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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled, phase II clinical trial with a cross-over design assessing efficacy of a single dose of bumetamide in reducing focal attack severity in hypokalaemic periodic paralysis assessed using the McManis protocol.

    Summary
    EudraCT number
    		 2013-004195-36
    Trial protocol
    		 GB  
    Global end of trial date
    11 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Oct 2019
    First version publication date
    28 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    120542
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02582476
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Gower Street , London, United Kingdom, WC1E6BT
    Public contact
    Samim Patel, University College London , 020 76799320, samim.patel@ucl.ac.uk
    Scientific contact
    Dr Doreen Fialho , MRC Centre for Neuromuscular Diseases , 020 34484752, doreen.fialho@nhs.net
    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
    15 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    11 May 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy of bumetanide in reducing the severity of a focal attack of muscle weakness affecting a small hand muscle one hour after attack onset in hypokalaemic periodic paralysis.
    Protection of trial subjects
    This study was conducted in accordance with the final protocol and in compliance with all local regulatory requirements and laws. Subject Information and Written Informed Consent was obtained before initiation of any protocol-specified activities. The investigator explained the nature, purpose, and possible risks associated with study participation to each subject. Each subject was informed that he/she could withdraw from the study at any time and for any reason. Each subject was given sufficient time to consider the implications of the study before deciding whether to participate. Subjects who chose to participate signed an informed consent document. All subject were assessed in a hospital setting under strict monitoring by nurses and doctors. Rescue treatment for acute attacks of weakness (typical for the condition) were readily available if needed.
    Background therapy
    		 Subjects were allowed to take oral potassium for the duration of the trial as per standard of care. Subjects withheld carbonic anhydrase inhibitor medications and anti-inflammatory medication for 72 hours prior to assessment visit. Subjects started their usual medication as soon as the visit ended. Subjects were allowed to continue any other periodic paralysis or other medical treatments for the duration of the trial.
    Evidence for comparator
    		 To provide class 1 evidence for the efficacy of treatment with Bumetanide in this patient population.
    Actual start date of recruitment
    15 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    10
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was enrolled in February 2015. In May 2017 the study was terminated early due to slow recruitment and expiring funding. Subjects were invited by post, during their appointment at the channelopathy clinic at the National Hospital for Neurology and Neurosurgery in London and at their neurophysiology appointment at the same hospital

    Pre-assignment
    Screening details
    		 11 subjects were screened. One subject failed screening due to absence of HypoPP mutation (inclusion criterion).

    Period 1
    Period 1 title
    Visit 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Over-encapsulated bumetanide and matching placebo

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bumetanide V1 - Placebo V2
    Arm description
    		 Subjects who received Bumetanide in visit 1 and placebo in visit 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bumetanide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    single dose 2mg

    Arm title
    		 Placebo V1 - Bumetanide V2
    Arm description
    		 Subjects who received placebo in visit 1 and Bumetanide in visit 2
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    single dose

    Number of subjects in period 1
    		Bumetanide V1 - Placebo V2 Placebo V1 - Bumetanide V2
    Started
    5
    5
    Completed
    5
    5
    Period 2
    Period 2 title
    Washout period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    No IMP given

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bumetanide V1 - Placebo 2
    Arm description
    		 Subjects who received Bumetanide in visit 1 and placebo in visit 2
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo V1 - Bumetanide V2
    Arm description
    		 Subjects who received placebo in visit 1
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Bumetanide V1 - Placebo 2 Placebo V1 - Bumetanide V2
    Started
    5
    5
    Completed
    4
    5
    Not completed
    1
    0
         Pregnancy
    1
    -
    Period 3
    Period 3 title
    Visit 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Over-encapsulated bumetanide and matching placebo

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bumetanide V1 - Placebo V2
    Arm description
    		 Subjects who received Bumetanide in visit 1 and placebo in visit 2
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    single dose

    Arm title
    		 Placebo V1 - Bumetanide V2
    Arm description
    		 Subjects who received placebo in visit 1 and Bumetanide in visit 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bumetanide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    single dose 2mg

    Number of subjects in period 3
    		Bumetanide V1 - Placebo V2 Placebo V1 - Bumetanide V2
    Started
    4
    5
    Completed
    4
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Visit 1
    Reporting group description
    		 -

    Reporting group values
    		 Visit 1 Total
    Number of subjects
    		 10 10
    Age categorical
    Age was collected at the screening visit.
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 10 10
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Median age for all participants was 45 years. Age range 18-55 years.
    Units: years
        median (full range (min-max))
    		 45 (18 to 55) -
    Gender categorical
    3 female and 7 male participants were recruited.
    Units: Subjects
        Female
    		 3 3
        Male
    		 7 7
    Subject analysis sets

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo

    Subject analysis set title
    Bumetanide
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Treatment with Bumetanide

    Subject analysis sets values
    		 Placebo Bumetanide
    Number of subjects
    9
    10
    Age categorical
    Age was collected at the screening visit.
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    9
    10
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Median age for all participants was 45 years. Age range 18-55 years.
    Units: years
        median (full range (min-max))
    47 (18 to 55)
    45 (18 to 55)
    Gender categorical
    3 female and 7 male participants were recruited.
    Units: Subjects
        Female
    2
    3
        Male
    7
    7

    End points

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    End points reporting groups
    Reporting group title
    Bumetanide V1 - Placebo V2
    Reporting group description
    		 Subjects who received Bumetanide in visit 1 and placebo in visit 2

    Reporting group title
    Placebo V1 - Bumetanide V2
    Reporting group description
    		 Subjects who received placebo in visit 1 and Bumetanide in visit 2
    Reporting group title
    Bumetanide V1 - Placebo 2
    Reporting group description
    		 Subjects who received Bumetanide in visit 1 and placebo in visit 2

    Reporting group title
    Placebo V1 - Bumetanide V2
    Reporting group description
    		 Subjects who received placebo in visit 1
    Reporting group title
    Bumetanide V1 - Placebo V2
    Reporting group description
    		 Subjects who received Bumetanide in visit 1 and placebo in visit 2

    Reporting group title
    Placebo V1 - Bumetanide V2
    Reporting group description
    		 Subjects who received placebo in visit 1 and Bumetanide in visit 2

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo

    Subject analysis set title
    Bumetanide
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Treatment with Bumetanide

    Primary: Focal attack severity one hour after treatment

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    End point title
    		 Focal attack severity one hour after treatment
    End point description
    This was measured as CMAP amplitude expressed as a percent of peak CMAP during or after the McManis exercise 1 hour following IMP intake.
    End point type
    Primary
    End point timeframe
    The effect of treatment on focal attack severity one hour after treatment intake.
    End point values
    		 Placebo Bumetanide
    Number of subjects analysed
    9
    10
    Units: Percentage
    arithmetic mean (confidence interval 95%)
        CMAP amplitude
    34.9 (28.1 to 41.7)
    40.6 (33.6 to 47.6)
    Attachments
    		 Normal QQ plot of residuals
    Scatter plot of the residuals
    Normality checks for the primary outcome
    Statistical analysis title
    		 Primary Outcome Analysis
    Statistical analysis description
    The primary outcome is the CMAP amplitude relative to the peak value one hour after the administration of treatment. Treatment is administered when the CMAP amplitude reaches 60% of its peak value.
    Comparison groups
    Placebo v Bumetanide
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.059
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.057
         upper limit
    		 0.175
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.049
    Notes
    [1] - Nine participants completed both trial visits and received both placebo and bumetanide. The mean effect difference calculation was therefore based on these 9 participants. (One participant only received Bumetanide.)

    Secondary: Focal attack duration

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    End point title
    		 Focal attack duration
    End point description
    This was measured as the time between treatment administration until CMAP returns to 65% of peak CMAP within 4 hours following the treatment intake
    End point type
    Secondary
    End point timeframe
    4 hours following IMP intake
    End point values
    		 Placebo Bumetanide
    Number of subjects analysed
    9 [2]
    10
    Units: Minutes
    arithmetic mean (standard deviation)
        Minutes
    999 ( 0 )
    133 ( 151.3 )
    Notes
    [2] - NONE OF THE PARTICIPANTS RETURNED TO 65% OF PEAK VALUE WITHIN 4 HOURS (NO DATA AVAILABLE)
    Statistical analysis title
    		 Attack duration
    Statistical analysis description
    Attack duration has been defined as time in minutes between treatment administration until CMAP returns to 65% peak value.
    Comparison groups
    Bumetanide v Placebo
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.05 [4]
    Method
    		 Descriptive
    Parameter type
    		 Mean
    Confidence interval
    Notes
    [3] - None of the participants in the placebo group reached this endpoint, therefore it was not possible to analyse this outcome. Two patients reached this outcome after administration of Bumetanide at 240 and 26 minutes after IMP intake respectively.
    [4] - Descriptive analysis only, p-value is not available

    Secondary: The initial effect of treatment on severity of a focal attack

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    End point title
    		 The initial effect of treatment on severity of a focal attack
    End point description
    The effect of treatment on severity of a focal attack within the first two hours (0-2). This will be measured as CMAP amplitude (in percent compared to peak) area under the curve (AUC) from treatment administration until two hours post-treatment.
    End point type
    Secondary
    End point timeframe
    The initial effect of treatment on severity of a focal attack within the first two hours post treatment
    End point values
    		 Placebo Bumetanide
    Number of subjects analysed
    9
    10
    Units: Percentage
    arithmetic mean (confidence interval 95%)
        Percentage
    37 (30.9 to 42.7)
    41 (36.2 to 45.7)
    Statistical analysis title
    		 The initial effect of treatment
    Statistical analysis description
    The initial effect was analysed using the same regression model as per the primary outcome.
    Comparison groups
    Bumetanide v Placebo
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.043
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.048
         upper limit
    		 0.133
    Variability estimate
    Standard error of the mean
    Notes
    [5] - Nine participants completed both trial visits and received both placebo and bumetanide. Total sample: n=9

    Secondary: The late effect of treatment on severity of a focal attack

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    End point title
    		 The late effect of treatment on severity of a focal attack
    End point description
    The effect of treatment on severity of a focal attack within the last 2 hours (3-4). This will be measured as CMAP amplitude (in percent) AUC from treatment administration during the third and the fourth hours post-treatment.
    End point type
    Secondary
    End point timeframe
    The late effect of treatment on severity of a focal attack two to four hours post treatment
    End point values
    		 Placebo Bumetanide
    Number of subjects analysed
    9
    10
    Units: Percentage
    arithmetic mean (confidence interval 95%)
        Percentage
    31 (25.5 to 37.2)
    40 (32.9 to 46.5)
    Statistical analysis title
    		 The late effect of treatment
    Statistical analysis description
    The late treatment effect was analysed using the same regression model as per the primary outcome.
    Comparison groups
    Placebo v Bumetanide
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.085
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.021
         upper limit
    		 0.191
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the treatment visit until follow up telephone call
    Adverse event reporting additional description
    Adverse events were reviewed during the study visits following treatment intake. They were also assessed by a phone call consultation seven days following each study visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Bumetanide Treatment Visit
    Reporting group description
    		 Adverse events observed/recorded by the researcher and reported by the participant during the period of direct observation before and after treatment intake (between 5-7hours)

    Reporting group title
    Placebo Treatment Visit
    Reporting group description
    		 Adverse events observed/recorded by the researcher and reported by the participant during the period of direct observation before and after treatment intake (between 5-7hours)

    Reporting group title
    Placebo Treatment Phone Call
    Reporting group description
    		 Adverse events reported by the participant during one week after treatment intake following discharge. Information obtained via phone call.

    Reporting group title
    Bumetanide Treatment Phone Call
    Reporting group description
    		 Adverse events reported by the participant during one week after treatment intake following discharge. Information obtained via phone call.

    Serious adverse events
    		 Bumetanide Treatment Visit Placebo Treatment Visit Placebo Treatment Phone Call Bumetanide Treatment Phone Call
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Bumetanide Treatment Visit Placebo Treatment Visit Placebo Treatment Phone Call Bumetanide Treatment Phone Call
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    8 / 9 (88.89%)
    6 / 9 (66.67%)
    6 / 10 (60.00%)
    Investigations
    Haematoma
    Additional description: Small haematoma after cannula removal. Not clinically significant.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Bradychardia
    Additional description: Asymptomatic bradycardia - not clinically significant.
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    tingling
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    0
    1
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Paresis
    Additional description: Atypical attack of muscle weakness not due to the underlying diagnosis of periodic paralysis.
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Skin rash: reaction to cannula plaster
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Micturition disorder
    Additional description: Increased micturition.
         subjects affected / exposed
    6 / 10 (60.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    6
    0
    0
    1
    Hypokalaemia
    Additional description: Electrolyte imbalance.
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle Stiffness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Burning sensation
    Additional description: Burning pain while performing hand exercise.
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Paralysis
    Additional description: Acute/transitory muscle weakness attack related to the diagnosis of periodic paralysis. This is an expected recurrent symptom in this disorder. Includes focal and generalised weakness attacks.
         subjects affected / exposed
    7 / 10 (70.00%)
    5 / 9 (55.56%)
    5 / 9 (55.56%)
    5 / 10 (50.00%)
         occurrences all number
    7
    5
    7
    5
    Muscle swelling
    Additional description: "Muscle soreness": reported by participants at phone call consultations, recorded using their own words.
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Cold symptoms
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2014
    Substantial amendment to reply to the comments raised by the ethics committee
    27 Jul 2015
    Substantial amendment 2 to advertise the trial through a patient association to accelerate recruitment
    04 Jan 2016
    Substantial amendment to clarify screening visit and include news flash advertisement by MDC
    16 Jun 2016
    Amendment made following a pregnancy
    11 Nov 2016
    Substantial amendment to allow patients to be re-consented remotely

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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