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    Clinical Trial Results:
    An exploratory phase II, randomised, double-blind, placebo-controlled, parallel-group study investigating the efficacy and safety of Sepranolone in women with menstrual migraine

    Summary
    EudraCT number
    		 2019-001081-15
    Trial protocol
    		 SE   FI  
    Global end of trial date
    06 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Apr 2022
    First version publication date
    21 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APH204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Asarina Pharma ApS
    Sponsor organisation address
    Ole Maaloes Vej 3, Kobenhavn N, Denmark, 2200
    Public contact
    Peter Nordkild, Asarina Pharma ApS, peter.nordkild@asarinapharma.com
    Scientific contact
    Peter Nordkild, Asarina Pharma ApS, peter.nordkild@asarinapharma.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
    31 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of two different doses (10 mg and 16 mg) of sepranolone on number of menstrual migraine days compared with placebo in patients with menstrual migraine.
    Protection of trial subjects
    The clinical safety of the women was followed throughout their participation in the study with for example physical examinations (including also vital signs and inspection of injection sites), safety blood sampling and AE and concomitant medication reporting. Women received training in IMP self-administration by a qualified health care professional at the clinical site prior to drug dispensing. Due to possible local injection reactions seen in a previous study, women in this study were instructed to aim to inject the IMP at discrete sites using a rotating scheme periumbilically.
    Background therapy
    		 Patients were allowed to take rescue medication and be on stable doses of any allowed chronic or PRN concomitant migraine treatment or other pain medications, including treatments for migraine prophylaxis, at the discretion of the investigator. The rescue medication was the patient’s standard of care symptomatic migraine treatment on an as-needed basis. Hormonal treatments, CGRP-monoclonal antibody treatment and Botulinum toxin for migraine prophylaxis were not allowed.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Aug 2019
    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
    Sweden: 62
    Country: Number of subjects enrolled
    Finland: 24
    Worldwide total number of subjects
    86
    EEA total number of subjects
    86
    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)
    86
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First subject first visit (FSFV) was 27Aug2019. First subject randomised was 02Dec2019. Last subject last visit (LSLV) was 06Apr2021.

    Pre-assignment
    Screening details
    		 A telephone eligibility pre-screening was performed to filter out women that may have the potential to meet the menstrual migraine criteria. Women passing this pre-screening interview were invited to a first study site Visit 1 to provide their informed consent, after which they could be formally screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sepranolone 10 mg
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sepranolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Solution for injection , Subcutaneous use
    Dosage and administration details
    25 mg/mL. 0.4 mL in prefilled syringes.

    Arm title
    		 Sepranolone 16 mg
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sepranolone 16 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use, Solution for injection
    Dosage and administration details
    40 mg/mL. 0.4 mL in prefilled syringes.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Intralipid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Solution for injection , Subcutaneous use
    Dosage and administration details
    0.4 mL(out of which 16µL of Intralipid®) in prefilled syringes.

    Number of subjects in period 1
    		Sepranolone 10 mg Sepranolone 16 mg Placebo
    Started
    28
    27
    31
    Completed
    26
    26
    28
    Not completed
    2
    1
    3
         Subject choice due to worsening of migraine
    -
    1
    -
         Consent withdrawn by subject
    -
    -
    1
         did not want to take IMP for the last cycle
    -
    -
    1
         last study drug 29APR2020 and decided not to cont
    1
    -
    -
         lack of efficacy
    -
    -
    1
         AE myom increasing in size. Hysterectomy scheduled
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sepranolone 10 mg
    Reporting group description
    		 -

    Reporting group title
    Sepranolone 16 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Sepranolone 10 mg Sepranolone 16 mg Placebo Total
    Number of subjects
    		 28 27 31 86
    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
        median (full range (min-max))
    		 39 (24 to 45) 39 (28 to 47) 40 (23 to 44) -
    Gender categorical
    Units: Subjects
        Female
    		 28 27 31 86
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Sepranolone 10 mg
    Reporting group description
    		 -

    Reporting group title
    Sepranolone 16 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    modified intention-to-treat analysis set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified intention-to-treat (mITT) analysis set includes patients in the FAS who did not substantially deviate from the protocol, have a valid baseline assessment, and have completed at least one confirmed ovulatory treatment cycle with evaluable primary data. Only cycles during which the patient gets at least 4 doses of study drug are considered to have evaluable primary data. Only cycles where the subject has taken the study treatment during the period of Day -14 and Day 1 of the menstrual cycle will be considered as valid cycles. The mITT will be the primary analysis set for efficacy analyses.

    Primary: Change from baseline in the mean number of menstrual migraine days during Day -2 to Day +5

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    End point title
    		 Change from baseline in the mean number of menstrual migraine days during Day -2 to Day +5 [1]
    End point description
    T1
    End point type
    Primary
    End point timeframe
    during Day -2 to Day +5 of three menstrual cycles compared to baseline
    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: Statistical analyse specified for pooled Sepranolone (10 and 16 mg) versus placebo - see statistical analysis for T2 valid for all three period T1. T2 and T3.
    End point values
    		 Sepranolone 10 mg Sepranolone 16 mg Placebo
    Number of subjects analysed
    28
    27
    31
    Units: day
        median (full range (min-max))
    4.000 (1.00 to 7.00)
    2.000 (0.00 to 7.00)
    3.000 (0.00 to 7.00)
    No statistical analyses for this end point

    Primary: Change from baseline in the mean number of menstrual migraine days during Day -2 to Day +5

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    End point title
    		 Change from baseline in the mean number of menstrual migraine days during Day -2 to Day +5
    End point description
    T2
    End point type
    Primary
    End point timeframe
    during Day -2 to Day +5
    End point values
    		 Sepranolone 10 mg Sepranolone 16 mg Placebo
    Number of subjects analysed
    26
    25
    27
    Units: day
        median (full range (min-max))
    3.000 (0.00 to 7.00)
    3.000 (0.00 to 7.00)
    2.000 (0.00 to 7.00)
    Statistical analysis title
    		 primary endpoint mITT
    Statistical analysis description
    Missing data = 5.73090 %. Missing data did not exceed over 15%, no sensitivity analysis was performed. The p-values are one-sided. A day during which the woman was needed to take rescue treatment will count as a migraine day, whether or not she has reported headache of any intensity. Data based on modified intention-to-treat analysis set APH204_14_02_08_04_mITT.rtf Primary endpoint: Change from baseline in the mean number of menstrual migraine days during Day -2 to Day +5, SAS program
    Comparison groups
    Sepranolone 10 mg v Sepranolone 16 mg v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8705 [2]
    Method
    		 p-value one-sided
    Confidence interval
    Notes
    [2] - p-value Sepranolone (pooled 10 and 16 mg) versus placebo - change from baseline. Applicable for T1 (subjects included in analysis = 84), T2 (subjects included in analysis = 78) and T3 (subjects included in analysis = 76).

    Primary: Change from baseline in the mean number of menstrual migraine days during Day -2 to Day +5

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    End point title
    		 Change from baseline in the mean number of menstrual migraine days during Day -2 to Day +5 [3]
    End point description
    T3
    End point type
    Primary
    End point timeframe
    during Day -2 to Day +5
    Notes
    [3] - 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: Statistical analyse specified for pooled Sepranolone (10 and 16 mg) versus placebo - see statistical analysis for T2 valid for all three period T1. T2 and T3.
    End point values
    		 Sepranolone 10 mg Sepranolone 16 mg Placebo
    Number of subjects analysed
    25
    24
    27
    Units: day
        median (full range (min-max))
    3.000 (0.00 to 7.00)
    2.900 (0.00 to 7.00)
    2.000 (0.00 to 7.00)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs (including SAEs) were collected from the start of IMP administration until the end-of-study visit (Visit 9).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Sepranolone 10 mg
    Reporting group description
    		 -

    Reporting group title
    Sepranolone 16 mg
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Sepranolone 10 mg Sepranolone 16 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Sepranolone 10 mg Sepranolone 16 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 31 (80.65%)
    25 / 28 (89.29%)
    26 / 27 (96.30%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 28 (3.57%)
    2 / 27 (7.41%)
         occurrences all number
    1
    2
    3
    Migraine
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 28 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    1
    5
    0
    Injection site erythema
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 28 (7.14%)
    10 / 27 (37.04%)
         occurrences all number
    4
    2
    16
    Injection site haematoma
         subjects affected / exposed
    10 / 31 (32.26%)
    11 / 28 (39.29%)
    13 / 27 (48.15%)
         occurrences all number
    14
    12
    17
    Injection site pain
         subjects affected / exposed
    6 / 31 (19.35%)
    12 / 28 (42.86%)
    14 / 27 (51.85%)
         occurrences all number
    8
    15
    23
    Injection site pruritus
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 28 (3.57%)
    6 / 27 (22.22%)
         occurrences all number
    1
    1
    6
    Injection site swelling
         subjects affected / exposed
    4 / 31 (12.90%)
    6 / 28 (21.43%)
    15 / 27 (55.56%)
         occurrences all number
    7
    8
    27
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 28 (10.71%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    0
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 28 (7.14%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Infections and infestations
    Corona virus infection
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 28 (7.14%)
    2 / 27 (7.41%)
         occurrences all number
    3
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    5 / 31 (16.13%)
    5 / 28 (17.86%)
    11 / 27 (40.74%)
         occurrences all number
    5
    6
    12
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 28 (3.57%)
    3 / 27 (11.11%)
         occurrences all number
    4
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Nov 2019
    Addition of endpoints related to reduction in migraine days over a longer time period, changes to recall period of MPFID, adding a depression scale to monitor any mood change, addition of one new laboratory sample, addition or clarification to eligibility criteria, change in signs related to assessment of injection related adverse events.
    01 Apr 2020
    Changes to ensure safety of the subjects and site staff, enable secure IMP distribution to subjects as well as adaptation of monitoring in order to maintain data quality due to Covid-19 pandemic.
    14 Dec 2020
    IMP shelf-life extension due to expiry date.

    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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    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
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