divided doses, with no single dose >15 mg in patients up to 16 years of age or >20 mg in patients >16 years of age was chosen based on completed animal and in vitro pharmacology, pharmacokinetic, and toxicology studies. The dose of amifampridine phosphate was individually determined by the investigator, within the bounds of a total daily dose of 10 mg to 80 mg, divided into doses taken 2 to 4 times per day. Doses of amifampridine phosphate were taken with food (e.g., breakfast, lunch, dinner, and snack before bed) as prescribed by the investigator, based on optimal neuromuscular benefit.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A placebo equivalent was provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo was administered consistent with the dosing regimen of amifampridine phosphate. The dose of amifampridine phosphate was individually determined by the investigator, within the bounds of a total daily dose of 10 mg to 80 mg, divided into doses taken 2 to 4 times per day. Doses of amifampridine phosphate were taken with food (e.g., breakfast, lunch, dinner, and snack before bed) as prescribed by the investigator, based on optimal neuromuscular benefit.

    Number of subjects in period 2
    		Amifampridine phosphate Placebo
    Started
    7
    8
    Completed
    7
    7
    Not completed
    0
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Amifampridine phosphate
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Amifampridine phosphate Placebo Total
    Number of subjects
    		 8 8 16
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.56 ± 15.70 27.35 ± 25.00 -
    Gender categorical
    Units: Subjects
        Female
    		 5 3 8
        Male
    		 3 5 8
    Mutations
    Units: Subjects
        Pre-synaptic mutation
    		 2 0 2
        Post-synaptic mutation
    		 6 8 14
    Race
    Units: Subjects
        White
    		 8 5 13
        Black or African America
    		 0 1 1
        Asian
    		 0 0 0
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Other
    		 0 2 2
        Decline/refuse to answer
    		 0 0 0
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 27.81 ± 11.15 54.00 ± 28.22 -
    SGI Score Day 0
    The SGI was a 7-point scale on which the patient rated their global impression of the effects of a study treatment (1=terrible to 7=delightful). The SGI was assessed by the patient or the patient’s parent/guardian/caregiver if the patient was unable to complete the SGI. The SGI had demonstrated concordance with the physician’s assessment of improvement.
    Units: Score
        arithmetic mean (standard deviation)
    		 5.11 ± 1.45 5.75 ± 1.04 -
    SGI Score Day 21
    The SGI was a 7-point scale on which the patient rated their global impression of the effects of a study treatment (1=terrible to 7=delightful). The SGI was assessed by the patient or the patient’s parent/guardian/caregiver if the patient was unable to complete the SGI. The SGI had demonstrated concordance with the physician’s assessment of improvement
    Units: Score
        arithmetic mean (standard deviation)
    		 5.88 ± 0.64 6.14 ± 1.21 -
    Slurp test Day 0
    The slurp test was optional. Subjects were instructed to drink four ounces of water through a standard flex straw as quickly as possible, making a loud slurping sound at the end. The duration of time from the start of drinking the water to the slurp sound was recorded. On Day 0 this test was performed by 2 subjects in the group of amifampridine and 3 subjects in the placebo group.
    Units: second
        arithmetic mean (standard deviation)
    		 12.95 ± 5.59 7.73 ± 2.88 -
    Slurp test Day 21
    The slurp test was optional. Subjects were instructed to drink four ounces of water through a standard flex straw as quickly as possible, making a loud slurping sound at the end. The duration of time from the start of drinking the water to the slurp sound was recorded. On Day 21 this test was performed by 6 subjects in the group of amifampridine and 4 subjects in the placebo group.
    Units: second
        arithmetic mean (standard deviation)
    		 13.64 ± 10.73 8.33 ± 1.83 -

    End points

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    End points reporting groups
    Reporting group title
    Amifampridine phosphate
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    Amifampridine phosphate
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Change from baseline SGI score

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    End point title
    		 Change from baseline SGI score
    End point description
    The SGI allowed patients to rate the impression of the effects of study medication on their physical wellbeing during the preceding week using a 7-point scale. In studies of patients with chronic pain, a reduction of approximately two points represented a clinically important difference.
    End point type
    Primary
    End point timeframe
    On Day 0 (baseline), day 8, day 21 (baseline) day 29.
    End point values
    		 Amifampridine phosphate Placebo Amifampridine phosphate Placebo
    Number of subjects analysed
    8
    8
    7
    8
    Units: Score
        arithmetic mean (standard deviation)
    -0.13 ± 1.81
    -1.75 ± 2.12
    -1.14 ± 1.68
    -0.75 ± 1.75
    Statistical analysis title
    		 Change from baseline at the end of period 1
    Comparison groups
    Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.085 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - A Mann-Whitney-Wilcoxon test demonstrated that the difference in mean CFB in SGI score at the end of Study Period 1 was not statistically significant (p=0.085) between the two sequences.
    Statistical analysis title
    		 Change from baseline crossover
    Comparison groups
    Amifampridine phosphate v Placebo v Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    P-value
    		 = 0.441
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - The difference between the Period 1 CFB and Period 2 CFB was analyzed in the Mann-Whitney-Wilcoxon test. The results demonstrate that while subjects may have experienced an improvement in raw SGI scores while taking amifampridine phosphate versus placebo the treatment effect was not statistically significant.

    Secondary: Change from baseline MFM-20 score

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    End point title
    		 Change from baseline MFM-20 score
    End point description
    D-1, Standing Position and Transfers; D-2, Axial and Proximal Limb Motor Function; and D-3, Distal Motor Function. The MFM was not the best scale for measuring symptoms and individual patient deficits. Particularly, in patients who had oculo-bulbar deficits (e.g., difficulty swallowing and respiratory deficits) the MFM is focused on motor movements and, as such, these patients may not have demonstrated improvement on the MFM scale. Nevertheless, the MFM was the only validated scale to include children as young as 2 years old and was therefore chosen for measurement of the secondary efficacy endpoint in this first placebo-controlled trial of genetically confirmed CMS patients.
    End point type
    Secondary
    End point timeframe
    Day 8 and Day 29
    End point values
    		 Amifampridine phosphate Placebo Amifampridine phosphate Placebo
    Number of subjects analysed
    4
    2
    2
    2
    Units: Score
    arithmetic mean (standard deviation)
        Total
    -1.50 ± 4.20
    -0.50 ± 6.36
    1.50 ± 2.12
    -0.75 ± 0.50
        D-1
    -1.00 ± 2.58
    1.00 ± 4.24
    1.00 ± 4.24
    -1.75 ± 0.96
        D-2
    0.25 ± 0.50
    -1.50 ± 2.12
    0.00 ± 0.00
    0.25 ± 0.50
        D-3
    -0.75 ± 1.50
    0.00 ± 0.00
    0.50 ± 0.71
    0.75 ± 0.96
    Statistical analysis title
    		 Change from baseline
    Comparison groups
    Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.8 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - A Mann-Whitney-Wilcoxon test demonstrated that the difference in mean CFB in MFM-20 score at the end of Study Period 1 was not statistically significant (p=0.800) between the two sequences.
    Statistical analysis title
    		 Change from baseline crossover
    Statistical analysis description
    A Mann-Whitney-Wilcoxon test compared the difference between the Period 1 CFB and Period 2 CFB. were not statistically significant for any of the three dimensions (D-1, Standing Position and Transfers; D-2, Axial and Proximal Limb Motor Function; and D-3, Distal Motor Function). Therefore, while subjects may have experienced an improvement in raw MFM-20 scores while taking amifampridine phosphate versus placebo, the treatment effect was not statistically significant.
    Comparison groups
    Amifampridine phosphate v Placebo v Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.933
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from baseline MFM-32 score

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    End point title
    		 Change from baseline MFM-32 score
    End point description
    D-1, Standing Position and Transfers; D-2, Axial and Proximal Limb Motor Function; and D-3, Distal Motor Function
    End point type
    Secondary
    End point timeframe
    Day 8 and day 29
    End point values
    		 Amifampridine phosphate Placebo Amifampridine phosphate Placebo
    Number of subjects analysed
    4
    6
    5
    4
    Units: Score
    arithmetic mean (standard deviation)
        Total
    3.00 ± 3.92
    -0.17 ± 4.58
    -0.60 ± 0.89
    0.75 ± 2.22
        D-1
    0.00 ± 1.83
    -0.67 ± 4.37
    0.20 ± 1.10
    0.50 ± 1.83
        D-2
    0.75 ± 0.96
    0.33 ± 0.82
    -0.20 ± 0.45
    0.00 ± 0.00
        D-3
    2.25 ± 1.26
    0.17 ± 0.41
    -0.60 ± 0.89
    0.25 ± 1.71
    Statistical analysis title
    		 Change from baseline
    Comparison groups
    Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.376 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - A Mann-Whitney-Wilcoxon test demonstrated that the difference in mean CFB in MFM-32 total score at the end of Study Period 1 was not statistically significant (p=0.376) between sequences.
    Statistical analysis title
    		 Change from baseline crossover
    Statistical analysis description
    A Mann-Whitney-Wilcoxon test compared the difference between the Period 1 CFB and Period 2 CFB. There were no statistically significant differences for dimensions 1 or 2 but were statistically significant for Period 1 of dimension 3 (p=0.010). These results demonstrate that subjects experienced a treatment benefit in regard to dimension 3 (distal motor function) while continuing amifampridine phosphate.
    Comparison groups
    Amifampridine phosphate v Placebo v Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.452
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Clinical Global Impression – Severity Day 8

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    End point title
    		 Clinical Global Impression – Severity Day 8
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Day 8
    End point values
    		 Amifampridine phosphate Placebo
    Number of subjects analysed
    8
    6
    Units: subject
        1 normal, not ill at all
    0
    1
        2 borderline mentally ill
    3
    3
        3 mildly ill
    3
    1
        4 moderately ill
    2
    1
    Attachments
    		 Untitled (Filename: Clinical Global Impression.pdf)
    No statistical analyses for this end point

    Secondary: Clinical Global Impression – Severity Day 29

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    End point title
    		 Clinical Global Impression – Severity Day 29
    End point description
    End point type
    Secondary
    End point timeframe
    From Day 21 to Day 29
    End point values
    		 Amifampridine phosphate Placebo
    Number of subjects analysed
    7
    8
    Units: subject
        1 normal, not at all ill
    1
    2
        2 borderline mentally ill
    1
    2
        3 mildly ill
    4
    3
        4 moderately ill
    1
    1
    Attachments
    		 Untitled (Filename: Clinical Global Impression.pdf)
    No statistical analyses for this end point

    Secondary: Clinical Global Impression - Improvement Day 8

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    End point title
    		 Clinical Global Impression - Improvement Day 8
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Day 8
    End point values
    		 Amifampridine phosphate Placebo
    Number of subjects analysed
    8
    7
    Units: subject
        1 very much improved
    0
    0
        2 much improved
    1
    1
        3 minimally improved
    2
    1
        4 no change
    4
    3
        5 minimally worse
    1
    1
        6 much worse
    0
    1
        7 very much worse
    0
    0
    Attachments
    		 Untitled (Filename: Clinical Global Impression Improvement.pdf)
    No statistical analyses for this end point

    Secondary: Clinical Global Impression - Improvement Day 29

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    End point title
    		 Clinical Global Impression - Improvement Day 29
    End point description
    End point type
    Secondary
    End point timeframe
    From Day 21 to Day 29
    End point values
    		 Amifampridine phosphate Placebo
    Number of subjects analysed
    7
    6
    Units: subject
        1 very much improved
    0
    1
        2 much improved
    2
    1
        3 minimally improved
    3
    4
        4 no change
    2
    0
        5 minimally worse
    0
    0
        6 much worse
    0
    0
        7 very much worse
    0
    0
    Attachments
    		 Untitled (Filename: Clinical Global Impression Improvement.pdf)
    No statistical analyses for this end point

    Secondary: Slurp Test Day 8

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    End point title
    		 Slurp Test Day 8
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Day 8
    End point values
    		 Amifampridine phosphate Placebo
    Number of subjects analysed
    2
    3
    Units: second
        arithmetic mean (standard deviation)
    2.25 ± 1.07
    -0.40 ± 2.91
    No statistical analyses for this end point

    Secondary: Slurp Test Day 29

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    End point title
    		 Slurp Test Day 29
    End point description
    End point type
    Secondary
    End point timeframe
    From Day 21 to Day 29
    End point values
    		 Amifampridine phosphate Placebo
    Number of subjects analysed
    4
    6
    Units: second
        arithmetic mean (standard deviation)
    -0.48 ± 1.72
    -2.66 ± 9.04
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent signature to through the last visit (Study Day 29) or at the early termination visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 The safety population consisted of all randomized patients who received at least one dose of study medication.

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 16 (6.25%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Rhinovirus infection
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 16 (75.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Ear haemorrhage
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Ear pain
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Immune system disorders
    Allergy to animal
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Food poisoning
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Paraesthesia oral
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Retching
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    Reproductive system and breast disorders
    Menstruation irregular
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Anger
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Irritability
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Migraine
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    Parainfluenzae virus
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Rhinovirus infection
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2016
    Administrative change to clarify the original intent of a reasonable time (at least three months) between the last SGI and MFM 20 or MFM 30 assessments and the first incidence of these assessments in the protocol. This was done to provide clarity on duration between testing to avoid testing bias.
    07 Mar 2016
    An administrative change to correct the use of the term “sequence” from “period” and “outpatient” versus “office visit”. This was done to provide clarity.
    25 Apr 2017
    This amendment increased the age range of eligible subjects, expanded the statistical analysis section of the protocol increased the number of patients in the study from 10 to 23 and updated previous instruction language regarding dosing on the days of clinic evaluations.
    26 Jun 2017
    Amendments 4 and 5 formally removed videotaping of patients from the protocol, clarified start and stop times of Periods 1 and 2, blinded medication dosing, and removed the Day 36 visit. The patient was either on a stable dose of amifampridine phosphate or had been titrated over a period of 4 weeks. Additionally, the patient was observed on open-label medication for 2 weeks during the restabilization period. Therefore, the Day 36 visit on open-label medication provided no new information to the efficacy or safety profile of amifampridine phosphate and the patient could then go directly into the expanded access program.

    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
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