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    Clinical Trial Results:
    SPACE trial SMA and Pyridostigmine in Adults and Children; Efficacy trial Phase II, mono-center, doubleblind, placebo-controlled, crossover trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2, 3 and 4

    Summary
    EudraCT number
    		 2011-004369-34
    Trial protocol
    		 NL  
    Global end of trial date
    17 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Nov 2021
    First version publication date
    20 Nov 2021
    Other versions
    Summary report(s)
    		 Summary of results - SPACE trial

    Trial information

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    Trial identification
    Sponsor protocol code
    UMC-NMZ-SMA2011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02941328
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UMC Utrecht
    Sponsor organisation address
    Heidelberglaan, 100, Utrecht, Netherlands, 3584CX
    Public contact
    METC, UMC Utrecht, 0031 887555555, r.i.wadman@umcutrecht.nl
    Scientific contact
    METC, UMC Utrecht, 31 887555555, r.i.wadman@umcutrecht.nl
    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
    17 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this placebo-controlled cross-over trial in adult patients with SMA type 2, 3 and 4 is to investigate the effect and efficacy of pyridostigmine on muscle strength and fatiquabillity in patients with SMA.
    Protection of trial subjects
    We conducted the study according to the principles of the Declaration of Helsinki (WMA General Assembly 2013, Fortaleza, Brazil) and in accordance with the Medical Research Involving Human Subjects Act.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 35
    Worldwide total number of subjects
    35
    EEA total number of subjects
    35
    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)
    4
    Adults (18-64 years)
    31
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 We conducted an investigator-initiated, phase II, monocentre, placebo-controlled, double-blind cross-over trial at the SMA Centre at the University Medical Centre Utrecht, a tertiary referral centre for patients with SMA in the Netherlands. We enrolled the first patient in this study on November 24, 2015. Study was ended in January 2018.

    Pre-assignment
    Screening details
    		 We published the trial design and procedures previously, including detailed in- and exclusion criteria (Stam M et al. Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2-4 (SPACE trial). BMJ Open. 2018;8(7):e019932.)

    Period 1
    Period 1 title
    Pyridostigmine-placebo
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    An independent pharmacist, who was not part of the study team, randomised eligible patients in a permuted four-block design. Both patients and investigators were blinded for treatment allocation.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 pyridostigmine
    Arm description
    		 Crossover trial Pyridostigmine-Placebo arm Patients administered the study medication four times daily because of the short half-life of pyridostigmine, leading to an effect duration of approximately 4-6 hours. In order to minimize side-effects, we increased the dosage from 2 mg/kg/day to 4 mg/kg/day and finally to the targeted 6 mg/kg/day in the course of the first week of each treatment period.
    Arm type
    		 Cross-over

    Investigational medicinal product name
    pyridostigmine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The study medication was administered four times daily because of the short half-life of pyridostigmine, leading to an effect duration of approximately 4-6 hours. In order to minimize side-effects, dosage was increased from 2 mg/kg/day to 4 mg/kg/day and finally to the targeted 6 mg/kg/day in the course of the first week of each treatment period. If side-effects after a dosage increase were not acceptable for the patient, the treatment period was continued with the highest tolerated dose.

    Arm title
    		 placebo
    Arm description
    		 Crossover trial Pyridostigmine-Placebo arm Same dosing schedule as active comparator
    Arm type
    		 Cross-over

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		pyridostigmine placebo
    Started
    17
    17
    Completed
    17
    17
    Period 2
    Period 2 title
    Placebo-Pyridostigmine
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    An independent pharmacist, who was not part of the study team, randomised eligible patients in a permuted four-block design. Both patients and investigators were blinded for treatment allocation.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 placebo
    Arm description
    		 Crossover trial Placebo-pyridostigmine arm Same schedule as comparator
    Arm type
    		 Cross-over

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The study medication was administered four times daily because of the short half-life of pyridostigmine, leading to an effect duration of approximately 4-6 hours. In order to minimize side-effects, dosage was increased from 2 mg/kg/day to 4 mg/kg/day and finally to the targeted 6 mg/kg/day in the course of the first week of each treatment period. If side-effects after a dosage increase were not acceptable for the patient, the treatment period was continued with the highest tolerated dose.

    Investigational medicinal product name
    pyridostigmine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The study medication was administered four times daily because of the short half-life of pyridostigmine, leading to an effect duration of approximately 4-6 hours. In order to minimize side-effects, dosage was increased from 2 mg/kg/day to 4 mg/kg/day and finally to the targeted 6 mg/kg/day in the course of the first week of each treatment period. If side-effects after a dosage increase were not acceptable for the patient, the treatment period was continued with the highest tolerated dose.

    Arm title
    		 pyridostigmine
    Arm description
    		 Crossover trial Placebo-pyridostigmine arm Patients administered the study medication four times daily because of the short half-life of pyridostigmine, leading to an effect duration of approximately 4-6 hours. In order to minimize side-effects, we increased the dosage from 2 mg/kg/day to 4 mg/kg/day and finally to the targeted 6 mg/kg/day in the course of the first week of each treatment period.
    Arm type
    		 Cross-over

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		placebo pyridostigmine
    Started
    18
    18
    Completed
    18
    18

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Pyridostigmine-placebo
    Reporting group description
    		 -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: This is a crossover trial with two different treatment periods, either pyridostigmine --> placebo (n=17) or placebo--> pyridostigmine (n=18)
    Reporting group values
    		 Pyridostigmine-placebo Total
    Number of subjects
    		 17 17
    Age categorical
    Mean 34 (SD 12; range 13-53)
    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)
    		 34 ± 12 -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 8 8
    Subject analysis sets

    Subject analysis set title
    Placebo-Pyridostigmine
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo to crossover to pyridostigmine

    Subject analysis set title
    Pyridostigmine-Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Pyridostigmine to crossover to placebo

    Subject analysis sets values
    		 Placebo-Pyridostigmine Pyridostigmine-Placebo
    Number of subjects
    18
    17
    Age categorical
    Mean 34 (SD 12; range 13-53)
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38 ± 14
    34 ± 12
    Gender categorical
    Units: Subjects
        Female
    13
    9
        Male
    5
    8

    End points

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    End points reporting groups
    Reporting group title
    pyridostigmine
    Reporting group description
    		 Crossover trial Pyridostigmine-Placebo arm Patients administered the study medication four times daily because of the short half-life of pyridostigmine, leading to an effect duration of approximately 4-6 hours. In order to minimize side-effects, we increased the dosage from 2 mg/kg/day to 4 mg/kg/day and finally to the targeted 6 mg/kg/day in the course of the first week of each treatment period.

    Reporting group title
    placebo
    Reporting group description
    		 Crossover trial Pyridostigmine-Placebo arm Same dosing schedule as active comparator
    Reporting group title
    placebo
    Reporting group description
    		 Crossover trial Placebo-pyridostigmine arm Same schedule as comparator

    Reporting group title
    pyridostigmine
    Reporting group description
    		 Crossover trial Placebo-pyridostigmine arm Patients administered the study medication four times daily because of the short half-life of pyridostigmine, leading to an effect duration of approximately 4-6 hours. In order to minimize side-effects, we increased the dosage from 2 mg/kg/day to 4 mg/kg/day and finally to the targeted 6 mg/kg/day in the course of the first week of each treatment period.

    Subject analysis set title
    Placebo-Pyridostigmine
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo to crossover to pyridostigmine

    Subject analysis set title
    Pyridostigmine-Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Pyridostigmine to crossover to placebo

    Primary: repeated nine-hole peg test (R9HPT)

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    End point title
    		 repeated nine-hole peg test (R9HPT) [1]
    End point description
    A trend was observed in the repeated nine-hole PEG test favoring pyridostigmine, with a slowing in the rate of increase in time needed over trials of -0.68s (95% CI -1.47 to 0.12, p-value = 0.09) or 44.7%.
    End point type
    Primary
    End point timeframe
    Change in time needed to complete one round during the R9HPT
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: crossover statistics is not possible to put in data
    End point values
    		 pyridostigmine placebo placebo pyridostigmine
    Number of subjects analysed
    17
    17
    18
    18
    Units: time needed to complete one round
        number (not applicable)
    17
    17
    18
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 weeks
    Adverse event reporting additional description
    Most AEs were mild, self-limiting and acceptable for patients. The most common AEs were gastro-intestinal (GI) complaints. Other related side-effects included increased saliva production and blurry sight. Participants reported muscle cramps and pain after study visits. There were four serious adverse events (SAEs), all unrelated to studymedication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Systematic
    Dictionary version
    1
    Reporting groups
    Reporting group title
    General disorders and administration site conditions
    Reporting group description
    		 -

    Serious adverse events
    		 General disorders and administration site conditions
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 General disorders and administration site conditions
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 9 (33.33%)
    Injury, poisoning and procedural complications
    administration site conditions
         subjects affected / exposed [1]
    3 / 3 (100.00%)
         occurrences all number
    9
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The system is not accepting the actual data

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30061431
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