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    Clinical Trial Results:
    A multi centre, double blind, randomised, placebo controlled crossover study to evaluate the efficacy and tolerability of picotamide in the prophylaxis of migraine in patients presenting with migraine with aura

    Summary
    EudraCT number
    		 2011-006207-36
    Trial protocol
    		 HU  
    Global end of trial date
    12 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Nov 2018
    First version publication date
    21 Nov 2018
    Other versions
    Summary report(s)
    		 Clinical study report summary

    Trial information

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    Trial identification
    Sponsor protocol code
    19122011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Proreo Pharma Innovation AG
    Sponsor organisation address
    Weierweg 7, Liestal, Switzerland, CH-4410
    Public contact
    Prof. Klaus Kutz, Proreo Pharma Innovation AG, 41 795432152, klaus.kutz@bluewin.ch
    Scientific contact
    Prof. Klaus Kutz, Proreo Pharma Innovation AG, 41 795432152, klaus.kutz@bluewin.ch
    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
    06 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy of picotamide compared to placebo in the reduction of the number of auras in patients with migraine with aura.
    Protection of trial subjects
    Patients were permitted to use their usual symptomatic or acute treatment as rescue medication throughout the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 A cross-over design with treatment periods of picotamide and placebo substantially improves the power to detect a difference between treatment regimens with a small number of patients compared to a parallel group design and thus a smaller number of patients are needed.
    Actual start date of recruitment
    11 Jul 2012
    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
    Denmark: 27
    Country: Number of subjects enrolled
    Hungary: 35
    Worldwide total number of subjects
    62
    EEA total number of subjects
    62
    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)
    62
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started on 11/July/2012 in Denmark, and on 06/Mar/2013 in Hungary. Last patient last visit took place on 12/Oct/2016.

    Pre-assignment
    Screening details
    		 Screening and randomisation could be performed at once. Patients with an established medical history of migraine with aura were considered for the study. During the screening a laboratory test was performed to exclude renal and hepatic dysfunction.

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Picotamide
    Arm description
    		 Picotamide 300 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    picotamide
    Investigational medicinal product code
    Other name
    Plactidil
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet of 300 mg picotamide two times daily for 12 weeks orally.

    Arm title
    		 Placebo
    Arm description
    		 Placebo 300 mg
    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
    300 mg twice daily

    Number of subjects in period 1 [1]
    		Picotamide Placebo
    Started
    32
    30
    Completed
    54
    53
    Not completed
    2
    8
         Consent withdrawn by subject
    1
    2
         Adverse event, non-fatal
    1
    4
         Lost to follow-up
    -
    1
         Protocol deviation
    -
    1
    Joined
    24
    31
         Transferred in from other group/arm
    24
    31
    Notes
    [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: Crossover design.
    Period 2
    Period 2 title
    Washout
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Washout
    Arm description
    		 Placebo
    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
    300 mg twice daily

    Number of subjects in period 2
    		Washout
    Started
    55
    Completed
    55
    Period 3
    Period 3 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo 300 mg twice daily
    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
    300 mg twice daily

    Arm title
    		 Picotamide
    Arm description
    		 Picotamide 300 mg twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    picotamide
    Investigational medicinal product code
    Other name
    Plactidil
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet of 300 mg picotamide two times daily for 12 weeks orally.

    Number of subjects in period 3
    		Placebo Picotamide
    Started
    31
    24
    Completed
    29
    23
    Not completed
    2
    1
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Period 1
    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: Crossover design.
    Reporting group values
    		 Period 1 Total
    Number of subjects
    		 62 62
    Age categorical
    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)
    		 62 62
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.9 ± 13.12 -
    Gender categorical
    Units: Subjects
        Female
    		 55 55
        Male
    		 7 7
    Migraine
    The estimated number of migraine attacks over the last three months before entering the study
    Units: events
        arithmetic mean (standard deviation)
    		 14.7 ± 15.1 -
    Headache
    the estimated number of migraine headache over the last three months before entering the study
    Units: events
        arithmetic mean (standard deviation)
    		 17.8 ± 16.2 -
    Aura
    the estimated number of auras over the last three months before entering the study
    Units: events
        arithmetic mean (standard deviation)
    		 15.7 ± 18.8 -

    End points

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    End points reporting groups
    Reporting group title
    Picotamide
    Reporting group description
    		 Picotamide 300 mg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 300 mg
    Reporting group title
    Washout
    Reporting group description
    		 Placebo
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 300 mg twice daily

    Reporting group title
    Picotamide
    Reporting group description
    		 Picotamide 300 mg twice daily

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This population consists of all patients who are randomized.

    Subject analysis set title
    ITT2
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The intention to treat population 2 (ITT2) consists of all patients in ITT, who received at least one dose of study medication during period 1 and period 2 and documented at least one day in the diary during period 1 and period 2.

    Subject analysis set title
    SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients were included into the safety population if they had received at least one drug administration (picotamide or placebo).

    Subject analysis set title
    PPP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients were included in the per-protocol population (PPP) if they • had met all inclusion criteria; • did not fulfill any exclusion criteria; • had met all inclusion criteria during the study; • did not fulfill any exclusion criteria during the study; • had completed the study in accordance with the protocol.

    Primary: Days with Aura

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    End point title
    		 Days with Aura
    End point description
    A possible effect of active treatment was evaluated by a comparison between the mean number of auras in sequence A (period 1-2) and sequence B (period 1-2).
    End point type
    Primary
    End point timeframe
    During each treatment period
    End point values
    		 Picotamide Placebo ITT2
    Number of subjects analysed
    56 [1]
    60 [2]
    47
    Units: days
        arithmetic mean (standard deviation)
    8.2 ± 9.29
    7.8 ± 8.98
    4.6 ± 5.29
    Notes
    [1] - Combined with treatment period 2.
    [2] - Combined with treatment period 2.
    Statistical analysis title
    		 Statistical analysis of Days with Aura
    Statistical analysis description
    The statistical analysis of days with aura in the ITT2 showed no treatment effect and no carry-over effect. However, there was a very strong period effect indicating that in the second treatment period the days with aura were signifantly lower.
    Comparison groups
    Picotamide v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Days with Migraine Headache

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    End point title
    		 Days with Migraine Headache
    End point description
    A migraine headache day is a calendar day at which a migraine headache started and/or ended. Mean number of migraine headache days in each treatment period.
    End point type
    Secondary
    End point timeframe
    Per treatment (12 weeks)
    End point values
    		 Picotamide Placebo
    Number of subjects analysed
    56 [3]
    60 [4]
    Units: days
        arithmetic mean (standard deviation)
    9.7 ± 8.79
    9.6 ± 10.08
    Notes
    [3] - Including patients in Treatment period 2.
    [4] - Including patients in Treatment period 2.
    No statistical analyses for this end point

    Secondary: Number of Migraine Headache

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    End point title
    		 Number of Migraine Headache
    End point description
    Mean number of migraine headache attacks in each treatment period.
    End point type
    Secondary
    End point timeframe
    Treatment period (12 weeks)
    End point values
    		 Picotamide Placebo
    Number of subjects analysed
    56 [5]
    60 [6]
    Units: episodes
        arithmetic mean (standard deviation)
    8.3 ± 7.16
    8.2 ± 8.88
    Notes
    [5] - Including patients in Treatment period 2.
    [6] - Including patients in Treatment period 2.
    No statistical analyses for this end point

    Secondary: Days with Headache

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    End point title
    		 Days with Headache
    End point description
    Mean number of any headache (migraine or not) days in each treatment period
    End point type
    Secondary
    End point timeframe
    Treatment period (12 weeks)
    End point values
    		 Picotamide Placebo
    Number of subjects analysed
    56 [7]
    60 [8]
    Units: days
        arithmetic mean (standard deviation)
    12.7 ± 11.28
    13.0 ± 12.61
    Notes
    [7] - Including patients in Treatment period 2.
    [8] - Including patients in Treatment period 2.
    No statistical analyses for this end point

    Secondary: Number of Auras followed by Headache

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    End point title
    		 Number of Auras followed by Headache
    End point description
    Mean number of auras followed by headache in each treatment period.
    End point type
    Secondary
    End point timeframe
    Treatment period (12 weeks)
    End point values
    		 Picotamide Placebo
    Number of subjects analysed
    56 [9]
    60 [10]
    Units: Episodes
        arithmetic mean (standard deviation)
    5.1 ± 5.84
    5.0 ± 6.70
    Notes
    [9] - Including patients in Treatment period 2.
    [10] - Including patients in Treatment period 2.
    No statistical analyses for this end point

    Secondary: Days with Aura and / or Migraine Headache

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    End point title
    		 Days with Aura and / or Migraine Headache
    End point description
    Mean number of auras and/or migraine headache during each treatment period.
    End point type
    Secondary
    End point timeframe
    Treatment period(12 weeks)
    End point values
    		 Picotamide Placebo
    Number of subjects analysed
    56 [11]
    60 [12]
    Units: days
        arithmetic mean (standard deviation)
    12.3 ± 10.97
    12.1 ± 11.39
    Notes
    [11] - Including patients in Treatment period 2.
    [12] - Including patients in Treatment period 2.
    No statistical analyses for this end point

    Secondary: Number of Migraine Headache Attacks

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    End point title
    		 Number of Migraine Headache Attacks
    End point description
    Mean number of migraine headache attacks in each treatment period.
    End point type
    Secondary
    End point timeframe
    Treatment period (12 weeks)
    End point values
    		 Picotamide Placebo
    Number of subjects analysed
    56 [13]
    60 [14]
    Units: episodes
        arithmetic mean (standard deviation)
    7.4 ± 6.99
    7.3 ± 8.34
    Notes
    [13] - Including patients in Treatment period 2.
    [14] - Including patients in Treatment period 2.
    No statistical analyses for this end point

    Secondary: Days with Consumption of Rescue Medication

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    End point title
    		 Days with Consumption of Rescue Medication
    End point description
    Mean monthly consumption of rescue medication during the last month and the whole of each treatment period from the baseline period to Month 3.
    End point type
    Secondary
    End point timeframe
    Treatment period (12 weeks)
    End point values
    		 Picotamide Placebo
    Number of subjects analysed
    56 [15]
    60 [16]
    Units: days
        arithmetic mean (standard deviation)
    6.9 ± 7.62
    6.2 ± 7.47
    Notes
    [15] - Including patients in Treatment period 2.
    [16] - Including patients in Treatment period 2.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the period of observation in the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Safety analysis
    Reporting group description
    		 Patients receiving at least one dose of IMP were included in the saftey analysis

    Reporting group title
    Picotamide
    Reporting group description
    		 Patients on picotamide treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Patients receiving placebo treatment

    Serious adverse events
    		 Safety analysis Picotamide Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 56 (1.79%)
    1 / 60 (1.67%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Gastrointestinal disorders
    Inguinal hernia repair
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 56 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystectomy
    Additional description: Laparoscopic cholecystectomy for cholelithiasis
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 56 (1.79%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety analysis Picotamide Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 62 (62.90%)
    22 / 56 (39.29%)
    17 / 60 (28.33%)
    Gastrointestinal disorders
    diarhhea
         subjects affected / exposed
    7 / 62 (11.29%)
    3 / 56 (5.36%)
    4 / 60 (6.67%)
         occurrences all number
    7
    3
    4
    gastrointestinal reflux disease
         subjects affected / exposed
    6 / 62 (9.68%)
    4 / 56 (7.14%)
    2 / 60 (3.33%)
         occurrences all number
    6
    4
    2
    Nausea
         subjects affected / exposed
    4 / 62 (6.45%)
    4 / 56 (7.14%)
    0 / 60 (0.00%)
         occurrences all number
    4
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    3 / 62 (4.84%)
    3 / 56 (5.36%)
    0 / 60 (0.00%)
         occurrences all number
    3
    3
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    5 / 62 (8.06%)
    3 / 56 (5.36%)
    2 / 60 (3.33%)
         occurrences all number
    5
    3
    2
    Pneumonia
         subjects affected / exposed
    3 / 62 (4.84%)
    2 / 56 (3.57%)
    1 / 60 (1.67%)
         occurrences all number
    3
    2
    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
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