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    Clinical Trial Results:
    A Randomized, Placebo-Controlled, Crossover Study to Evaluate the Safety and Efficacy of Amifampridine Phosphate in Ambulatory Patients with Spinal Muscular Atrophy (SMA) Type 3

    Summary
    EudraCT number
    		 2017-004600-22
    Trial protocol
    		 IT  
    Global end of trial date
    17 Sep 2020

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

    Trial information

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    Trial identification
    Sponsor protocol code
    SMA-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 106263
    Sponsors
    Sponsor organisation name
    Catalyst Pharmaceuticals Inc.
    Sponsor organisation address
    355 Alhambra Circle, Suite 1250, Coral Gables, United States, 33134
    Public contact
    Gary Ingenito, Catalyst Pharmaceuticals, Inc, +1 3054203200, gingenito@catalystpharma.com
    Scientific contact
    Gary Ingenito, Catalyst Pharmaceuticals, Inc, +1 3054203200, 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 Mar 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Sep 2020
    Was the trial ended prematurely?
    No
    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 SMA Type 3. To assess the clinical efficacy of amifampridine phosphate compared with placebo in ambulatory patients with SMA Type 3 using the Hammersmith Functional Motor Scale Expanded (HFMSE).
    Protection of trial subjects
    Patients with concomitant use of medicinal products with a known potential to cause QTc prolongation and patients with long QT syndromes were no longer excluded. Exclusions for patients with uncontrolled asthma, concomitant use with sultopride, and concomitant use with medicinal products with a narrow therapeutic window were added. Additional contraindicated concomitant medications were also added including medicinal products with a narrow therapeutic window and sultopride. Caution when taking amifampridine with the following concomitant medications was added: medicinal products known to lower the epileptic threshold, medicinal products with atropine effects, medicinal products with cholinergic effects, non-depolarizing muscle relaxant acting medicinal products, and depolarizing muscle relaxant acting medicinal products.
    Background therapy
    		 None
    Evidence for comparator
    		 Not reported
    Actual start date of recruitment
    15 Mar 2018
    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
    Italy: 6
    Country: Number of subjects enrolled
    Serbia: 7
    Worldwide total number of subjects
    13
    EEA total number of subjects
    6
    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)
    13
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 14 January 2019 to 17 September 2020, 13 SMA Type 3 ambulatory patients were recruited in Italy and Serbia.

    Pre-assignment
    Screening details
    		 Patients were screened for eligibility and those who had procedures/assessments completed during Run-in, until an optimized stable dose and frequency of amifampridine phosphate was established. At the end of seven days on a stable daily regimen, the patient was required to show ≥ a 3-point improvement in HFMSE score to be randomized.

    Pre-assignment period milestones
    Number of subjects started
    		 13
    Number of subjects completed
    		 12

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening failure: 1
    Period 1
    Period 1 title
    Period 1 Week 1-2
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Amifampridine phosphate
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    amifampridine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg

    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
    10 mg, as the experimental product

    Number of subjects in period 1 [1]
    		Amifampridine phosphate Placebo
    Started
    6
    6
    Completed
    6
    6
    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: The worldwide number consists of all patients enrolled; one of them has not been randomized and, therefore, is not included in the study groups.
    Period 2
    Period 2 title
    Period 2 Week 3-4
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Amifampridine phosphate
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    amifampridine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg, as the experimental product

    Number of subjects in period 2
    		Amifampridine phosphate Placebo
    Started
    6
    6
    Completed
    6
    6

    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
    		 6 6 12
    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)
    		 37.2 ± 8.5 30.2 ± 13.5 -
    Gender categorical
    Units: Subjects
        Female
    		 4 1 5
        Male
    		 2 5 7
    Ethnicity
    Units: Subjects
        Caucasian
    		 6 5 11
        Black
    		 0 0 0
        Asian
    		 0 1 1
        Other
    		 0 0 0
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 169.3 ± 9.0 174.8 ± 6.1 -
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 64.7 ± 9.3 67.8 ± 11.8 -
    Body Mass Index
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 22.5 ± 1.4 22.3 ± 4.3 -

    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 HFMSE score

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    End point title
    		 Change from baseline HFMSE score
    End point description
    End point type
    Primary
    End point timeframe
    The change in the HFMSE score was measured at baseline and after two weeks of treatment, in each period.
    End point values
    		 Amifampridine phosphate Placebo Amifampridine phosphate Placebo
    Number of subjects analysed
    6
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    0.333 ± 0.816
    -0.833 ± 1.722
    0.667 ± 1.366
    -0.333 ± 1.506
    Statistical analysis title
    		 Change from baseline Overall
    Statistical analysis description
    The LS Means, p-value, and 95% CI were obtained using a 2-period 2- treatment crossover model through Day 28.
    Comparison groups
    Amifampridine phosphate v Placebo v Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0083 [1]
    Method
    		 Crossover model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.792
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 1.37
    Notes
    [1] - P-value (Period) and P-value (Carry-over) are the p-values for the corresponding effects in the model. P-value period 0.9449 P-value Carry-over 0.1931

    Secondary: CFB in 6-minute Walk Test

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    End point title
    		 CFB in 6-minute Walk Test
    End point description
    End point type
    Secondary
    End point timeframe
    The change in the 6-minute Walk Test was measured at baseline and after two weeks of treatment, in each period.
    End point values
    		 Amifampridine phosphate Placebo Amifampridine phosphate Placebo
    Number of subjects analysed
    6
    6
    6
    6
    Units: meter
        arithmetic mean (standard deviation)
    1.500 ± 55.945
    0.833 ± 9.283
    15.000 ± 19.055
    12.333 ± 39.603
    Statistical analysis title
    		 Change from baseline Overall
    Statistical analysis description
    The LS Means, p-value, and 95% CI were obtained using a 2-period 2-treatment crossover model through Day 28.
    Comparison groups
    Amifampridine phosphate v Placebo v Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0 [2]
    Method
    		 Crossover model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.25
         upper limit
    		 10.25
    Notes
    [2] - P-value (Period) and P-value (Carry-over) are the p-values for the corresponding effects in the model. P-value Period 0.9260 P-value Carry-over 0.0682

    Secondary: CFB in Rising from Floor

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    End point title
    		 CFB in Rising from Floor
    End point description
    End point type
    Secondary
    End point timeframe
    The change in the Rising from floor test was measured at baseline and after two weeks of treatment, in each period.
    End point values
    		 Amifampridine phosphate Placebo Amifampridine phosphate Placebo
    Number of subjects analysed
    2
    3
    2
    2
    Units: second
        arithmetic mean (standard deviation)
    7.420 ± 5.063
    11.000 ± 4.000
    10.500 ± 3.536
    6.500 ± 3.536
    Statistical analysis title
    		 Change from baseline Overall
    Statistical analysis description
    The LS Means, p-value, and 95% CI were obtained using a 2-period 2-treatment crossover model through Day 28.
    Comparison groups
    Amifampridine phosphate v Placebo v Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.415 [3]
    Method
    		 Crossover model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.48
         upper limit
    		 2.86
    Notes
    [3] - P-value (Period) and P-value (Carry-over) are the p-values for the corresponding effects in the model.

    Secondary: CFB in Rising from a Chair

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    End point title
    		 CFB in Rising from a Chair
    End point description
    End point type
    Secondary
    End point timeframe
    The change in the rising from a chair test was measured at baseline and after two weeks of treatment, in each period.
    End point values
    		 Amifampridine phosphate Placebo Amifampridine phosphate Placebo
    Number of subjects analysed
    5
    3
    3
    5
    Units: second
        arithmetic mean (standard deviation)
    -1.296 ± 2.224
    -0.040 ± 0.069
    -0.140 ± 0.242
    -0.738 ± 2.928
    Statistical analysis title
    		 Change from baseline Overall
    Comparison groups
    Placebo v Amifampridine phosphate v Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.4548 [5]
    Method
    		 Crossover model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.367
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.37
         upper limit
    		 0.63
    Notes
    [4] - The LS Means, p-value, and 95% CI were obtained using a 2-period 2-treatment crossover model through Day 28.
    [5] - P-value (Period) and P-value (Carry-over) are the p-values for the corresponding effects in the model. P-value period: 0.4422 P-value carry-over: 0.9336

    Secondary: CFB in Climbing 4 Steps

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    End point title
    		 CFB in Climbing 4 Steps
    End point description
    End point type
    Secondary
    End point timeframe
    The change in the climbing 4 steps test was measured at baseline and after two weeks of treatment, in each period.
    End point values
    		 Amifampridine phosphate Placebo Amifampridine phosphate Placebo
    Number of subjects analysed
    6
    3
    3
    6
    Units: second
        arithmetic mean (standard deviation)
    -1.122 ± 0.743
    0.127 ± 0.155
    0.000 ± 0.000
    -3.403 ± 6.019
    Statistical analysis title
    		 Change from baseline Overall
    Comparison groups
    Amifampridine phosphate v Placebo v Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.4908 [7]
    Method
    		 Crossover model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.479
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.93
         upper limit
    		 1.89
    Notes
    [6] - The LS Means, p-value, and 95% CI were obtained using a 2-period 2-treatment crossover model through Day 28.
    [7] - P-value (Period) and P-value (Carry-over) are the p-values for the corresponding effects in the model.

    Secondary: CFB in Walking 10 Meters

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    End point title
    		 CFB in Walking 10 Meters
    End point description
    End point type
    Secondary
    End point timeframe
    The change in the Walking 10 meters test was measured at baseline and after two weeks of treatment, in each period.
    End point values
    		 Amifampridine phosphate Placebo Amifampridine phosphate Placebo
    Number of subjects analysed
    6
    6
    6
    6
    Units: second
        arithmetic mean (standard deviation)
    -0.667 ± 0.387
    -1.225 ± 1.874
    -5.382 ± 12.555
    -0.690 ± 0.531
    Statistical analysis title
    		 Change from baseline Overall
    Comparison groups
    Placebo v Amifampridine phosphate v Amifampridine phosphate v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.0867 [9]
    Method
    		 Crossover model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.803
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.88
         upper limit
    		 0.27
    Notes
    [8] - The LS Means, p-value, and 95% CI were obtained using a 2-period 2-treatment crossover model through Day 28.
    [9] - P-value (Period) and P-value (Carry-over) are the p-values for the corresponding effects in the model.

    Secondary: CFB in the INQOL Subscales Scores

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    End point title
    		 CFB in the INQOL Subscales Scores
    End point description
    The change from baseline is reported for each item.
    End point type
    Secondary
    End point timeframe
    The change in the INQOL score was measured at baseline and after two weeks of treatment, in each period.
    End point values
    		 Amifampridine phosphate Placebo Amifampridine phosphate Placebo
    Number of subjects analysed
    6
    6
    6
    6
    Units: score
    arithmetic mean (standard deviation)
        Weakness score
    2.632 ± 18.459
    -1.754 ± 13.175
    -7.018 ± 10.872
    0.877 ± 20.632
        Pain score
    -2.632 ± 28.586
    -0.877 ± 5.175
    0.000 ± 0.000
    2.632 ± 30.463
        Fatigue score
    0.000 ± 24.686
    2.632 ± 18.156
    -9.649 ± 25.442
    5.263 ± 6.657
        Muscle locking score
    -7.018 ± 17.189
    0.000 ± 9.986
    -4.386 ± 16.448
    -5.263 ± 18.533
        Droopy eyelids score
    0.000 ± 0.000
    0.000 ± 0.000
    0.000 ± 0.000
    0.000 ± 0.000
        Double vision score
    -5.263 ± 12.892
    0.000 ± 0.000
    0.000 ± 0.000
    -5.263 ± 12.892
        Swallowing difficulties score
    0.000 ± 0.000
    0.000 ± 0.000
    0.000 ± 0.000
    0.000 ± 0.000
        Activities score
    -5.556 ± 11.142
    -12.654 ± 22.150
    -19.907 ± 18.525
    -7.562 ± 11.164
        Independence score
    -2.778 ± 10.541
    -1.852 ± 17.003
    -9.259 ± 18.481
    -1.852 ± 17.003
        Social relationship score
    3.395 ± 9.563
    -5.093 ± 9.049
    -3.549 ± 8.966
    2.623 ± 9.719
        Emotions score
    0.000 ± 15.516
    1.389 ± 11.752
    1.389 ± 7.607
    -5.556 ± 17.830
        Body image score
    0.000 ± 9.129
    -8.796 ± 12.097
    -8.333 ± 17.830
    -0.463 ± 20.126
        Perceived treatment effects score
    -8.333 ± 24.721
    -8.333 ± 21.082
    -12.500 ± 25.685
    -2.778 ± 20.861
        Expected treatment effects score
    -16.667 ± 23.570
    -6.944 ± 17.808
    -12.500 ± 20.242
    -6.944 ± 14.353
        Quality of life score
    7.593 ± 13.299
    -3.611 ± 5.630
    -3.704 ± 11.367
    8.796 ± 15.008
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the enrolment to the end of the study
    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
    		 -

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    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 / 12 (100.00%)
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gait disturbance
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Influenza like illness
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Paraesthesia oral
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Intranasal paraesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1

    More information

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    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.

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